Aim
Sphingosine‐1‐phosphate (S1P) and ceramide are bioactive sphingolipids known to be important in regulating numerous processes involved in cancer progression. The aim of this study was to ...determine the absolute levels of sphingolipids in hepatocellular carcinoma (HCC) utilizing data obtained from surgical specimens. In addition, we explored the clinical significance of S1P in patients with HCC and the biological role of S1P in HCC cells.
Methods
Tumors and normal liver tissues were collected from 20 patients with HCC, and sphingolipids were measured by mass spectrometry. The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate gene expression of enzymes related to sphingolipid metabolism. Immunohistochemistry of phospho‐sphingosine kinase 1 (SphK1), an S1P‐producing enzyme, was performed for 61 surgical specimens. CRISPR/Cas9‐mediated SphK1 knockout cells were used to examine HCC cell biology.
Results
S1P levels were substantially higher in HCC tissue compared with normal liver tissue. Levels of other sphingolipids upstream of S1P in the metabolic cascade, such as sphingomyelin, monohexosylceramide and ceramide, were also considerably higher in HCC tissue. Enzymes involved in generating S1P and its precursor, ceramide, were found in higher levels in HCC compared with normal liver tissue. Immunohistochemical analysis found that phospho‐SphK1 expression was associated with tumor size. Finally, in vitro assays indicated that S1P is involved in the aggressiveness of HCC cells.
Conclusions
Sphingolipid levels, including S1P and ceramide, were elevated in HCC compared with surrounding normal liver tissue. Our findings suggest S1P plays an important role in HCC tumor progression, and further examination is warranted.
Patient-Derived Xenograft (PDX) is now accepted as a murine model that better mimics human cancer when compared to a conventional cancer cell-line inoculation model. Some claim the advantage of ...orthotopic site implantation of patient tumor (OS) over ectopic implantation into the subcutaneous space (SQ); however, there has been no study that describes a head-to-head comparison of oncological differences between these two models to date. We hypothesize that OS tumors re-transplant and grow better than SQ tumors and are therefore a better model to evaluate tumor aggressiveness. Breast cancer PDXs were generated using the tumors derived from 11 patients into NOD scid gamma (NSG) mice. We used six ER(+)HER2(−) tumors and five triple negative (TN) tumors for a total of 11 tumors. Five PDX lines grew for an overall engraftment rate of 45%. We present our OS implantation method in detail. The re-transplantation rate of TN tumors in each transplant site was significantly higher in OS when compared to SQ tumors (70.1% vs. 32.1%,
p
< 0.01). OS tumors grow significantly faster than SQ tumors. Similarly, OS tumors demonstrated significantly more mitotic figures and Ki-67 positive cells than SQ tumors. The tumor re-transplantation rate significantly increased by the second and third generations with the OS method. The time from implantation to development of a palpable tumor dramatically decreased after the first passage. PDX of ER(+) tumors demonstrated significantly lower engraftment rates and slower tumor growth than TN tumors, which remarkably improved by the first passage. Orthotopically implanted PDX tumors showed better re-transplantation rates, greater tumor size, and more significant growth compared to the subcutaneously implanted model.
Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support ...estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (
< 0.001,
< 0.001, respectively) and it correlated with ER expression (
= 0.630,
= 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01,
< 0.001), and AR low tumors enriched DNA repair (NES = -2.02,
< 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (
< 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.
Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of ...triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data were obtained from The Cancer Genome Atlas (TCGA,
= 1079) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (
= 1904). TNBC patients had significantly higher levels of ANXA1 expression compared to the other subtypes in both TCGA and METABRIC cohorts (
< 0.001). ANXA1 protein expression was assessed by immunohistochemistry in Japanese TNBC patient cohort (
= 48), where 17 cases (35.4%) had positive ANXA1 staining, and their overall survival was significantly shorter compared with negative staining group (
= 0.008). The CIBERSORT algorithm was used to calculate immune cell infiltrations. ANXA1 high tumors were associated with activated mast cells and M2 macrophages (
> 0.01), but did not show any association with tumor heterogeneity nor cytolytic activity. High expression of ANXA1 group enriched inflammation, epithelial-to-mesenchymal transition (EMT), and angiogenesis-related genes in a gene set enrichment assay in both cohorts. To our knowledge, this is the first study to demonstrate that ANXA1 is associated with infiltration of mast cells and inflammation that is associated with the aggressive phenotype of TNBC, such as EMT and angiogenesis.
For the last several years, predatory journals have been a topic of discussion in top scientific journals, such as
Nature
. Predatory journals are problematic because they create public mistrust of ...scientific publication as a whole by the mass production of non-credible publications with the sole aim of profit. Recently, articles in a Japanese newspaper and online articles exposed domestic institutions for the number of publications in predatory journals, saying that they “abused predatory journals to increase the number of their publications and falsely inflate their academic achievements.” We do not subscribe to this point of view because publications in predatory journals do not count as scholarly achievements, and we believe it is an information literacy problem. We feel strongly that it is both important and beneficial for the readers of
The Japan Medical Association
Journal
to be aware of and understand this issue.
Background
Despite the advantages of laparoscopic cholecystectomy, major bile duct injury (BDI) rates during this operation remain unacceptably high. In October 2018, SAGES released the Safe ...Cholecystectomy modules, which define specific strategies to minimize the risk of BDI. This study aims to investigate whether this curriculum can change the knowledge and behaviors of surgeons in practice.
Methods
Practicing surgeons were recruited from the membership of SAGES and the American College of Surgeons Advisory Council for Rural Surgery. All participants completed a baseline assessment (pre-test) that involved interpreting cholangiograms, troubleshooting difficult cases, and managing BDI. Participants' dissection strategies during cholecystectomy were also compared to the strategies of a panel of 15 experts based on accuracy scores using the Think Like a Surgeon validated web-based platform. Participants were then randomized to complete the Safe Cholecystectomy modules (Safe Chole module group) or participate in usually scheduled CME activities (control group). Both groups completed repeat assessments (post-tests) one month after randomization.
Results
Overall, 41 participants were eligible for analysis, including 18 Safe Chole module participants and 23 controls. The two groups had no significant differences in pre-test scores. However, at post-test, Safe Chole module participants made significantly fewer errors managing BDI and interpreting cholangiograms. Safe Chole module participants were less likely to convert to an open operation on the post-test than controls when facing challenging dissections. However, Safe Chole module participants displayed a similar incidence of errors when evaluating adequate critical views of safety.
Conclusions
In this randomized-controlled trial, the SAGES Safe Cholecystectomy modules improved surgeons' abilities to interpret cholangiograms and safely manage BDI. Additionally, surgeons who studied the modules were less likely to convert to open during difficult dissections. These data show the power of the Safe Cholecystectomy modules to affect practicing surgeons' behaviors in a measurable and meaningful way.
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