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Background A growing body of evidence suggests that the DSG family plays a key role in tumorigenesis and progression; however, the function of DSG family members in PAAD remains unclear. Methods Comprehensive bioinformatics analysis was performed to investigate the clinicopathological characteristics, prognostic value, imnological features, and functional mechanisms of DSG family members in PAAD, using UALCAN, the HPA, Kaplan–Meier Plotter, cBioPortal, TISIDB, LinkedOmics, STRING and GSCALite Database. Results The expression of DSG family members was significantly higher in PAAD tissues compared with paraneoplastic or normal tissues, and their copy number variation was significantly associated with poorer clinicopathological characteristics and prognosis in PAAD patients. Furthermore, the roles of DSG family members in immune regulation are diverse and complex. Mechanistically, TP53 mutations are significantly associated with promoter methylation and the expression of DSG family members, and EGFR may be key to the role of DSG family members in PAAD. DSG family members activate several oncogenic pathways, including EMT, PI3K/AKT, and RAS/MAPK signaling pathway. In addition, we found that the expression of DSG family members was significantly correlated with sensitivity to multiple conventional chemotherapeutic agents and novel targeted drugs. Conclusions DSG family members play an oncogenic role in the development of PAAD and may serve as novel biomarkers or therapeutic targets.

Supplementary Figure 1. The rate of proliferation is the same in the orthotopic and transgenic KPC mouse models Supplementary Figure 2. Single c-Met or Hh inhibitor treatment leads to the enhanced expression of the other target and the combination of both c-Met and Hh inhibitors suppresses the expression of both targets more effectively Supplementary Figure 3. Prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to single targeted agents, which can be overcome by the combination of both c-Met and Hh inhibitors. Supplementary Figure 4. Lentiviral knockdown of c-Met in KPC tumor cells results in decrease of Shh expression. Supplementary Materials and Methods

How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

Background: The liver was the most common metastatic site in ampullary adenocarcinoma (AC) patients. This study aims to investigate the overall survival and to establish a prognostic nomogram for AC patients with liver metastasis. Methods:AC patients with liver metastasis were retrospectively reviewed in the National Cancer Center of China and SEER database. The Cox proportional hazard model was performed to determine the independent prognostic risk factors. Then the prognostic nomogram was established and the internal validation was performed to assess the predictive value of the model. In addition, the area under the receiver operating curve (ROC) curve (AUC) and decision curve analyses (DCA) were conducted to validate the nomogram model. Results: A total of 4305 AC patients in the SEER database and 237 AC patients in the National Cancer Center of China were initially retrieved. The overall incidence of liver metastasis in AC patients was 6.3% (132 patients). Overall, the 1-year, 2-year and 5-year OS in AC patients with liver metastasis were 31.2%, 18.0%, and 4.3%. The survival analysis demonstrated that age [HR: 1.536, 95%CI: 1.031-2.289, P = 0.035], poor differentiation [HR: 2.320, 95%CI: 1.156-4.655, P=0.018] were independent risk factors for OS. Based on this, a prognostic nomogram was established. The C-index for the internal validation was 0.677. The internal calibration curve, ROC curve (AUC: 0.714), and DCA curve showed relatively good predictive ability of the current nomogram. Conclusions: The prognosis for AC patients with liver metastasis were poor. A prognostic overall survival nomogram for AC patients with liver metastasis was established and showed relatively good predictive ability. Nevertheless, further prospective studies with large sample are needed to validate our results.

BackgroundSpontaneously ruptured hepatocellular carcinoma (rHCC) with hemorrhage is characterized by rapid onset and progression. The aim of this systematic review was to explore the current studies on rHCC with hemorrhage and determine the optimum treatment strategy.MethodThe PubMed, Web of Science, Embase, and the Cochrane Library databases were searched for studies reporting survival outcomes with comparison between emergency resection (ER) and transarterial embolization following staged hepatectomy (SH) were included by inclusion and exclusion criteria, the perioperative and survival data were statistically summarized using Review Manager 5.3 software.ResultA total of 8 retrospective studies were included, with a total sample size of 556, including 285 (51.3%) in the ER group and 271 (48.7%) in the SH group. The perioperative blood loss and blood transfusion volume in the SH group were less than those in the ER group, and there were no significant differences in the operative time, incidence of complications, mortality and recurrence rate of tumors between the two groups. The 1-, 2-, 3-year overall survival and 1-, 2-, 3-, 5-year disease-free survival of the ER group were not significantly different from those of the SH group, and the 5-year overall survival rate of ER group was lower than that of the SH group (hazard ratios=1.52; 95% confidence intervals: 1.14-2.03, P=0.005).ConclusionThere was no significant difference in the short-term efficacy of ER or SH in the treatment of ruptured HCC, and SH was superior to ER in the long-term survival.

Background: Many studies have confirmed that diabetes was associated with prognosis in many malignant cancer types. However, the impact of diabetes on ampullary carcinoma (AC) has not been investigated. Methods: A total of 266 AC patients in the National Cancer Center of China between January 1998 and December 2020 were retrospectively reviewed. The postoperative complication rate, postoperative recurrence rate, and long-term survival were compared between the diabetes group and the no diabetes group. Results: A total of 32 AC patients (12.03%) were diagnosed with diabetes before surgery. In total, 111 patients (41.73%) had one or more postoperative complications, and there was no perioperative death. There was no statistically significant difference regarding postoperative complications between the diabetes group and the no diabetes group. Altogether, 120 patients (45.11%) experienced postoperative recurrence. Multivariate analysis revealed that diabetes was an independent risk factor for the recurrence (OR: 2.384, 95% CI: 1.065–5.336, p = 0.035), OS (HR: 1.597, 95% CI: 1.005–2.537, p = 0.047), and RFS (HR: 1.768, 95% CI: 1.068–2.925, p = 0.027) in AC patients after curative pancreatoduodenectomy. Conclusions: Diabetes may adversely affect the recurrence of patients with AC after curative pancreaticoduodenectomy, leading to an increased risk of poor prognosis in early-stage patients. Further studies involving a large sample size are needed to validate our results.

The molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target., The implications of long intergenic non-coding RNAs (lincRNAs) on cancer metabolism is unclear. Here, the authors identify that LINC00842 binds to PGC-1α and prevents PGC-1α from deacetylation by SIRT1, resulting in a metabolic reprogramming in pancreatic cancer cells.

The internal temperature of a gas bubble caused by a fault arc is a key basic parameter for investigating the bubble behavior and the pressure rise inside oil-filled power equipment. Due to the constraints imposed by the measurement methods and experimental conditions, this temperature has always been estimated as a constant value of 2000 K in past decades. In this letter, we present direct experimental evidence of the gas bubble temperature around an arc. A large oil-filled transformer was reformed and used to conduct arcing fault tests. A sapphire fiber optic infrared thermometer was established and used to detect the internal gas bubble temperature. The experimental results confirm that this internal temperature is not constant but rather varies over a wide range from 2100 K to 1500 K, plummeting with rapid bubble growth and then exhibiting small variations until arc extinction. Furthermore, the bubble growth process throughout the arc duration can be approximately regarded as first polytropic and then isothermal.

Due to the low incidence of ampullary adenocarcinoma (AA), the recurrence patterns, risk factors for recurrence and post-recurrence treatment are still debated. The purpose of this study is to clarify such clinical issues based on the retrospective data at the National Cancer Center in China. Finally, one hundred and eighty-two AA patients after curative Whipple’s resection from 1998 to 2019 were retrospectively reviewed. Among them, 27 patients had locoregional recurrence and 61 patients had systemic recurrence. However, no significant difference of clinicopathological features and survival were found between locoregional recurrence and distant metastasis. In the recurrence group, the 1-year, 2-year, and 3-year recurrence-free survival and overall survival were 59.1%, 29.5%, 10.2%, 88.6%, 61.6%, and 37.6%, respectively. AA patients with recurrence have a worse prognosis than those without recurrence, regardless of stage. In addition, we found that advanced T stage and lymphovascular invasion were two independent risk factors for RFS in AA patients after curative Whipple’s resection. In conclusion, AA patients with recurrence have a poor prognosis. Advanced T stage and lymphovascular invasion were two independent risk factors for recurrence-free survival in AA patients after curative Whipple’s resection. Nevertheless, further studies with larger sample sizes are needed to fully validate.

Effective biomarkers play a critical role in improving clinical approaches to treat lung adenocarcinoma (LUAD). However, many existing biomarkers have limitations due to a lot of factors, requiring the development of additional biomarkers to effectively predict the disease course and prognosis of LUAD. Guanine-rich RNA sequence binding factor 1 (GRSF1) participates in multiple biological processes, but its regulatory effect on LUAD remains unknown. The present study aimed to investigate the clinicopathological importance and biological role of GRSF1 in LUAD.The expression of GRSF1 was evaluated using multiple service portals. X-Tile software were used to determine the high and low GRSF1 groups and the relationships between GRSF1 expression and clinicopathological characteristics were then analyzed by R packages. Besides, prognostic significance was identified by the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Kaplan-Meier (K-M) Plotter. Overall survival (OS) and disease-free survival (DFS) was the main outcome of prognosis analysis. The DNA copy number alterations (CNAs) and methylations were calculated using cBioPortal and R packages. The co-expressed genes of GRSF1 were obtained from LinkedOmics, and functional networks were then constructed by R clusterProfiler. Additionally, cell counting kit 8 (CCK-8) and colony formation assays were applied to verify the proliferation effects of GRSF1 on LUAD cells.GRSF1 was significantly upregulated in the LUAD tissues compared to the non-tumor lung tissues (all P0.05), and its expression was significantly correlated with gender (χThe high expression of GRSF1 indicated an unfavorable prognosis and was closely related to LUAD tumor occurrence and development, which could be used as an effective prognostic biomarker for patients suffering from LUAD.

ObjectiveWe evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial.MethodsPatients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate.ResultsWe enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively.ConclusionsS-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT.Trial registrationClinicalTrial.gov NCT02301481

Vitamin D is widely considered to have a regulatory effect on the immune system. Some clinical investigations have shown that the demand for vitamin D increases with age. Calcitriol is the biologically active form of vitamin D. However, its effect on human natural killer (NK) cells remains unclear. Therefore, in this study, we investigated the anti-aging and immunomodulatory effects of calcitriol on NK cells using a series of immunological methods to explore its important role in innate immunity. We found that calcitriol reversed the expression of aging-related biomarkers in NK cells and inhibited their expansion by maintaining these cells in the G1 phase, without any apoptosis and exhaustion. Calcitriol repressed the release of inflammation-related cytokines, such as interleukin-5 (IL-5), interleukin-13 (IL-13), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). The degranulation of NK cells was downregulated by calcitriol when these cells were co-cultured with K562 tumor cells. We also found that calcitriol upregulated the aging-related sirtuin 1- protein/kinase R-like endoplasmic reticulum kinase (SIRT1/pERK) pathway and SIRT1-deltaExon8 (SIRT1-∆Exon8) expression by activating the vitamin D receptor (VDR). Moreover, calcitriol could be a potential negative regulator of NK cell apoptosis and mitochondrial inactivation which caused by oxidative stress. Thus, calcitriol exhibits anti-aging effects on human NK cells in vitro by activating the SIRT1-PERK axis and resisting oxidative senescence.

ASB17, a member of the ankyrin repeat and SOCS box-containing protein (ASB) family, has been supposed to act as an E3 ubiquitin ligase. Actually, little is known about its biological function. In this study, we found that ASB17 knocking-out impaired the expression of the pro-inflammatory cytokines CCL2 and IL-6 in bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS), indicating an inflammation-promoting role of this gene. We reveal that ASB17 promotes LPS-induced nuclear factor kappa B (NF-κB) signal activation through interacting with TNF receptor-associated factor 6 (TRAF6) which is a crucial adaptor protein downstream of toll-like receptors (TLR). ASB17 via its aa177–250 segment interacts with the Zn finger domain of TRAF6. The interaction of ASB17 stabilizes TRAF6 protein through inhibiting K48-linked TRAF6 polyubiquitination. Therefore, we suggest that ASB17 facilitates LPS-induced NF-κB activation by maintaining TRAF6 protein stability. The inflammation enhancer role of ASB17 is recognized here, which provides new understanding of the activation process of inflammation and immune response.

BackgroundLymph node metastasis (LNM) is closely associated with the prognosis of ampullary carcinoma (AC). The purpose of this study is to explore the relationship between lymph node ratio (LNR) and the prognosis of patients with AC after curative pancreaticoduodenectomy and to establish a new LNR-based staging system.MethodsAC patients in the Cancer Hospital, Chinese Academy of Medical Sciences, between 1998 and 2020 were retrospectively reviewed as the training cohort; and AC patients in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018 were obtained as the validation cohort. Within the training group, Kaplan–Meier survival analyses and Cox proportional hazards regression were conducted to assess the prognostic value of LNR and establish a new LNR-based staging system. Then, the new staging system was compared with the 8th American Joint Committee on Cancer (AJCC) TNM staging system in both the training and validation cohorts.ResultsA total of 264 patients in the training cohort and 199 patients in the validation cohort were enrolled. Significant overall survival (OS) difference was observed between LNR-low stage and LNR-high stage in both training (p = 0.001) and validation cohorts (p < 0.001). Then a new LNR-based staging system was developed. Under the new system, the number of patients in the training cohort and validation cohort of stage I, stage II, and stage III was 30 (11%) vs. 18 (9%), 190 (72%) vs. 96 (48%), and 44 (17%) vs. 85 (43%), respectively. The new staging system classified patients with respect to survival better than did the 8th AJCC TNM staging system.ConclusionsThe new LNR-based staging system had better discriminability for predicting survival in AC patients after curative pancreaticoduodenectomy. More data are needed for further validation.

Background: Radiofrequency ablation (RFA) is a curative modality for hepatocellular carcinoma (HCC) patients who are not suitable for resection. It remains controversial whether a surgical or percutaneous approach is more appropriate for HCC.Method: A search was performed on the PubMed, Web of Science, Embase, and Cochrane Library databases from the date of database inception until April 17, 2021. Studies reporting outcomes of comparisons between surgical RFA (SRFA) and percutaneous RFA (PRFA) were included in this study. The meta-analysis was performed using the Review Manager 5.3 and Stata 12.0 software.Result: A total of 10 retrospective studies containing 12 cohorts, involving 740 patients in the PRFA group and 512 patients in the SRFA group, were selected. Although the tumor size in PRFA group was smaller than the SRFA group (p = 0.007), there was no significant difference in complete ablation rate between the SRFA and PRFA groups (95.63% and 97.33%, respectively; Odds ratio [OR], 0.56; 95% confidence intervals [CI], 0.26–1.24; p = 0.15). However, the SRFA group showed a significantly lower local tumor recurrence than the PRFA group in the sensitivity analysis (28.7% in the PRFA group and 21.79% in the SRFA group, respectively; OR, 1.84; 95% CI, 1.14–2.95; p = 0.01). Pooled analysis data showed that the rate of severe perioperative complications did not differ significantly between the PRFA and SRFA groups (14.28% and 12.11%, respectively; OR, 1.30; 95% CI, 0.67-2.53; p = 0.44). There was no significant difference in the 1-, 3-, and 5-year overall survival rates, as well as the 1- and 3-year disease-free survival (DFS) between the PRFA and SRFA groups. The 5-year DFS of the PRFA group was significantly lower than the SRFA group (hazard ratio 0.73; 95% CI 0.54–0.99).Conclusion: Based on our meta-analysis, the surgical route was superior to PRFA in terms of local control rate. Furthermore, the surgical approach did not increase the risk of major complications.