crossing96/oncoscreening huggingface dataset:
High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery.	Esophageal adenocarcinoma (EAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies, contributing to poor outcomes for patients. We describe the application of a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six EAC cell lines and two tissue-matched control lines. We built an automated high-content image analysis pipeline to identify compounds that selectively modified the phenotype of EAC cell lines. We further trained a machine-learning model to predict the mechanism of action of EAC selective compounds using phenotypic fingerprints from a library of reference compounds. We identified a number of phenotypic clusters enriched with similar pharmacological classes, including methotrexate and three other antimetabolites that are highly selective for EAC cell lines. We further identify a small number of hits from our diverse chemical library that show potent and selective activity for EAC cell lines and that do not cluster with the reference library of compounds, indicating they may be selectively targeting novel esophageal cancer biology. Overall, our results demonstrate that our EAC phenotypic screening platform can identify existing pharmacologic classes and novel compounds with selective activity for EAC cell phenotypes.	esophagus
Transdiaphragmatic herniation after transthoracic esophagectomy: an underestimated problem.	Diaphragmatic transposition of intestinal organs is a major complication after esophagectomy and can be associated with significant morbidity and mortality. This study aims of to analyze a large series of patients with this condition in a single high-volume center for esophageal surgery and to suggest a novel treatment algorithm. Patients who received surgery for postesophagectomy diaphragmatic herniation between October 2003 and December 2017 were included. Retrospective analysis of demographic, clinical and surgical data was performed. Outcomes of measure were initial clinical presentation, postoperative complications, in-hospital mortality and herniation recurrence. A total of 39 patients who had surgery for postesophagectomy diaphragmatic herniation were identified. Diaphragmatic herniation occurred after a median time of 259 days following esophagectomy with the highest prevalence between 1 and 12 months. A total of 84.6% of the patients had neoadjuvant radiochemotherapy prior to esophagectomy. The predominantly effected organ was the transverse colon (87.2%) prolapsing into the left hemithorax (81.6%). A total of 20 patients required emergency surgery. Surgery always consisted of reposition of the intestinal organs and closure of the hiatal orifice; a laparoscopic approach was used in 25.6%. Major complications (Dindo-Clavien ≥ IIIb) were observed in 35.9%, hospital mortality rate was 7.7%. Three patients developed recurrent diaphragmatic herniation during follow-up. Postesophagectomy diaphragmatic herniation is a functional complication of the late postoperative course and predominantly occurs in patients with locally advanced adenocarcinoma having chemoradiation before Ivor-Lewis esophagectomy. Due to a high rate of emergency surgery with life-threatening complications not a 'wait-and-see' strategy but early surgical repair may be indicated.	esophagus
Epigenetic Alterations in Oesophageal Cancer: Expression and Role of the Involved Enzymes.	Oesophageal cancer is a life-threatening disease, accounting for high mortality rates. The poor prognosis of this malignancy is mostly due to late diagnosis and lack of effective therapies for advanced disease. Epigenetic alterations may constitute novel and attractive therapeutic targets, owing to their ubiquity in cancer and their reversible nature. Herein, we offer an overview of the most important studies which compared differences in expression of enzymes that mediate epigenetic alterations between oesophageal cancer and normal mucosa, as well as in vitro data addressing the role of these genes/proteins in oesophageal cancer. Furthermore, The Cancer Genome Atlas database was interrogated for the correlation between expression of these epigenetic markers and standard clinicopathological features. We concluded that most epigenetic players studied thus far are overexpressed in tumours compared to normal tissue. Furthermore, functional assays suggest an oncogenic role for most of those enzymes, supporting their potential as therapeutic targets in oesophageal cancer.	esophagus
LINC00657/miR-26a-5p/CKS2 ceRNA network promotes the growth of esophageal cancer cells via the MDM2/p53/Bcl2/Bax pathway.	LncRNA LINC00657 has oncogenic or anti-carcinoma roles in different cancers, and yet its detailed molecular mechanism in esophageal cancer (EC) remains unclear. In addition, competitive endogenous RNA (ceRNA) regulatory lncRNA-miRNA-mRNA networks are critical for tumorigenesis and progression. Hence, the present study explored the roles of LINC00657 in EC and identified its relevant ceRNA network. We first detected the expression of LINC00657 in EC. Then, we applied starBase and TargetScan websites to find miR-26a-5p binding to LINC00657 and obtain CKS2 as a target of miR-26a-5p. The roles of LINC00657, miR-26a-5p or CKS2 in the proliferation, migration, invasion, and apoptosis of EC cells were respectively assessed by CCK-8, wound healing assay, transwell invasion assay, and flow cytometry. The changes of the MDM2/p53/Bcl2/Bax pathway were measured via Western blot. The results revealed that LINC00657 showed an aberrant high expression in EC cells, which promoted the growth of EC cells. Additionally, LINC00657 functioned as a sponge of miR-26a-5p, and LINC00657 negatively mediated miR-26a-5p to regulate the growth of EC cells. Furthermore, CKS2 was observed as a direct target of miR-26a-5p, and CKS2 controlled the growth of EC cells via the MDM2/p53/Bcl2/Bax pathway. Moreover, there was a positive correlation between LINC00657 and CKS2. LINC00657 knockdown inhibited CKS2 expression to suppress the proliferation, migration, and invasion of EC cells and induced apoptosis via regulating the MDM2/p53/Bcl2/Bax pathway. Collectively, LINC00657/miR-26a-5p/CKS2 ceRNA network could promote the progression of EC, which is good for understanding the molecular mechanism of EC and offers novel biomarkers for EC diagnosis and therapy.	esophagus
MiR-27b-3p exerts tumor suppressor effects in esophageal squamous cell carcinoma by targeting Nrf2.	MiR-27b-3p has been reported to function as tumor suppressor in several tumors, including breast cancer and lung cancer. Recently, miR-27b-3p has been identified to be significantly down-regulated in esophageal cancer. However, the clinical significance and biological role of miR-27b-3p in esophageal squamous cell carcinoma (ESCC) still remain unclear. In this study, the expression levels of miR-27b-3p were significantly reduced in ESCC clinical tissues and ESCC cell lines (EC97069 and TE-1). Moreover, down-regulated expression of miR-27b-3p was associated with poor cell differentiation, TNM stage and lymph node metastasis. Specially, overexpression of miR-27b-3p significantly suppressed cell proliferation, migration and invasion in vitro using CCK-8 and transwell assays. Targetscan bioinformatics predictions and luciferase reporter assay confirmed that nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) was a direct target gene of miR-27b-3p. Nrf2 expression was significantly increased in ESCC tissues compared with adjacent tissues. Up-regulated expression of Nrf2 was correlated with TNM stage and lymph node metastasis. Functionally, knockdown of Nrf2 exhibited similar effects to overexpression of miR-27b-3p. Higher expression of ZO-1, E-cadherin and lower expression of N-cadherin, Vimentin and Claudin-1 were observed after miR-27b-3p overexpression of Nrf2 knockdown. Rescue experiments proved that miR-27b-3p suppressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT) via suppression of Nrf2. Taken together, the newly identified miR-27b-3p/Nrf2 axis might represent a new candidate therapeutic target for ESCC treatment.	esophagus
TBRG4 silencing promotes progression of squamous cell carcinoma via regulation of CAV-1 expression and ROS formation.	Esophageal cancer is the eighth most common cancer globally. Transforming growth factor β regulator 4 (TBRG4) and caveolin-1 (CAV-1) are implicated in tumor progression. The aim of this study was to investigate the expressions of TBRG4 and CAV-1 in esophageal squamous cell carcinoma (ESCC), and their relationship with reactive oxygen species (ROS) formation. Human ESCC cell lines (EC9706, TE-1, and Eca109), and normal esophageal mucosal cell line (Het-1) were used in this study. The silencing of TBRG4 and/or CAV-1 by sh-RNA or overexpression of CAV-1 after TBRG4 knockdown was used to assess ROS levels. The results showed that down-regulation of TBRG4 reduced CAV-1 expression, and promoted ROS formation in ESCCs (p &lt; 0.01). However, CAV-1 overexpression increased the expression level of TBRG4, but decreased ROS level in EC9706 cells (p &lt; 0.01). Similarly, TBRG4 knockdown significantly reduced CAV-1 expression, promoted ROS formation, and caused cell cycle arrest at G0/G1 phase (p &lt; 0.01). Caveolin-1 (CAV-1) knockdown also promoted cell apoptosis, cellular ROS formation and cell cycle arrest at G0/G1 phase (p &lt; 0.01). However, CAV-1 overexpression in sh-TBRG4-treated EC9706 cells significantly upregulated TBRG4 expression, but significantly reduced the level of ROS, and inhibited cell-cycle arrest and apoptosis (p &lt; 0.01). The enhancements in bcl-2/bax ratio, cytochrome c expression, and ROS levels by sh-TBRG4 were significantly reversed by CAV-1 overexpression in EC9706 cells. These results show that the upregulated expression of TBRG4 or CAV-1 promotes ESCC progression via regulation of intracellular ROS levels and inhibition of mitochondria-dependent apoptotic pathway.	esophagus
Risk Factors and Prognostic Impact of Mediastinal Lymph Node Metastases in Patients with Esophagogastric Junction Cancer.	PURPOSE: We retrospectively investigated the risk factors for mediastinal lymph node (MLN) metastasis in esophagogastric junction (EGJ) cancer with an epicenter within 2 cm above and below the anatomical cardia, including both adenocarcinoma (AC) and squamous cell carcinoma (SCC). METHODS: Fifty patients who underwent initial surgery for EGJ cancer from January 2002 to December 2013 were included in this study. We defined metastatic lymph nodes as pathological metastases in resected specimens and recurrence within 2 years postoperatively. RESULTS: Thirty-four patients had AC and 16 had SCC; 24 patients underwent transhiatal resection and 26 underwent transthoracic resection. MLN metastasis was observed in 13 patients (26%) regardless of the histological type, 9 of whom had metastasis in the upper and middle mediastinum. Metastasis occurred when the esophageal invasion length (EIL) exceeded 20 mm. In addition, 10/13 patients had stage pN2-3 cancer. Multivariable analysis identified EIL ≥ 20 mm and stage pN2-3 as significant risk factors for MLN metastasis. The 5-year overall survival was 38% and 65% in the MLN-positive and -negative groups, respectively (p = 0.12). Multivariable Cox regression analysis showed that only stage pN2-3, and not the presence of MLN metastasis, was a significantly poor prognostic factor. CONCLUSION: MLN metastasis in EGJ cancer may have a close association with the EIL of the tumor, but the presence of MLN metastasis itself was not a poor prognostic factor. The significance and indications for MLN dissection should be clarified in prospective clinical trials.	esophagus
Rehabilitation strategies following oesophagogastric and Hepatopancreaticobiliary cancer (ReStOre II): a protocol for a randomized controlled trial.	BACKGROUND: Curative treatment for upper gastrointestinal (UGI) and hepatopancreaticobiliary (HPB) cancers, involves complex surgical resection often in combination with neoadjuvant/adjuvant chemo/chemoradiotherapy. With advancing survival rates, there is an emergent cohort of UGI and HPB cancer survivors with physical and nutritional deficits, resultant from both the cancer and its treatments. Therefore, rehabilitation to counteract these impairments is required to maximise health related quality of life (HRQOL) in survivorship. The initial feasibility of a multidisciplinary rehabilitation programme for UGI survivors was established in the Rehabilitation Strategies following Oesophago-gastric Cancer (ReStOre) feasibility study and pilot randomised controlled trial (RCT). ReStOre II will now further investigate the efficacy of that programme as it applies to a wider cohort of UGI and HPB cancer survivors, namely survivors of cancer of the oesophagus, stomach, pancreas, and liver. METHODS: The ReStOre II RCT will compare a 12-week multidisciplinary rehabilitation programme of supervised and self-managed exercise, dietary counselling, and education to standard survivorship care in a cohort of UGI and HPB cancer survivors who are > 3-months post-oesophagectomy/ gastrectomy/ pancreaticoduodenectomy, or major liver resection. One hundred twenty participants (60 per study arm) will be recruited to establish a mean increase in the primary outcome (cardiorespiratory fitness) of 3.5 ml/min/kg with 90% power, 5% significance allowing for 20% drop out. Study outcomes of physical function, body composition, nutritional status, HRQOL, and fatigue will be measured at baseline (T0), post-intervention (T1), and 3-months follow-up (T2). At 1-year follow-up (T3), HRQOL alone will be measured. The impact of ReStOre II on well-being will be examined qualitatively with focus groups/interviews (T1, T2). Bio-samples will be collected from T0-T2 to establish a national UGI and HPB cancer survivorship biobank. The cost effectiveness of ReStOre II will also be analysed. DISCUSSION: This RCT will investigate the efficacy of a 12-week multidisciplinary rehabilitation programme for survivors of UGI and HPB cancer compared to standard survivorship care. If effective, ReStOre II will provide an exemplar model of rehabilitation for UGI and HPB cancer survivors. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov, registration number: NCT03958019, date registered: 21/05/2019.	esophagus
Tumor volume regression during neoadjuvant chemoradiotherapy for esophageal cancer: a prospective study with weekly MRI.	Background: Neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer causes tumor regression during treatment. Tumor regression can induce changes in the thoracic anatomy, with smaller target volumes and displacement of organs at risk (OARs) surrounding the tumor as a result. Adaptation of the radiotherapy treatment plan according to volumetric changes during treatment might reduce radiation dose to the OARs, while maintaining adequate target coverage. Data on the magnitude of the volumetric changes and its impact on the thoracic anatomy is scarce. The aim of this study was to assess the volumetric changes in the primary tumor during nCRT for esophageal cancer based on weekly MRI scans.Material and methods: In this prospective study, patients with adeno- or squamous cell carcinoma of the esophagus treated with neoajduvant chemoradiotherapy according to the CROSS regimen (carboplatin + paclitaxel + 23 × 1.8 Gy) were included. Of each patient, six sequential MRI scans were acquired: one prior to nCRT, and five in each subsequent week during nCRT. Tumor volumes were delineated on the transversal T2 weighted images by two radiation oncologists. Volumetric changes were analyzed using linear mixed effects models.Results: A total of 170 MRI scans from 29 individual patients were included. The mean (± standard deviation (SD)) tumor volume at baseline was 45 cm(3) (± 23). Tumor volume regression started after the first week of nCRT with a significant decrease in tumor volumes every subsequent week. A decrease to 42 cm(3) (91% of initial volume), 38 cm(3) (81%), 35 cm(3) (77%), and 32 cm(3) (72%) was observed in the second, third, fourth and fifth week of nCRT, respectively.Conclusion: Based on weekly MRI scanning during nCRT for esophageal cancer, a considerable decrease in tumor volume was observed during treatment. Volume regression and consequential anatomical changes suggest the possible benefit of adaptive radiotherapy.	esophagus
Effect of Preoperative Nutritional Risk Screening and Enteral Nutrition Support in Accelerated Recovery after Resection for Esophageal Cancer.	Patients with esophageal cancer are often accompanied by malnutrition, especially in patients with obvious swallowing tract. Many studies have shown that preoperative nutritional support can reduce postoperative complications, but there are few studies comparing preoperative enteral nutrition with intravenous nutrition. The aim of the study was to compare the effects of the two nutritional support path in esophageal cancer patients undergoing surgery. We used the nutritional risk screening 2002 (NRS2002) for preoperative nutritional risk screening in patients with esophageal cancer treated at our department between April 2016 and March 2019. A total of 56 patients with an NRS2002 score ≥ 3 and with apparent difficulty swallowing received preoperative parenteral nutrition (PN; n = 29) or enteral nutrition (EN; n = 27). Both groups received 7 day of nutritional support before surgery. Nutritional indicators were measured on preoperative day 7, preoperative day 1, and postoperative day 7. The baseline characteristics, perioperative condition, nutritional status, and postoperative complications of the two groups were compared and analysed. There was no significant difference in baseline characteristics and perioperative nutrition indicators between two groups. Postoperative hospital stay and the costs of nutrition support were significantly reduced in the EN group compared with PN group (P = 0.000). The times of first passing gas and bowel movement were shorter in the EN group compared with PN group (P = 0.001). The incidence of gastrointestinal complications was lower in the EN group compared with PN group (P = 0.039). For esophageal cancer patients with an NRS2002 score ≥ 3 and apparent difficulty swallowing, preoperative EN with a gastric tube is safe and easy to perform. Preoperative EN can shorten the recovery time of gastrointestinal function, reduce the incidence of gastrointestinal complications, finally accelerate postoperative recovery.	esophagus
Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma.	Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients' outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients' outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.	esophagus
Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells.	BACKGROUND: Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. METHODS: The expression of relevant proteins of NF-κB/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. RESULTS: For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate IκBα to block NF-κB activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. CONCLUSIONS: In our study, we elucidates a novel mechanism of NF-κB/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924). Video abstract.	esophagus
Alpinumisoflavone triggers GSDME-dependent pyroptosis in esophageal squamous cell carcinomas.	Esophageal squamous cell carcinoma (ESCC) presents a common human malignancy in the digestive system. We aimed to explore the critical effects of alpinumisoflavone (AIF) on ESCC in vitro and in vivo. The cell counting kit-8 assay was used to determine cell viability. Colony formation assay was employed to examine the effect of AIF on the long-term growth of ESCC cells. Cell apoptosis was determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Cell morphologies were observed by light microscopy. The enzyme-linked immunosorbent assay was performed to examine the lactate dehydrogenase release from AIF-treated cells. Immunofluorescent labeling was utilized to examine AIF-induced GSDME expression. Western blot was employed to determine the expression levels of the associated proteins. Immunohistochemistry was performed to determine the localization and expression of the associated proteins in mice tumor tissues. AIF inhibited ESCC cell viability and suppressed cell growth in a dose- and time-dependent fashion. Results showed that AIF promoted apoptosis in ESCC cells. Meanwhile, our results also showed that AIF triggered pyroptotic cell death in ESCC, which was mediated by gasdermin E (GSDME) cleavage. In addition, our experiments provided experimental evidence that AIF-induced GSDME cleavage was dependent on caspase-3 activation. Moreover, the inhibition of GSDSE by knockdown was able to switch the form of cell death from pyroptosis to apoptosis. Furthermore, the results from the xenograft animal model also supported our findings in vitro that AIF was able to promote GSDME-mediated pyroptotic cell death in ESCC. AIF inhibited ESCC growth in vitro and in vivo by triggering GSDME-mediated pyroptotic cell death, which is dependent on caspase-3 activation.	esophagus