Multi-omics pan-cancer analyses identify MCM4 as a promising prognostic and diagnostic biomarker.

Minichromosome Maintenance Complex Component 4 (MCM4) is a vital component of the mini-chromosome maintenance complex family, crucial for initiating the replication of eukaryotic genomes. Recently, there has been a growing interest in investigating the significance of MCM4 in different types of cancer. Despite the existing research on this topic, a comprehensive analysis of MCM4 across various cancer types has been lacking. This study aims to bridge this knowledge gap by presenting a thorough pan-cancer analysis of MCM4, shedding light on its functional implications and potential clinical applications. The study utilized multi-omics samples from various databases. Bioinformatic tools were employed to explore the expression profiles, genetic alterations, phosphorylation states, immune cell infiltration patterns, immune subtypes, functional enrichment, disease prognosis, as well as the diagnostic potential of MCM4 and its responsiveness to drugs in a range of cancers. Our research demonstrates that MCM4 is closely associated with the oncogenesis, prognosis and diagnosis of various tumors and proposes that MCM4 may function as a potential biomarker in pan-cancer, providing a deeper understanding of its potential role in cancer development and treatment.

Evolution analysis of low-carbon cooperation of service providers based on Moran process in cloud manufacturing.

Low-carbon cooperation among cloud manufacturing service providers is one way to achieve carbon peak and neutrality. Such cooperation is related to the benefits to service providers adopting low-carbon strategies and stochastic factors such as government low-carbon policies, providers' environmental awareness, and demanders' low-carbon preferences. Focusing on the evolutionary process of service providers' low-carbon strategy selection under uncertain factors, a stochastic evolutionary game model is constructed based on the Moran process, and the equilibrium conditions for low-carbon cooperation among providers are analyzed under benefit-dominated and stochastic factor-dominated situations. Through numerical simulation, the effects of the cloud platform's cost-sharing coefficient for low-carbon investment, matching growth rate, carbon trading price, and group size on providers' low-carbon strategy evolution are analyzed. The research results show that increasing the cloud platform's low-carbon cost-sharing, carbon trading price, and group size can promote low-carbon cooperation among service providers. With greater low-carbon investment costs and greater stochastic factor interference, the providers' enthusiasm for low-carbon cooperation decreases. This study fills the research gap in the low-carbon cooperation evolution of cloud manufacturing providers based on the stochastic evolutionary game and provides decision-making suggestions for governments and cloud platforms to encourage provider participation in low-carbon cooperation and for providers to adopt low-carbon strategies.

The incidence and risk factors of marginal ulcers in the short and medium term in symptomatic post-pancreaticoduodenectomy patients ---- single-center experience.

BACKGROUND: Marginal ulcer (MU) is one of the postoperative complications of pancreaticoduodenectomy (PD), which needs particular attention in postoperative treatments. METHODS: The data of 190 patients who underwent PD and follow-up gastroscopic review due to upper GI symptoms within two years were retrospectively analyzed. The incidence of MU and risk factors were analyzed based on personal history, surgical procedure, past medical history, postoperative complications, and other relevant indicators. RESULTS: The proportion of MU in patients who underwent endoscopic follow-up for upper gastrointestinal symptoms in the postoperative period in this cohort was 10.5% (20/190). Advanced age (69y vs. 59y, P â€‹= â€‹0.012), alcohol consumption (20% vs. 8.2%, P â€‹= â€‹0.03), and cigarette smoking (35% vs. 14.7%, P â€‹= â€‹0.022) were associated with an increased incidence of MU. Longer surgery time (276.5min vs. 240min, P â€‹= â€‹0.049), postoperative bleeding (10% vs. 1.8%, P â€‹= â€‹0.030), and failure to take antacid regularly postoperatively (75% vs. 97.1%, P â€‹= â€‹0.000) would increase the risk of MU; taking antacid regularly was an independent protective factor for postoperative anastomotic ulceration (OR: 0.091, CI: 0.022-0.383, P â€‹= â€‹0.001). CONCLUSION: Advanced age, alcohol consumption, smoking, longer operation time, or postoperative extraluminal hemorrhage are associated with MU. Regular use of antacids is an independent protective factor against the development of MU.

A Fast Self-Calibration Method for Dual-Axis Rotational Inertial Navigation Systems Based on Invariant Errors.

In order to ensure that dual-axis rotational inertial navigation systems (RINSs) maintain a high level of accuracy over the long term, there is a demand for periodic calibration during their service life. Traditional calibration methods for inertial measurement units (IMUs) involve removing the IMU from the equipment, which is a laborious and time-consuming process. Reinstalling the IMU after calibration may introduce new installation errors. This paper focuses on dual-axis rotational inertial navigation systems and presents a system-level self-calibration method based on invariant errors, enabling high-precision automated calibration without the need for equipment disassembly. First, navigation parameter errors in the inertial frame are expressed as invariant errors. This allows the corresponding error models to estimate initial attitude even more rapidly and accurately in cases of extreme misalignment, eliminating the need for coarse alignment. Next, by utilizing the output of a gimbal mechanism, angular velocity constraint equations are established, and the backtracking navigation is introduced to reuse sensor data, thereby reducing the calibration time. Finally, a rotation scheme for the IMU is designed to ensure that all errors are observable. The observability of the system is analyzed based on a piecewise constant system method and singular value decomposition (SVD) observability analysis. The simulation and experimental results demonstrate that this method can effectively estimate IMU errors and installation errors related to the rotation axis within 12 min, and the estimated error is less than 4%. After using this method to compensate for the calibration error, the velocity and position accuracies of a RINS are significantly improved.

The Impact of Chat Generative Pre-trained Transformer (ChatGPT) on Oncology: Application, Expectations, and Future Prospects.

The integration of Chat Generative Pre-trained Transformer (ChatGPT) into the field of oncology has recently garnered significant attention, with potential implications for enhancing both research and clinical practice. This paper presents a comprehensive review of the evolving landscape of ChatGPT applications in oncology, emphasizing its contributions to diagnosis, treatment, research, and patient education. We examine its role in assisting medical professionals, researchers, and patients in understanding complex cancer-related data and making informed decisions. Ethical considerations and potential challenges associated with the implementation of ChatGPT in oncology are also discussed. This article highlights the promising role of ChatGPT as a valuable tool in the oncology domain and outlines future directions for research and application.

Flexible Fabrication and Hybridization of Bioactive Hydrogels with Robust Osteogenic Potency.

Osteogenic scaffolds reproducing the natural bone composition, structures, and properties have represented the possible frontier of artificially orthopedic implants with the great potential to revolutionize surgical strategies against the bone-related diseases. However, it is difficult to achieve an all-in-one formula with the simultaneous requirement of favorable biocompatibility, flexible adhesion, high mechanical strength, and osteogenic effects. Here in this work, an osteogenic hydrogel scaffold fabricated by inorganic-in-organic integration between amine-modified bioactive glass (ABG) nanoparticles and poly(ethylene glycol) succinimidyl glutarate-polyethyleneimine (TSG-PEI) network was introduced as an all-in-one tool to flexibly adhere onto the defective tissue and subsequently accelerate the bone formation. Since the N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG polymer could quickly react with the NH2-abundant polyethyleneimine (PEI) polymer and ABG moieties, the TSG-PEI@ABG hydrogel was rapidly formed with tailorable structures and properties. Relying on the dense integration between the TSG-PEI network and ABG moieties on a nano-scale level, this hydrogel expressed powerful adhesion to tissue as well as durable stability for the engineered scaffolds. Therefore, its self-endowed biocompatibility, high adhesive strength, compressive modulus, and osteogenic potency enabled the prominent capacities on modulation of bone marrow mesenchymal stem cell (BMSCs) proliferation and differentiation, which may propose a potential strategy on the simultaneous scaffold fixation and bone regeneration promotion for the tissue engineering fields.

Investigation and analysis of training injury and its psychological effects on firefighters in Beijing A cross-sectional study.

Firefighters' high-intensity training often leads to injuries in the musculoskeletal system. Studies have found that these injuries in the musculoskeletal system may contribute to poor psychological issues. At the same time, low psychological well-being increases the risk of injuries, illness, and mortality. According to research reports, firefighters generally have a good psychological state. So this study aims to survey and analyze the training-related injuries and psychological states of firefighting and rescue personnel in Beijing. This cross-sectional study employed a questionnaire survey to gather data from a total of 214 firefighters in a certain city. The participants were required to complete a questionnaire about musculoskeletal injuries and psychological status, and then these data were statistically analyzed. The incidence of training-related injuries is relatively high among firefighting and rescue teams, with the highest proportions observed in the lower back, knees, and ankles. Overweight and obese firefighters are more prone to ankle injuries. In the group with injuries, the subjective well-being index is lower compared to the group without injuries. Firefighters experiencing moderate to severe pain due to injuries exhibit lower subjective well-being indices compared to those with mild pain. Psychological resilience and the impact of pain on training and sleep can predict the subjective well-being index of firefighters. It is recommended that firefighting and rescue teams enhance preventive measures for musculoskeletal injuries during training to elevate the subjective well-being of firefighters.

The distance between the anterior and posterior edges of the fibula at a lateral internal rotation of 15° is associated with postoperative malreduction in patients with an ankle joint fracture combined with a lower tibiofibular syndesmosis injury.

BACKGROUND: Malreduction remains a problem in patients with an ankle joint fracture combined with a lower tibiofibular syndesmosis injury. Current methods of malreduction evaluation have many limitations, and novel techniques are required. OBJECTIVES: The aim of the study was to investigate the association between the distance between the anterior and posterior edges of the fibula at a 15° lateral internal rotation and postoperative malreduction in patients with an ankle joint fracture combined with a lower tibiofibular syndesmosis injury. MATERIAL AND METHODS: This prospective observational cohort study enrolled 187 patients diagnosed with an ankle joint fracture combined with a lower tibiofibular syndesmosis injury between January 2020 and January 2022. The patients were divided into 2 groups according to their postoperative malreduction condition: the malreduction group and the non-malreduction group. After tibiofibular syndesmosis reduction, a computed tomography (CT) scan was used to measure the distance between the anterior and posterior edges of the fibula at a standard lateral position and a position with a lateral internal rotation of 15°. Demographic data and basic clinical characteristics were recorded for all patients. RESULTS: The mean distance between the anterior and posterior edges of the fibula was longer in malreduction patients than non-malreduction patients at the standard lateral and 15° lateral internal rotation positions. At a lateral internal rotation of 15°, the distance between the anterior and posterior edges correlated negatively with the postoperative Mazur and American Orthopaedic Foot and Ankle Society (AOFAS) scores, and correlated positively with the length of hospitalization and fracture healing time. Receiver operating characteristic (ROC) curves revealed the potential postoperative malreduction diagnostic value of fibular anterior-posterior edge distance using an internal rotation of 15°. Postoperative AOFAS score, length of hospitalization, fracture healing time, and the distance between the anterior and posterior edges of the fibula at a lateral internal rotation of 15° were independent risk factors of malreduction. CONCLUSIONS: The fibular anterior-posterior edge distance at an internal rotation of 15° is associated with postoperative ankle joint function and the occurrence of malreduction.

m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway.

BACKGROUND: Gemcitabine resistance has brought great challenges to the treatment of pancreatic cancer. The N6-methyladenosine (m6A) mutation has been shown to have a significant regulatory role in chemosensitivity; however, it is not apparent whether gemcitabine resistance can be regulated by fat mass and obesity-associated protein (FTO). METHODS: Cells with established gemcitabine resistance and tissues from pancreatic cancer patients were used to evaluate FTO expression. The biological mechanisms of the effects of FTO on gemcitabine resistant cells were investigated using CCK-8, colony formation assay, flow cytometry, and inhibitory concentration 50. Immunoprecipitation/mass spectrometry, MeRIP-seq, RNA sequencing and RIP assays, RNA stability, luciferase reporter, and RNA pull down assays were employed to examine the mechanism of FTO affecting gemcitabine resistant pancreatic cancer cells. RESULTS: The results revealed that FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, the gemcitabine resistance of pancreatic cancer could be enhanced by FTO, while its depletion inhibited the growth of gemcitabine resistant tumor cells in vivo. Immunoprecipitation/mass spectrometry showed that the FTO protein can be bound to USP7 and deubiquitinated by USP7, leading to the upregulation of FTO. At the same time, FTO knockdown significantly decreased the expression level of NEDD4 in an m6A-dependent manner. RNA pull down and RNA immunoprecipitation verified YTHDF2 as the reader of NEDD4, which promoted the chemoresistance of gemcitabine resistant cells. FTO knockdown markedly increased the PTEN expression level in an NEDD4-dependent manner and influenced the chemosensitivity to gemcitabine through the PI3K/AKT pathway in pancreatic cancer cells. CONCLUSION: In conclusion, we found that gemcitabine resistance in pancreatic cancer can be influenced by FTO that demethylates NEDD4 RNA in a m6A-dependent manner, which then influences the PTEN expression level and thereby affects the PI3K/AKT pathway. We also identified that the FTO level can be upregulated by USP7.

A Risk Score for Predicting the Necessity of Surgical Necrosectomy in the Treatment of Infected Necrotizing Pancreatitis.

BACKGROUND: For infected necrotizing pancreatitis (INP), percutaneous catheter drainage (PCD) is now widely acknowledged as the initial intervention in a step-up approach, followed, if necessary, by minimally invasive necrosectomy or even open pancreatic necrosectomy. However, an overemphasis on PCD may cause a patient's condition to deteriorate, leading to missed surgical opportunities or even death. This study aimed to develop a simple and convenient scoring tool for assessing the need for surgery in INP patients who received PCD procedures. METHODS: In an observational study conducted between April 2015 and December 2020, PCD was utilized as the initial step to treat 143 consecutive INP patients. A surgical necrosectomy was performed when the patient failed to respond. Risk factors of PCD failure (i.e., need for surgical necrosectomy) were identified by multivariate logistic regression models. An integer-based risk scoring tool was developed using the ß coefficients derived from the logistic regression model. RESULTS: In 62 (43.4%) patients, PCD was successful, while the remaining 81 (56.6%) individuals required subsequent surgical necrosectomy. In the multivariate model, organ failure, percentage of pancreatic necrosis, extrapancreatic necrosis volume, and mean CT density of extrapancreatic necrosis volume were associated with a need for surgical necrosectomy. A predictive scoring tool based on these four factors demonstrated an area under the receiver operating characteristic curve (AUC) of 0.893. Under the scoring tool, a total score of 4 or more indicates a high possibility of surgical necrosectomy being required (at least 80%). Using the coordinates of the receiver operating characteristic curve (ROC), the sensitivity and specificity at this threshold are 0.802 and 0.903, respectively. CONCLUSIONS: A risk score model integrating organ failure, percentage of pancreatic necrosis, extrapancreatic necrosis volume, and mean CT density of extrapancreatic necrosis volume can identify INP patients at high risk for necrosectomy. The straightforward risk assessment tool assists clinicians in stratifying INP patients and making more judicious medical decisions.

Risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: a comprehensive systematic review and meta-analysis.

BACKGROUND: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy (PD) or pylorus-preserving pancreaticoduodenectomy (PPPD). However, its risk factors are still unclear. This meta-analysis aimed to identify the potential risk factors of DGE among patients undergoing PD or PPPD. MATERIALS AND METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Library, Google Scholar, and ClinicalTrial.gov for studies that examined the clinical risk factors of DGE after PD or PPPD from inception through 31 July 2022. We pooled odds ratios (ORs) with 95% CIs using random-effects or fixed-effects models. We also performed heterogeneity, sensitivity, and publication bias analyses. RESULTS: The study included a total of 31 research studies, which involved 9205 patients. The pooled analysis indicated that out of 16 nonsurgical-related risk factors, three risk factors were found to be associated with an increased incidence of DGE. These risk factors were older age (OR 1.37, P =0.005), preoperative biliary drainage (OR 1.34, P =0.006), and soft pancreas texture (OR 1.23, P =0.04). On the other hand, patients with dilated pancreatic duct (OR 0.59, P =0.005) had a decreased risk of DGE. Among 12 operation-related risk factors, more blood loss (OR 1.33, P =0.01), postoperative pancreatic fistula (POPF) (OR 2.09, P <0.001), intra-abdominal collection (OR 3.58, P =0.001), and intra-abdominal abscess (OR 3.06, P <0.0001) were more likely to cause DGE. However, our data also revealed 20 factors did not support stimulative factors influencing DGE. CONCLUSION: Age, preoperative biliary drainage, pancreas texture, pancreatic duct size, blood loss, POPF, intra-abdominal collection, and intra-abdominal abscess are significantly associated with DGE. This meta-analysis may have utility in guiding clinical practice for improvements in screening patients with a high risk of DGE and selecting appropriate treatment measures.

Development of a basement membrane gene signature and identification of the potential candidate therapeutic targets for pancreatic cancer.

Background: Pancreatic cancer is a deadly cancer with a poor prognosis. In light of mounting evidence that basement membrane genes (BMGs) play a role in the development of cancer, we sought to examine the prognostic importance and role of BMGs in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: BMGs were obtained from previous top research studies. The clinical and messenger ribonucleic acid expression data were retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data sets, respectively. Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used for the PDAC risk modeling and gene identification. The Kaplan-Meier method was used to compare outcomes between the low- and high-risk groups. Finally, we analyzed small-molecule drugs that could be used to target BMGs for treatment using the Enrichr data set and validated the function of the tubulointerstitial nephritis antigen (TINAG) in pancreatic cancer. Results: We successfully constructed and validated a 7 BMG-based model to predict PDAC patient outcomes. Additionally, we discovered that 7 BMG-based model was an independent predictive factor for PDAC. According to our functional analysis, the majority of the signaling pathways enriched in BMGs were those connected to malignancy. Immune cell infiltration and immunological checkpoints were also linked to the BMG-based model. Further, we identified 5 small-molecule drugs that may be useful in treating PDAC patients. We also found that TINAG promoted cell proliferation in pancreatic cancer. Conclusions: Our study extended understandings of how BMGs work in PDAC. We identified a credible predictive biomarker for PDAC patients' survival.

Identification of adaptor proteins by incorporating deep learning and PSSM profiles.

Adaptor proteins, also known as signal transduction adaptor proteins, are important proteins in signal transduction pathways, and play a role in connecting signal proteins for signal transduction between cells. Studies have shown that adaptor proteins are closely related to some diseases, such as tumors and diabetes. Therefore, it is very meaningful to construct a relevant model to accurately identify adaptor proteins. In recent years, many studies have used a position-specific scoring matrix (PSSM) and neural network methods to identify adaptor proteins. However, ordinary neural network models cannot correlate the contextual information in PSSM profiles well, so these studies usually process 20×N (N > 20) PSSM into 20×20 dimensions, which results in the loss of a large amount of protein information; This research proposes an efficient method that combines one-dimensional convolution (1-D CNN) and a bidirectional long short-term memory network (biLSTM) to identify adaptor proteins. The complete PSSM profiles are the input of the model, and the complete information of the protein is retained during the training process. We perform cross-validation during model training and test the performance of the model on an independent test set; in the data set with 1224 adaptor proteins and 11,078 non-adaptor proteins, five indicators including specificity, sensitivity, accuracy, area under the receiver operating characteristic curve (AUC) metric and Matthews correlation coefficient (MCC), were employed to evaluate model performance. On the independent test set, the specificity, sensitivity, accuracy and MCC were 0.817, 0.865, 0.823 and 0.465, respectively. Those results show that our method is better than the state-of-the art methods. This study is committed to improve the accuracy of adaptor protein identification, and laid a foundation for further research on diseases related to adaptor protein. This research provided a new idea for the application of deep learning related models in bioinformatics and computational biology.

Complex genome assembly based on long-read sequencing.

High-quality genome chromosome-scale sequences provide an important basis for genomics downstream analysis, especially the construction of haplotype-resolved and complete genomes, which plays a key role in genome annotation, mutation detection, evolutionary analysis, gene function research, comparative genomics and other aspects. However, genome-wide short-read sequencing is difficult to produce a complete genome in the face of a complex genome with high duplication and multiple heterozygosity. The emergence of long-read sequencing technology has greatly improved the integrity of complex genome assembly. We review a variety of computational methods for complex genome assembly and describe in detail the theories, innovations and shortcomings of collapsed, semi-collapsed and uncollapsed assemblers based on long reads. Among the three methods, uncollapsed assembly is the most correct and complete way to represent genomes. In addition, genome assembly is closely related to haplotype reconstruction, that is uncollapsed assembly realizes haplotype reconstruction, and haplotype reconstruction promotes uncollapsed assembly. We hope that gapless, telomere-to-telomere and accurate assembly of complex genomes can be truly routinely achieved using only a simple process or a single tool in the future.

Surgical revision for pancreatojejunostomy stricture: a case series of 14 patients.

BACKGROUND: Pancreatojejunostomy stricture (PJS) is a rare long-term complication of pancreaticojejunal anastomosis. This study aimed to investigate the role of surgery in the management of pancreatojejunostomy strictures. METHODS: The database of the Pancreas Center of Nanjing Medical University was retrospectively screened for patients who underwent a surgical revision for PJS between June 2012 and August 2019, and their clinical characteristics and management modalities were reviewed. RESULTS: Fourteen consecutive cases were retrieved, the median age at index operation was 41.1 years (19-71). The average time between the two operations was 70.6 months (8-270 months). Index procedures included pancreaticoduodenectomy (PD) (7/14, 50%), pylorus-preserving PD (4/14, 28.6%), Berger procedure (2/14, 14.3%), and middle pancreatectomy (1/14, 7.1%). The diameter of the main pancreatic duct was < 4 mm in all 14 cases, and nine underwent pancreaticojejunostomy (PJ) stenting during the index operation. The most frequent complaints were abdominal pain (6/14, 42.9%), recurrent acute pancreatitis (6/14, 42.9%), pancreatic fistula (1/14, 7.1%), and abdominal distention (1/14, 7.1%). The diagnosis of PJ stricture was confirmed by computed tomography or magnetic resonance imaging in all cases. All patients had a main duct diameter > 5 mm before surgical revision. All patients underwent wedge excision with interrupted one-layer suturing with absorbable sutures and without stent placement. In this series, only one patient required reoperation. Upon follow-up, 11 of 12 patients had complete resolution of the PJ stricture. CONCLUSION: PJS is a long-term complication of pancreatojejunostomy. Surgical revision of the anastomosis is a safe and effective treatment modality.

Pomegranate Peel as a Source of Bioactive Compounds: A Mini Review on Their Physiological Functions.

The production and consumption of pomegranates have always been increasing owing to their taste and nutrition. However, during fruit processing, a large number of by-products are produced, such as peels and seeds, which can lead to environmental pollution problems if not handled properly. The pomegranate peel takes up about 26-30% of the total weight, while it contains abundant bioactive substances. This paper carries out a mini review of the characterization and physiological functions of key bioactive compounds in pomegranate peel, comprehensively assessing their effects on human health. The overview summarizes the main phenolic substances in pomegranate peel, including tannins, flavonoids, and phenolic acids. Dietary fiber and other bioactive substances such as alkaloids, minerals, and vitamins are also mentioned. These components act as antioxidants by improving oxidative biomarkers and scavenging or neutralizing reactive oxygen species, further contributing to their extensive functions like anti-inflammatory, anti-cancer, antibacterial, and cardiovascular protection. Overall, it is envisaged that through the deeper understanding of bioactive compounds in pomegranate peel, the waste sources can be better reused for physiological applications.

Ypsilandrosides U-Y, five new steroidal saponins from Ypsilandra thibetica.

Phytochemical reinvestigation on the whole plants of Ypsilandra thibetica obtained four new spirostanol glycosides, named ypsilandrosides U-X (1-4), and one new cholestanol glycoside, named ypsilandroside Y (5). Their structures have been established by extensive spectroscopic data and chemical methods. Among them, compound 4 is a rare spirostanol glycoside which possesses a novel 5(6 → 7) abeo-steroidal aglycone, while compound 1 is a first spirostanol bisdesmoside attached to C-3 and C-12, respectively, isolated from the genus Ypsilandra. The induced platelet aggregation activity of the isolates was tested.

Undifferentiated Carcinoma of Pancreas with Osteoclast-Like Giant Cells: One Center's Experience of 13 Cases and Characteristic Pre-Operative Images.

Background: Undifferentiated carcinoma of pancreas with osteoclast-like giant cells is an extremely rare tumor in pancreas. It is relatively difficult to have preoperative diagnosis due to the lack of specific tumor markers and pre-operative images. Methods: In the present study, database of the pancreas center in the First Affiliated Hospital of Nanjing Medical University was retrospectively screened. A total of thirteen cases diagnosed as undifferentiated carcinoma of pancreas with osteoclast-like giant cells were included. Their clinical data and treatments were collected. Results: Thirteen patients include eight males and five females, and the median age was 67 (60-72) years old. The lesions were found in more than half patients through health examination with no symptoms. NSE was elevated in eight cases (66%). CT scan revealed that cystic and solid lesions often had thick (4/5), contrast-enhanced (5/5) wall with smooth edges (5/5) and the boundary of lesions mainly with solid composition (4/10) is not well demarcated with normal pancreatic parenchyma. All patients received surgical resection. Eight patients had adjuvant chemotherapy and only one patient had adjuvant radiotherapy. The median survival time was 13 months. Five patients had postoperative metastasis or recurrence of tumor and four of them had died of this disease during follow-up. Conclusion: Our data showed that elevated level of NSE and characteristic pre-operative images might provide aid with the pre-operative diagnosis for undifferentiated carcinoma of pancreas with osteoclast-like giant cells. Patients with suspected diagnosis should receive surgical intervention as soon as possible, supplemented with postoperative chemotherapy, in order to prolong the survival of patients.

Tim-3 mediates T cell trogocytosis to limit antitumor immunity.

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1-positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen-specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide-major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.

Development and validation of risk prediction nomogram for pancreatic fistula and risk-stratified strategy for drainage management after pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is the major complication following pancreaticoduodenectomy (PD). We sought to develop and validate a risk prediction model for POPF after PD with the aim of determining personal risk probability and proposing a novel strategy for intraoperative placement and/or early-removal of prophylactic drainage. METHODS: Data from 993 patients undergoing PD from January 2012 to December 2016 were retrospectively analyzed. Patients were randomly assigned to either training cohort or validation cohort. A nomogram was formulated based on the results from multivariable regression model for prediction of POPF. Internal and external validation were carried out with calibration plot respectively. RESULTS: POPF occurred in 162 (16.3%) patients. The final pre-/intra-operative prediction model included alanine transaminase level [odds ratio (OR) 1.00, 95% confidence interval (CI): 1.00-1.00, P=0.023], combined portal-superior mesenteric vein resection (OR 0.22, 95% CI: 0.05-0.95, P=0.043), pancreatic duct diameter (OR 1.48, 95% CI: 1.11-1.96, P=0.007), intraoperative colloid infusion (OR 1.00, 95% CI: 1.00-1.00, P=0.001), pathology (OR 1.71, 95% CI: 1.09-2.66, P=0.018). The area under the curve (AUC) was 0.667 in the training cohort and 0.621 in the validation cohort. The final postoperative prediction model included pancreatic duct diameter (OR 1.58, 95% CI: 1.14-2.19, P=0.006), intraoperative colloid infusion (OR 2.52, 95% CI: 1.26-5.06, P=0.009), drainage fluid amylase on postoperative day 3 (POD3) (OR 4.70, 95% CI: 3.30-6.70, P<0.001), and neutrophil count on POD3 (OR 2.83, 95% CI: 1.63-4.93, P<0.001). The AUC was 0.809 in the training cohort and 0.797 in the validation cohort. Based on these variables, two nomogram prediction models were developed respectively. The calibration plot of the two models showed a good correlation between the expected risk and the actual risk in the low-risk range. Our risk-stratified strategy for drain management according to nomograms may be beneficial for 34.5% of patients. CONCLUSIONS: Our study formulated and validated two nomogram models for predicting POPF that performed particularly well in the low-risk range. This tool may allow surgeons to propose a risk stratified strategy for intraoperative drain placement and early drain removal, which may be beneficial for a substantial proportion of patients.