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Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs’ reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation.

Abstract In recent years there has been a growing interest in treating many-body systems as Bell scenarios, where lattice sites play the role of distant parties and only near-neighbor statistics are accessible. We investigate contextuality arising from three Bell scenarios in infinite, translation-invariant 1D models: nearest-neighbor with two dichotomic observables per site; nearest- and next-to-nearest neighbor with two dichotomic observables per site, and nearest-neighbor with three dichotomic observables per site. For the first scenario, we give strong evidence that it cannot exhibit contextuality, not even in non-signaling physical theories beyond quantum mechanics. For the second one, we identify several low-dimensional models that reach the ultimate quantum limits, paving the way for self-testing ground states of quantum many-body systems. For the last scenario, which generalizes the Heisenberg model, we give strong evidence that, in order to exhibit contextuality, the dimension of the local quantum system must be at least 3.

The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.

Abstract Background Previous studies have shown that the N6-methyladenosine (m6A) modification enhances the binding ability of mRNAs/long noncoding RNAs (lncRNAs) to microRNAs (miRNAs), but the impact of this modification on the competitive endogenous RNA (ceRNA) function of circular RNAs (circRNAs) is unclear. Methods We used a human circRNA microarray to detect the expression profiles of circRNAs in 3 pairs of cancer and paracancerous tissues from patients with colorectal cancer (CRC) and 3 pairs of peripheral blood specimens from patients with CRC and healthy individuals. The circRNAs highly expressed in both peripheral blood and tumour tissues of patients with CRC, including circALG1, were screened. A quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of an expanded sample size was performed to detect the expression level of circALG1 in peripheral blood and tumour tissues of patients with CRC and determine its correlation with clinicopathological features, and circRNA loop-forming validation and stability assays were then conducted. Transwell assays and a nude mouse cancer metastasis model were used to study the function of circALG1 in CRC and the role of altered m6A modification levels on the regulation of circALG1 function. qRT-PCR, western blot (WB), Transwell, RNA-binding protein immunoprecipitation (RIP), RNA antisense purification (RAP), and dual-luciferase reporter gene assays were performed to analyse the ceRNA mechanism of circALG1 and the effect of the m6A modification of circALG1 on the ceRNA function of this circRNA. Results CircALG1 was highly expressed in both the peripheral blood and tumour tissues of patients with CRC and was closely associated with CRC metastasis. CircALG1 overexpression promoted the migration and invasion of CRC cells, and circALG1 silencing and reduction of the circALG1 m6A modification level inhibited CRC cell migration and invasion. In vivo experiments further confirmed the prometastatic role of circALG1 in CRC. Further mechanistic studies showed that circALG1 upregulated the expression of placental growth factor (PGF) by binding to miR-342-5p and that m6A modification enhanced the binding of circALG1 to miR-342-5p and promoted its ceRNA function. Conclusion M6A modification enhances the binding ability of circALG1 to miR-342-5p to promote the ceRNA function of circALG1, and circALG1 could be a potential therapeutic target in and a prognostic marker for CRC.

Abstract Although endocrine therapies targeting estrogen receptor α (ERα) are effective in managing ER positive (+) breast cancer, many patients have primary resistance or develop resistance to endocrine therapies. In addition, ER+ breast cancer with PIK3CA activating mutations and 11q13-14 amplification have poor survival with unclear mechanism. We uncovered that higher expression of deubiquitinase USP35, located in 11q14.1, was associated with ER+ breast cancer and poor survival. Estrogen enhanced USP35 protein levels by downregulating USP35-targeting miRNA-140-3p and miRNA-26a-5p. USP35 promoted the growth of ER+ breast cancer in vitro and in vivo, and reduced the sensitivity of ER+ breast cancer cells to endocrine therapies such as tamoxifen and fulvestrant. Mechanistically, USP35 enhanced ERα stability by interacting and deubiquitinating ERα, and transcriptional activity of ERα by interacting with ERα in DNA regions containing estrogen response element. In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERα transcriptional activity, and the growth of ER+ breast cancer cells. Our data indicate that USP35 and ERα form a positive feedback loop in promoting the growth of ER+ breast cancer. USP35 may be a treatment target for ER+ breast cancer with endocrine resistance or with PIK3CA mutations or hyperactivation of the PI3K pathway.

Hypoxia plays a major role in various tumor types. However, few studies have concentrated on the prognostic model of hypoxia-related genes in rectal cancer and the effect of hypoxia on neutrophil-mediated immunosuppression. We performed Kaplan–Meier analysis, random survival forest analysis, and Cox regression analysis on 342 hypoxia-related genes, constructed hypoxia score in the Gene Expression Omnibus (GEO) cohort, and verified them in the Cancer Genome Atlas (TCGA) cohort. Then the patients were divided into two groups according to the risk level. The overall survival rate of the high-risk (HRisk) group was significantly higher than that of the low-risk (LRisk) group (GEO, p < 0.001; TCGA, p = 0.016). Through receiver operating characteristic and decision curve analysis, the nomogram based on hypoxia score has excellent prediction ability. Functional enrichment analysis showed that hypoxia, metastasis, inflammation, immunity, and other related pathways were enriched. The HRisk group was associated with lower tumor purity, higher immune and stromal score, higher neutrophils, and lower activated memory CD4 + T cells. More importantly, the checkpoint of neutrophil-mediated immunosuppression increased in the HRisk group. In conclusion, a hypoxia score based on 5 hypoxia-related genes can be used to predict the prognosis of rectal cancer and ANLN with a cancer-suppressing effect and SRPX (Sushi Repeat Containing Protein X-Linked) with a cancer-promoting effect may be potential therapeutic targets for rectal cancer.

BackgroundFerroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function.MethodsRNA-seq data and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database, and a list of ferroptosis-related genes was extracted from the FerrDb website. Analysis of differentially expressed FRLs was performed using the ‘limma’ package in R software. By implementing coexpression analysis and univariate Cox analysis, we then identified prognostic FRLs. Using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a prognostic model based on 4 FRLs. We evaluated the prognostic power of this model using Kaplan–Meier (K-M) survival curve analysis and receiver operating characteristic (ROC) curve analysis. Moreover, the relationships between the signature and immune landscape, somatic mutation and drug sensitivity were explored. Finally, in vitro experiments were conducted to validate the functions of AP003555.1 and AC000584.1.ResultsA 4-FRL signature was constructed. Two risk groups were classified based on the risk score calculated by this signature. The signature-based risk score exhibited a more powerful capacity for survival prediction than traditional clinicopathological features in colon patients. Additionally, we observed a significant difference in immune cells, such as CD4+ and CD8+ T cells and macrophages, between the two groups. Moreover, the high-risk group exhibited lower IC50 values for certain chemotherapy drugs, such as cisplatin, docetaxel, bleomycin or axitinib. Finally, the in vitro experiments showed that ferroptosis processes were suppressed after AP003555.1 and AC000584.1 knockdown.ConclusionThe proposed 4-FRL signature is a promising biomarker to predict clinical outcomes and therapeutic responses in colon cancer patients.

Chimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in immune competent mouse model. The PDL1-positive mouse mammary tumor cell line 4T1 engineered to express luciferase and human HER2 was used as the target cell line (4T1-Luc-HER2). Anti-HER2 CAR-T cells were generated by transducing mouse spleen T cells with recombinant lentiviruses. ELISA analysis showed that IL-2 and IFN-γ secretion was increased in CAR-T cells co-cultured with the target cells, and the secretion of these two cytokines was increased further with the addition of anti-PD1 antibody. Lactate dehydrogenase assay revealed that CAR-T cells displayed a potent cytotoxicity against the target cells, and the addition of anti-PD1 antibody further enhanced the cytotoxicity. At the effector: target ratio of 16:1, cytotoxicity was 39.8% with CAR-T cells alone, and increased to 49.5% with the addition of anti-PD1 antibody. In immune competent syngeneic mouse model, CAR-T cells were found to be present in tumor stroma, inhibited tumor growth and increased tumor apoptosis significantly. Addition of anti-PD1 antibody further enhanced these anti-tumor activities. Twenty-one days after treatment, tumor weight was reduced by 50.0% and 73.3% in CAR-T group and CAR-T plus anti-PD1 group compared with blank T group. Our results indicate that anti-PD1 antibody can greatly increase the efficacy of anti-HER2 CAR-T against HER2-positive solid tumors.

PURPOSEWe aimed to evaluate the diagnostic accuracy of a combination of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and apparent diffusion coefficient (ADC) values in lesions that manifest with architectural distortion (AD) on mammography.METHODSAll full-field digital mammography (FFDM) images obtained between August 2010 and January 2013 were reviewed retrospectively, and 57 lesions showing AD were included in the study. Two independent radiologists reviewed all mammograms and MRI data and recorded lesion characteristics according to the BI-RADS lexicon. The gold standard was histopathologic results from biopsies or surgical excisions and results of the two-year follow-up. Receiver operating characteristic curve analysis was carried out to define the most effective threshold ADC value to differentiate malignant from benign breast lesions. We investigated the sensitivity and specificity of FFDM, DCE-MRI, FFDM+DCE-MRI, and DCE-MRI+ADC.RESULTSOf the 57 lesions analyzed, 28 were malignant and 29 were benign. The most effective threshold for the normalized ADC (nADC) was 0.61 with 93.1% sensitivity and 75.0% specificity. The sensitivity and specificity of DCE-MRI combined with nADC was 92.9% and 79.3%, respectively. DCE-MRI combined with nADC showed the highest specificity and equal sensitivity compared with other modalities, independent of the presentation of calcification.CONCLUSIONDCE-MRI combined with nADC values was more reliable than mammography in differentiating the nature of disease manifesting as primary AD on mammography.

Abstract Background DLC2, a unique RhoGAP, has been recently identified as a tumor suppressor gene in hepatocellular carcinoma (HCC). However, the expression of DLC2 protein, and its relationship with RhoA in clinical hepatocellular carcinoma have not been studied. The aim of this study was to investigate the DLC2 protein expression and its correlation with expression of RhoA, as well as to evaluate the prognostic value of DLC2 for HCC patients. Methods Western blot and immunohistochemical staining were employed to detect DLC2 protein expression in 128 HCC specimens. The correlation between DLC2 protein expression and clinicopathologic outcome, and prognostic value of DLC2 for HCC patients were analyzed. Results HCC tissues revealed significantly lower level of DLC2 protein than pericarcinomatous liver tissues (PCLT). There was significant correlation between underexpression of DLC2 protein and cell differentiation. Meanwhile, underexpression of DLC2 protein was correlated with overexression of RhoA. Furthermore, HCC Patients with DLC2-negative expression showed a significantly poorer prognosis than those with DLC2-positve expression. Conclusion Our data strongly suggested that decreased DLC2 expression in HCC correlates with cell differentiation of HCC and overexpression of RhoA, underexpression of DLC2 is associated with poor prognosis in HCC patients.

Gastric cancer is a malignant disease of the digestive system with high rates of incidence and mortality. S-phase kinase-associated protein 2 (Skp2) is a novel oncogene, which has been identified to be important in tumor progression and metastasis. In order to clarify the role of Skp2 in human gastric cancer, the present study detected the expression of Skp2 in human gastric cancer tissues, and investigated the molecular mechanism of Skp2 in the progression of gastric carcinoma. The results of the initial bioinformatics analysis showed that Skp2 was significantly upregulated in 31 specimens of primary gastric cancer from a UK patient cohort, and in 10 gastric cancer lines of a side population, compared with normal gastric tissues (P<0.01). Specimens from 47 patients with gastric cancer and 19 normal gastric tissue specimens were obtained and analyzed using western blot analysis. The positive rate of expression of Skp2 was 87.2%, indicating that the expression of Skp2 was observed in 41 specimens of the detected gastric cancer samples, whereas the positive rate of the expression of Skp2 was 5.6% in the normal gastric samples (P<0.01). In the human gastric cancer cell lines, the defective regulation of Skp2 or presence of an Skp2 inhibitor inhibited the proliferation of BGC-823 and MKN-45 cells. In addition, the Skp2 inhibitor suppressed the proliferation of gastric cancer cells in a time- and dose-dependent manner. Furthermore, transfection with Skp2 short hairpin (sh)RNA or treatment with SKP inhibitor C1 for 48 and 72 h led to the accumulation of p27kip1 in Hela cells. Tumorigenicity experiments involving nude mice showed that interference of the expression of Skp2 inhibited the growth of the human gastric tumor cells in the nude mice, and the tumor weights and volumes in the Skp2 shRNA group were significantly lower, compared with those in the negative control shRNA group (P<0.01) and untreated group (P<0.01). Taken together, these data suggested that Skp2 acted as an oncogene in human gastric cancer, and that Skp2-mediated p27kip1 degradation contributed to the progression of gastric cancer. Abrogating the effects of Skp2 may effectively inhibit the growth of gastric cancer cells, which may be useful as a novel target in the clinical treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Both mucinous cystadenoma of the appendix and intestinal schistosomiasis are rare lesions. We report a rare case of simultaneous giant mucinous cystadenoma of the appendix and intestinal schistosomiasis. A 64-year-old man from China presented with a one-year history of pain in the right lower quadrant of the abdomen. There were no other pertinent historical findings, other than schistosomiasis. Imaging showed a large, tubular, mesenteric cystic structure extending downwards from the inferior wall of the cecum. Right hemicolectomy was performed for the appendiceal tumor. The final pathological diagnosis was mucinous cystadenoma with calcified Schistosome eggs within the mucosa and submucosa of the appendix, small intestine, colon, and lymph nodes. We deduced that the pathogenesis of appendiceal mucinous cystadenoma in our case was Schistosome eggs causing luminal obstruction, finally resulting in intraluminal accumulation of mucoid material. Postoperatively, the patient recovered well. [ABSTRACT FROM AUTHOR]

We describe CT features of our three cases with localized Castleman disease in the retroperitoneum and review literature. Besides those CT features, which have been reported before, we mainly present some newly discovered CT findings of the disease. These new CT findings include the sign of peripheral ‘rim-like’ enhancement at the early phase of an enhanced CT scan, a higher ratio of the left sided retroperitoneal location to the right side and the presence of local peritoneal thickening around the lesion. In addition, the feeding artery of the lesion is more visually pronounced than ever before by a 16-detector CT scanner. After reviewing the literature and comparing with their histological findings, we suggest these newly discovered findings are relatively characteristic CT features of the disease. Moreover, multi-detector helical CT can now show more details of the disease than ever before. [ABSTRACT FROM AUTHOR]

We report CT features of four cases of Eosinophilic enteritis. The disease involves the jejunum in one case, the ileum in two cases, and the colon in the remaining case. Two cases demonstrate a predominantly mucosal type of eosinophilic enteritis, while the other two cases demonstrate a predominantly subserosal type. CT findings include bowel wall thickening in four cases, bowel fold thickening in two cases, layering of the bowel wall in two cases, luminal narrowing without obstruction in three cases, an intra-luminal granuloma mimicking a huge polyp in one case, an extra-luminal irregular granuloma markedly enhancing and slightly necrosing in one case, mesenteric lymphadenopathy with peripheral rim-like enhancement and marked necrosis in one case and ascites in one case. CT findings are more characteristic of an inflammatory disease rather than of a tumor, and these findings are helpful for assessing the extent and location of the disease. Moreover, combined with its typical clinical manifestations, CT findings may lead to the correct diagnosis. [ABSTRACT FROM AUTHOR]

Background: DLC2, a unique RhoGAP, has been recently identified as a tumor suppressor gene in hepatocellular carcinoma (HCC). However, the expression of DLC2 protein, and its relationship with RhoA in clinical hepatocellular carcinoma have not been studied. The aim of this study was to investigate the DLC2 protein expression and its correlation with expression of RhoA, as well as to evaluate the prognostic value of DLC2 for HCC patients. Methods: Western blot and immunohistochemical staining were employed to detect DLC2 protein expression in 128 HCC specimens. The correlation between DLC2 protein expression and clinicopathologic outcome, and prognostic value of DLC2 for HCC patients were analyzed. Results: HCC tissues revealed significantly lower level of DLC2 protein than pericarcinomatous liver tissues (PCLT). There was significant correlation between underexpression of DLC2 protein and cell differentiation. Meanwhile, underexpression of DLC2 protein was correlated with overexression of RhoA. Furthermore, HCC Patients with DLC2-negative expression showed a significantly poorer prognosis than those with DLC2-positve expression. Conclusion: Our data strongly suggested that decreased DLC2 expression in HCC correlates with cell differentiation of HCC and overexpression of RhoA, underexpression of DLC2 is associated with poor prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

Gastric cancer is a malignant disease of the digestive system with high rates of incidence and mortality. S-phase kinase-associated protein 2 (Skp2) is a novel oncogene, which has been identified to be important in tumor progression and metastasis. In order to clarify the role of Skp2 in human gastric cancer, the present study detected the expression of Skp2 in human gastric cancer tissues, and investigated the molecular mechanism of Skp2 in the progression of gastric carcinoma. The results of the initial bioinformatics analysis showed that Skp2 was significantly upregulated in 31 specimens of primary gastric cancer from a UK patient cohort, and in 10 gastric cancer lines of a side population, compared with normal gastric tissues (P<0.01). Specimens from 47 patients with gastric cancer and 19 normal gastric tissue specimens were obtained and analyzed using western blot analysis. The positive rate of expression of Skp2 was 87.2%, indicating that the expression of Skp2 was observed in 41 specimens of the detected gastric cancer samples, whereas the positive rate of the expression of Skp2 was 5.6% in the normal gastric samples (P<0.01). In the human gastric cancer cell lines, the defective regulation of Skp2 or presence of an Skp2 inhibitor inhibited the proliferation of BGC-823 and MKN-45 cells. In addition, the Skp2 inhibitor suppressed the proliferation of gastric cancer cells in a time- and dose-dependent manner. Furthermore, transfection with Skp2 short hairpin (sh)RNA or treatment with SKP inhibitor C1 for 48 and 72 h led to the accumulation of p27kip1 in Hela cells. Tumorigenicity experiments involving nude mice showed that interference of the expression of Skp2 inhibited the growth of the human gastric tumor cells in the nude mice, and the tumor weights and volumes in the Skp2 shRNA group were significantly lower, compared with those in the negative control shRNA group (P<0.01) and untreated group (P<0.01). Taken together, these data suggested that Skp2 acted as an oncogene in human gastric cancer, and that Skp2-mediated p27kip1 degradation contributed to the progression of gastric cancer. Abrogating the effects of Skp2 may effectively inhibit the growth of gastric cancer cells, which may be useful as a novel target in the clinical treatment of gastric cancer. [ABSTRACT FROM AUTHOR]