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There are unmet clinical needs for novel therapeutic targets and drugs for bladder cancer. Majority of previous work relied on limited bladder cancer cell lines, which could not well represent the tumor heterogeneity and pathology of this disease. Recently, it has been shown that cancer organoids can recapitulate pathological and molecular properties of bladder cancer. Here, we report, by our knowledge, the first bladder cancer organoid-based small molecule screening for epigenetic drugs. We found that SRT1720, a Sirtuin 1 (SIRT1) activator, significantly inhibits the growth of both mouse and human bladder cancer organoids. And it also restrains the development of mouse in situ bladder cancer and human PDX bladder cancer. Mutation of Sirt1 promotes the growth of cancer organoids and decreases their sensitivity to SRT1720, which validate Sirt1 as the target of SRT1720 in bladder cancer. Mechanistically, SRT1720 treatment represses the hypoxia pathway through deacetylating HIF1α by activating Sirt1. Genetic or pharmaceutic inhibitions of HIF mimic the anti-tumor effect of SRT1720. Furthermore, the SIRT1-repressed gene signature is associated with the hypoxia target gene signature and poor prognosis in human bladder cancers. Thus, our study demonstrates the power of cancer organoid-based drug discovery and, in principle, identifies SRT1720 as a new treatment for bladder cancer.

Psychological stress may be linked to cancer incidence; however, more direct evidence is required to support this viewpoint. In this study, we investigated the effects of stress on immunosurveillance against cancer cells using a previously established examination stress model. We showed that the cancer killing activity (CKA) of granulocytes (also known as polymorphic nuclear cells, PMNs) is sharply reduced during examination stress stimulation in some donors who are psychologically sensitive to examination stress, with the concentration of plasma stress hormones (cortisone, epinephrine, and norepinephrine) increasing accordingly. The effects of stress hormones on immune cell CKA were also investigated under two in vitro co-incubation conditions, with all three hormones found to exert inhibitory effects on the CKA of PMNs and mononuclear cells. We showed that stress triggered the release of stress hormones which had profound inhibitory effects on the innate anticancer functions of PMNs. These results provide a possible explanation for the relationship between psychological stress and cancer incidence.

Background Gallbladder cancer (GBC) is the most malignant cancer occurring in the biliary tract cancer featured with undesirable prognosis, in which most patients die within a year of cholecystectomy. Long noncoding RNAs (lncRNAs) function as critical regulators of multiple stages of cancers. Herein, the mechanism of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in GBC is investigated. Methods Microarray-based analysis initially provided data suggesting that the expression of MALAT1 was up-regulated while that of the ABI family member 3 binding protein (ABI3BP) was down-regulated in GBC tissues and cell lines. Kaplan-Meier method was then adopted to analyze the relationship between the MALAT1 expression and overall survival and disease-free survival of patients with GBC. A set of in vitro and in vivo experiments were conducted by transducing ABI3BP-vector or sh-MALAT1 into GBC cells. Results The results confirmed that the cancer prevention effects triggered by restored ABI3BP and depleted MALAT1 as evidenced by suppressed cell growth and enhanced cell senescence. MALAT1 was observed to down-regulate ABI3BP expression through recruitment of the enhancer of zeste homolog 2 (EZH2) to the ABI3BP promoter region while the silencing of MALAT1 or suppression of H3K27 methylation was observed to promote the expression of ABI3BP. Furthermore, GBC patients with high expression of MALAT1 indicated poor prognosis. Conclusion The current study clarifies that MALAT1 silencing and ABI3BP elevation impede the GBC development through the H3K27 methylation suppression induced by EZH2, highlighting a promising competitive paradigm for therapeutic approaches of GBC.

Purpose Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a key pathological event in proliferative retinal diseases such as proliferative vitreoretinopathy (PVR). This study aimed to explore a new method to reverse EMT in RPE cells to develop an improved therapy for proliferative retinal diseases. Methods In vitro, human embryonic stem cell-derived RPE cells were passaged and cultured at low density for an extended period of time to establish an EMT model. At different stages of EMT after treatment with known molecules or combinations of molecules, the morphology was examined, transepithelial electrical resistance (TER) was measured, and expression of RPE- and EMT-related genes were examined with RT-PCR, Western blotting, and immunofluorescence. In vivo, a rat model of EMT in RPE cells was established via subretinal injection of dispase. Retinal function was examined by electroretinography (ERG), and retinal morphology was examined. Results EMT of RPE cells was effectively induced by prolonged low-density culture. After EMT occurred, only the combination of the Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor Y27632 and the TGF-β receptor inhibitor RepSox (RY treatment) effectively suppressed and reversed the EMT process, even in cells in an intermediate state of EMT. In dispase-treated Sprague-Dawley rats, RY treatment maintained the morphology of RPE cells and the retina and preserved retinal function. Conclusions RY treatment might promote mesenchymal-epithelial transition (MET), the inverse process of EMT, to maintain the epithelial-like morphology and function of RPE cells. This combined RY therapy could be a new strategy for treating proliferative retinal diseases, especially those involving EMT of RPE cells.

Background: Gastric cardia cancer (GCC) arises in the area of the stomach adjoining the esophageal–gastric junction and has unique risk factors. It was suggested that the involvement of Helicobacter pylori is associated with GCC from high-risk population. Myeloid differentiation factor 88 (MyD88) is a crucial adaptor molecule in Toll-like signaling pathway recognizing H. pylori. Its role in GCC has not been elucidated yet. In this study, our purpose is to investigate the expression and significance of MyD88 in GCC tissue. Methods: Expression of MyD88 and nuclear factor κB (NF-κB) p105/p50 and infection of H. pylori were detected by immunohistochemistry in gastric cardia tissue. The correlation of MyD88 expression to NF-κB p105/p50 expression, H. pylori infection, and clinicopathologic characteristics in gastric cardia tissue was analyzed. The involvement of MyD88 in patient prognosis was also analyzed. Results: Our data showed that the expression of MyD88 elevated from normal mucosa to inflammation (p = 0.071). The expression of MyD88 was enhanced in GCC tissues by contrast to non-malignant cardia mucosa (p = 0.025). What's more, overexpression of MyD88 was detected in intestinal-type adenocarcinoma with inflammation. Patients with high MyD88 staining revealed a better differentiation (p = 0.02). MyD88 also positively correlated with NF-κB p105/p50 expression (p = 0.012) in cancer tissue. Expression of MyD88 was increased but not significantly in biopsies with H. pylori infection compared with non-infected biopsies. Multivariate analyses revealed lymph node metastasis but not MyD88 expression was an independent predictor for patient survival. Conclusion: These findings provide pathological evidence that upregulating MyD88 and inducing inflammation might be involved in gastric cardia carcinogenesis in high-risk population. MyD88 plays a role in gastric cardia carcinogenesis with NF-κB pathway activation. Higher MyD88 expression is not a major prognostic determinant in GCC, but it may relate to the tumor cell differentiation.

Modulating the surface properties of nanoparticles (NPs) is an important approach to accomplish immune escape, prolonged the blood retention time, and enhance the ability of targeted drug delivery. The camouflage of cancer cell membrane onto nanoparticles has been proved to be an ideal approach to enhance active targeting ability of NPs. Herein, we isolated the membrane of melanoma cells to coat doxorubicin (DOX) and indocyanine green (ICG)-loaded hollow copper sulfide NPs (ID-HCuSNP@B16F10) for targeted photothermal therapy, photoacoustic imaging, and chemotherapy. A remarkable in vitro anticancer effect after irradiation and homologous targeting can be observed in B16F10 cells after the treatment of ID-HCuSNP@B16F10. Moreover, ID-HCuSNP@B16F10 exhibits excellent photothermal effect in melanoma animal models and achieves a high tumor ablation rate. This biomimetic system can realize high drug loading efficiency, enhanced targeting ability, and ideal antitumor efficiency.

Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery. Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors. Among them, menin-MLL inhibitors MI-136 and MI-463 scored. The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo. CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136. Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment. Consistently, Men1, Kmt2a, and Ash2l knockout also repressed the expressions of the HIF target genes. Loss of Hif1a or Hif1b partially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth. Further, we found that MEN1 was upregulated in human endometrial cancers, which were tightly correlated with the expression levels of HIF1A, and associated with poor prognosis. Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients. Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer.

BACKGROUND: The influence of pretreatment anemia on the prognosis of patients with advanced gastric cancer (GC) remains controversial. We retrospectively examined the impact of pretreatment anemia on the overall survival (OS) of patients with GC with nonhypoalbuminemia undergoing curative resection. METHODS: The clinicopathological data of 2,916 patients with advanced GC who received a radical gastrectomy from 1994 to 2015 were analyzed. The patients were divided into two subgroups by hemoglobin level

Significance It remains formidable to predict what unreported RNA pairs can form new fusion transcripts. By systematic mapping of chromatin-associated RNAs and their respective genomic interaction loci, we obtained genome-wide RNA–DNA interaction maps from two noncancerous cell types. The gene pairs involved in RNA–DNA interactions in these normal cells exhibited strong overlap with those with cancer-derived fusion transcripts. These data suggest an RNA-poise model, where the spatial proximity of one gene’s transcripts and the other gene’s genomic sequence poises for the creation of fusion transcripts. We validated this model with 96 additional lung cancer samples. One of these additional samples exhibited fusion transcripts without a corresponding fusion gene, suggesting that genome recombination is not a required step of the RNA-poise model., Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common features have been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA–DNA interactions mapped in two normal, noncancerous cell types [using iMARGI, an enhanced version of the mapping of RNA–genome interactions (MARGI) assay]. Among the top 10 most significant RNA–DNA interactions in normal cells, 5 colocalized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA–DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA–DNA interactions in normal cells are predictive of fusion RNAs, we analyzed these in a validation cohort of 96 lung cancer samples using RNA sequencing (RNA-seq). Thirty-seven of 42 fusion transcripts in the validation cohort were found to exhibit RNA–DNA interactions in normal cells. Finally, by combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene. Collectively, these data suggest an RNA-poise model, where spatial proximity of RNA and DNA could poise for the creation of fusion transcripts.

Background: Dry eye patients suffer from all kinds of symptoms. Sometimes, the clinical signs evaluation does not disclose any obvious difference in routine examination; in vivo confocal microscopy (IVCM) is a powerful tool for ocular surface disease. This study aimed to clarify meibomian gland (MG) alterations in dry eye patients with different symptoms and to compare the findings using IVCM. Methods: A total of sixty patients were recruited, all subjected to Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ), and questionnaires for the assessment of dry eye symptoms before clinical sign examinations were given to the patients. Finally, IVCM was applied to observe MG's structure. Statistical analysis was performed using the t-test, Mann-Whitney U-test and Spearman correlation analysis. The differences were statistically significant when P < 0.05. Results: In the severe symptom group, OSDI and SEEQ scores were significantly higher (P < 0.05) compared with the mild symptoms group. All other clinical sign examinations had no statistical difference in the two groups (P > 0.05). However, all the IVCM-observed data showed that patients with severe symptoms had more significant fibrosis in MG (acinar unit area 691.87 ± 182.01 μm2 for the severe, 992.17 ± 170.84 μm2 for the mild; P < 0.05) and severer decrease in the size of MG acinar units than those observed in patients with mild symptoms (MG acinar unit density [MGAUD] 70.08 ± 18.78 glands/mm2, MG acinar unit longest diameter [MGALD] 51.50 ± 15.51 μm, MG acinar unit shortest diameter [MGASD] 20.30 ± 11.85 μm for the severe, MGAUD 89.53 ± 39.88 glands/mm2, MGALD 81.57 ± 21.14 μm, MGASD 42.37 ± 14.55 μm for the mild; P < 0.05). Dry eye symptoms were negatively correlated with MG confocal microscopic parameters and positively correlated with conjunctival inflammatory cells and Langerhans cells (P < 0.05). Conclusions: IVCM application provides a strong support to differentiate dry eye patients with different symptoms: meibomian gland dysfunction (MGD) plays a pivotal role in dry eye aggravation, and using IVCM to observe MG fibrosis, changes in size and density of MG as well as status of inflammation cells can help not only correctly diagnose the type and severity of dry eye, but also possibly prognosticate in routine eye examination in the occurrence of MGD.

Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common features have been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA-DNA interactions mapped in two normal, non-cancerous cell types (using iMARGI, an enhanced version of the MARGI [Mapping RNA-Genome Interactions assay]). Among the top 10 most significant RNA-DNA interactions in normal cells, 5 co-localized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA-DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA-DNA interactions in normal cells are predictive of fusion RNAs, we analyzed these in a validation cohort of 96 lung cancer samples using RNA-seq. 37 out of 42 fusion transcripts in the validation cohort were found to exhibit RNA-DNA interactions in normal cells. Finally, by combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene. Collectively, these data suggest a novel RNA-poise model, where spatial proximity of RNA and DNA could poise for the creation of fusion transcripts.

The incidence of gastric cardia cancer (GCC) is high in China. However, the clinicopathological characteristics and the carcinogenesis of GCC are unclear. Toll-like receptor 4 (TLR4) is an important innate immunity receptor and has a role in non-GCC (NGCC). We compared the clinicopathological characteristics of GCC patients from a high-risk area in China to esophageal cancer (EC) patients. Immunohistochemistry for TLR4 was performed in 201 histological samples of normal gastric cardia mucosa (n=11), gastric cardia inflammation (n=87), and GCC (n=103). We included 84 patients with EC and 99 with GCC. GCC tissue was more poorly differentiated than EC tissue and more invasive, with more histomorphologic variation. Lymph node metastasis was more frequent in GCC than in EC. TheHelicobacter pyloriinfection rate was higher but not significantly with GCC than EC. Survival was shorter with lymph node metastasis. We found a statistically significant trend for progressive increase of TLR4 expression from normal mucosa to inflammation in GCC. GCC in this high-risk area displays clinicopathologic characteristics different from those of EC and different from those of gastroesophageal junction carcinomas in other countries, although this was not analyzed statistically. Increased TLR4 expression in gastric cardia lesions may be associated with GCC tumorigenesis.

Descemet’s membrane (DM) helps maintain phenotype and function of corneal endothelial cells under physiological conditions, while little is known about the function of DM in corneal endothelial wound healing process. In the current study, we performed in vivo rabbit corneal endothelial cell (CEC) injury via CEC scraping, in which DM remained intact after CECs removal, or via DM stripping, in which DM was removed together with CECs. We found rabbit corneas in the CEC scraping group healed with transparency restoration, while there was posterior fibrosis tissue formation in the corneas after DM stripping on day 14. Following CEC scraping on day 3, cells that had migrated toward the central cornea underwent a transient fibrotic endothelial-mesenchymal transition (EMT) which was reversed back to an endothelial phenotype on day 14. However, in the corneas injured via DM stripping, most of the cells in the posterior fibrosis tissue did not originate from the corneal endothelium, and they maintained fibroblastic phenotype on day 14. We concluded that corneal endothelial wound healing in rabbits has different outcomes depending upon the presence or absence of Descemet’s membrane. Descemet’s membrane supports corneal endothelial cell regeneration in rabbits after endothelial injury.

Background: Poly(ADP-ribose) polymerase 1 (PARP1) plays an important role in the process of homologous recombination (HR) repair. The aim of this study was to observe the impact of olaparib (PARP1 inhibitor) on oxaliplatin treatment for XRCC2-defecient colorectal cancer (CRC). Methods: This study examined the influence of treatments on cells with the help of the γ-H2AX foci formation assay. The CCK-8 assay and clonogenic assay were employed to decide the sensitivity of XRCC2-defecient CRC cells to olaparib and/or oxaliplatin. Finally, we investigated the changes in cell cycle and apoptosis with the aid of flow cytometry and western blotting. Results: Gamma-H2AX focusing analysis has reached the conclusion that Olaparab is not the only factor inducing double-strand breaks (DSBs), but it can affect oxaliplatin-induced DSBs of XRCC2-defatted CRC cells. Cell proliferation of XRCC2-defecient CRC cell lines was restrained by combination treatment rather than olaparib or oxaliplatin alone. The flow cytometry and western blotting results gave the description cells exposed to connection treatment had more G2/M-phase cells and induced apoptosis than control. Conclusions: The combination of oxaliplatin and oxaliplatin in the treatment of XRCC2-defecient CRC cells provides a promising method for clinical treatment of XRCC2-defecient CRC.

Metastatic pancreatic tumor is relatively rare in clinic, accounting for only 2–5% of pancreatic cancer. About 50% of metastatic pancreatic tumor are caused by renal cell carcinoma. The symptoms of the tumor have no specificity but strong concealment. Most patients show no difference from ordinary population before the disease worsens. A small number of patients may have abdominal distention and pain, poor appetite, etc. Besides, there may be obstructive jaundice when the tumor blocks the common bile duct, and it can cause pancreatitis in the case of pancreatic duct obstruction. The case to be reported was asymptomatic and a mass of the head of the pancreas was found on examination. The diagnosis of this case depends mainly on ultrasound puncture to obtain pathological results, and CT can exert auxiliary effect during diagnosis. In addition, surgical resection is an effective means to treat this disease, and targeted therapy can be accepted as an alternative therapeutic approach.