The optimal treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. Surgery is the primary treatment but with poor results. Attempts to improve patient survival have been made by introducing chemotherapy, radiotherapy, or both. However, randomized comparisons for all these strategies are not always available. This network meta-analysis compared the overall survival of neoadjuvant and adjuvant therapy with surgery alone to identify the most effective approach.

Colorectal cancer (CRC) is one of the most lethal diseases with high morbidity and mortality worldwide. Clinically, tumors located in colon and rectum have diverse prognosis and therapeutic outcome. Here, we performed data mining derived from 20 CRC patient samples to compare proteomic difference between colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ). We found that differential expressed proteins (DEPs) upregulated in COAD were mainly enriched in immune response, moreover, higher immune scores were found in COAD than READ, as calculated by The Cancer Genome Atlas (TCGA) data. To identify the core protein of DEPs with high prognostic value for COAD, we performed topological overlap matrix (TOM) to investigate the hub proteins using 77 immune-relevant DEPs, and identified complement component 3 (C3) as the core protein in the immune-relevant DEPs matrix between the COAD and READ. Moreover, we found that C3 was up-regulated in COAD, and its expression was negatively associated with overall survival of COAD patients but not READ. In conclusion, we identified C3-mediated immune response as key feature to distinguish COAD and READ, and highlighted C3 as potential biomarker with high prognostic value for clinical application, which provided new clue for precise treatment of COAD.

Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.

The status of lymph node (LN) metastases plays a decisive role in the selection of surgical procedures and post-operative treatment. Several histopathologic features, known as predictors of LN metastasis, are commonly available post-operatively. Medical imaging improved pre-operative diagnosis, but the results are not fully satisfactory due to substantial false positives. Thus, a reliable and robust method for pre-operative assessment of LN status is urgently required. We developed a prediction model in a training set from the TCGA-BLCA cohort including 196 bladder urothelial carcinoma samples with confirmed LN metastasis status. Least absolute shrinkage and selection operator (LASSO) regression was harnessed for dimension reduction, feature selection, and LNM signature building. Multivariable logistic regression was used to develop the prognostic model, incorporating the LNM signature, and a genomic mutation of MLL2, and was presented with a LNM nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Internal validation was evaluated by the testing set from the TCGA cohort and independent validation was assessed by two independent cohorts. The LNM signature, which consisted of 48 selected features, was significantly associated with LN status (p < 0.005 for both the training and testing sets of the TCGA cohort). Predictors contained in the individualized prediction nomogram included the LNM signature and MLL2 mutation status. The model demonstrated good discrimination, with an area under the curve (AUC) of 98.7% (85.3% for testing set) and good calibration with p = 0.973 (0.485 for testing set) in the Hosmer-Lemeshow goodness of fit test. Decision curve analysis demonstrated that the LNM nomogram was clinically useful. This study presents a pre-operative nomogram incorporating a LNM signature and a genomic mutation, which can be conveniently utilized to facilitate pre-operative individualized prediction of LN metastasis in patients with bladder urothelial carcinoma.

Gastric cancer has one of the highest mortality rate in the world, but the treatment is still limited. Building on previous studies, mechanistic studies on propranolol in gastric cancer mice models and gastric cancer patients were performed. Propranolol inhibited the in vitro proliferation of gastric cancer cells in a time- and concentration-dependent manner. Consistent findings were observed in MFC tumors engrafted 615 mice, which were treated with propranolol at 10 mg/kg daily for 14 days. Propranolol inhibited the phosphorylation of AKT, MEK, and ERK proteins than control in mice tumor tissues respectively (p-AKT 26.16 vs. 56.82, P = 0.0196, p-MEK 28.27 vs. 59.28, P = 0.1102, p-ERK 48.2 vs. 107.4, P = 0.0062). Propranolol had antiproliferative activity in gastric cancer patients receiving 60 mg daily for 7 days prior to surgery(ki67 44.8 vs 125.3 for placebo; P = 0.02). Phosphorylated AKT, MEK, and ERK did not differ between propranolol and placebo treatment in gastric cancer patients. The expression of molecules on CD8+ T cells was not changed both in mice model and patients nor was there a statistically significant difference in CD8+ T cell subsets in patients, although suggestion of an effect was evident. These results prove that propranolol may inhibit the growth of gastric cancer in mice model and patients and the possible mechanism was via inhibiting the AKT and MAPK pathways, but the frequency of tumor infiltration CD8+ T cells did not increase significantly.

Cancer immunotherapy including adoptive T cell therapy (ACT) is widely used in the clinic and is highly beneficial for patients with hematological malignancies; however, it remains a challenge to develop effective immunotherapy strategies for the treatment of solid cancers, due to the inefficiency of the immune response and the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulate a systemic antigen-specific antitumor immune response, which can effectively subvert the immunosuppressive TME and enhance the efficiency of immune responses, relative to conventional immunotherapeutic regimens. However, the application of traditional inducers of ICD in anti-cancer immunotherapy has been limited because of low levels of ICD induction and a lack of tumor-targeting accumulation. Mitochondria are important for tumor-targeting strategies and have emerged as organelles with key roles in the immune system. We hypothesized that the alteration of mitochondria in cancer cells could be an important target for the development of an efficient ICD inducer for use in cancer immunotherapy. Here, we report the evaluation of a mitochondria-targeted small molecule, IR-780, that acts as an ICD inducer and exhibits exceptional antineoplastic activity. IR-780 specifically accumulated in tumor cells to elicit ICD in vitro and in vivo, effectively suppressed tumor growth and lung metastasis, and enhanced adoptive T-cell therapy effects against solid tumors in mouse models. These anticancer effects were linked to dendritic cell maturation and synergistic effector T cell priming and infiltration into tumors. The underlying mechanism involves the direct targeting of the mitochondria by IR-780, to destroy cancer cells, including drug-resistant cancer cells, leading to the full exposure of tumor-associated antigens (TAAs), thereby enhancing antigen-specific antitumor immune responses. These features of IR-780 suggest that it has the advantage of leading to complete TAA exposure and the stimulation of efficient antitumor immune responses in the TME. IR-780 has potential for use as a preparative ICD inducer, in combination with conventional immunostimulatory regimens for cancer immunotherapy, particularly in the context of solid tumor treatment.

Serum sphingolipids are widely involved in the development of hepatocellular carcinoma (HCC). We investigated the serum sphingolipid profile in patients with HCC or cirrhosis and explored the potential diagnostic efficiency of serum sphingolipid metabolites which may be helpful in differentiating HCC including α-fetoprotein (AFP)-negative HCC from cirrhosis.

The application and promotion of 125I seed implantation technology have increased the safety and effectiveness of the clinical treatment of advanced hepatocellular carcinoma (HCC). Epirubicin (EPI) is a traditional anthracycline chemotherapy agent that has minimal side effects and has been widely used in the clinical treatment of HCC. We hypothesized that EPI would enhance the anti-cancer effects of 125I seeds via the JAK/STAT1 signaling pathway. Thus, we aimed to investigate whether EPI could enhance the radiosensitivity of HCC cells to 125I and determine the underlying molecular mechanism. This basic study was conducted in an animal laboratory at Shandong University. BALB/C male nude mice were used, and all animals were fed and treated according to the standards of the Institutional Animal Care and Use Committee of Shandong University. Both in vitro and in vivo models of 125I irradiation of HCC cells were created. The anti-cancer effects of 125I and the role of EPI in promoting these effects were evaluated using flow cytometry for apoptosis and cell cycle, CCK-8 assay for EPI drug cytotoxicity, and transwell assays for migration and invasion. The potential mediating effect of the JAK/STAT1 pathway was assessed using an isobaric tag for relative and absolute quantitation analysis to identify differentially expressed proteins after 125I treatment. Transfection of HCC cells with STAT1-RNAi were performed to determine the effect of STAT1 downregulation on 125I and EPI treatment effects. The radiosensitivity concentration of EPI promoted 125I-induced anti-cancer effects, including apoptosis, anti-proliferation, and inhibition of migration and invasion. These effects were mediated via the JAK/STAT1 pathway. Downregulation of STAT1 compromised measured anti-cancer effects, which were both confirmed in the in vivo and in vitro models. EPI can promote 125I-induced anti-cancer effects in HCC. The JAK/STAT1 pathway may be a potential target for 125I seed implantation in the treatment of HCC.

Quinacrine has been identified as a potent DR5-inducing agent that sensitizes cancer cells to TRAIL-induced apoptosis. In the current study, we found that quinacrine increased DR5 mRNA levels significantly in ovarian cancer cell lines regardless of p53 status. Further study showed the half-life of DR5 in quinacrine-treated cells was significantly prolonged, indicating that DR5 protein degradation was inhibited by quinacrine. We tested if the combination of TRAIL and quinacrine could be effective in ovarian cancer treatment in vitro and in ovarian cancer xenograft mouse models. We found that quinacrine enhanced TRAIL sensitivity or reversed TRAIL resistance in all the ovarian cancer cell lines tested. Mice treated with quinacrine and TRAIL remained disease-free for up to 20 weeks, however, mice treated with TRAIL or quinacrine alone and in control group died within ~8 weeks after treatment. Intraperitoneal delivery of quinacrine and TRAIL is rational and practical with extraordinary synergistic anti-cancer effects in preclinical models of ovarian cancer. Clinical investigation of combining quinacrine with TRAIL for ovarian cancer treatment is warranted.

Purpose: The aim of this study was to evaluate the clinical benefit of different radiation doses in concurrent chemoradiotherapy (CCRT) for esophageal carcinoma using modern radiotherapy techniques. Methods: A systematic review was conducted by screening PubMed, EMBASE, Cochrane Central Register of Controlled Trials, SCOPUS, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases with prespecified searching strategy. Studies which compared high radiation dose group with low-dose radiation group using modern radiotherapy techniques for esophageal cancer patients in CCRT were identified. The hazard ratios (HR) for overall survival (OS) and the odds ratios (OR) for local-regional failure (LRF), distant metastasis (DM), and toxicities were considered as the outcomes of interest. R 3.6.2 software was used for statistical analysis. Results: Twelve studies involving 10,896 patients were included for analyses. The results showed that the high-dose group had better OS (HR = 0.79, 95% CI = 0.70-0.90, P = 0.0004) and the local-regional control (OR = 0.59, 95% CI = 0.46-0.76, P < 0.0001), especially for patients who were diagnosed with squamous cell carcinoma (SCC). The subgroup analyses further indicated that ≥ circa 60 Gy can significantly improve the OS (HR = 0.73, 95% CI = 0.68-0.80, P < 0.0001) as well as the local-regional control (OR = 0.54, 95% CI = 0.40-0.74, P < 0.0001) as compared with < circa 60 Gy. Another subgroup analysis comparing ≤ 50.4 Gy with > 50.4 Gy showed no substantial difference in OS (HR = 0.98, 95% CI = 0.93-1.03, P = 0.43). In addition, there are no significant differences between the two groups in grade 3-5 radiation pneumonitis (OR = 1.05, 95% CI = 0.54-2.05, P = 0.89), grade 3-5 radiation esophagitis (OR = 1.40, 95% CI = 0.93-2.11, P = 0.11), treatment-related death (OR = 1.60, 95% CI = 0.70-3.66, P = 0.27), and DM (OR = 1.21, 95% CI = 0.92-1.59, P = 0.17). Conclusions: For esophageal carcinoma receiving CCRT with modern radiation techniques, evidence suggested that high-dose radiotherapy, especially ≥circa 60 Gy, had potentials to improve the OS and local-regional control without increase in severe toxicities when compared with low-dose radiotherapy. The result needs to be confirmed by randomized clinical trials.

Reconstruction of maxillary defect resulting from trauma or oncology surgery is of great importance for patients with physical and psychological complications. The virtual surgical planning (VSP) and 3D printing technics had been used in recent years which simplified the surgical procedure and promoted success and accuracy. To assess the accuracy and outcome of VSP surgery, here we report our experience in maxillary reconstruction retrospectively.

Postoperative recurrence is a common and severe problem in the treatment of gastric cancer; consequently, a prolonged course of chemotherapy treatment is inevitable. Monitoring by imaging could provide an accurate evaluation of the therapeutic effects, which would be beneficial to guide a treatment strategy adjustment over time. However, current imaging technologies remain insufficient for the continuous postoperative monitoring of gastric cancer. In this case, molecular imaging offers an efficient strategy. Targetable contrast agents are an essential part of molecular imaging, which could greatly enhance the accuracy and quality of monitoring. Herein, we synthesized a Mn-based contrast agent for magnetic resonance imaging (MRI) of gastric cancer monitoring. Initially, small-sized Mn3O4 nanoparticles (NPs) were synthesized. Then, a functionalized polyethylene glycol (PEG) lipid was attached to the surface of the Mn3O4 NPs, to improve biocompatibility. The targetable MRI contrast agent (Mn3O4@PEG-RGD NPs) was further prepared by the conjugation of the arginine-glycine-aspartic acid (RGD) peptides. The completed Mn3O4@PEG-RGD NPs had the small size of 7.3 ± 2.7 nm and exhibited superior colloidal stability in different solution environments. In addition, Mn3O4@PEG-RGD NPs exhibited reliable biotolerance and low toxicity both in vitro and in vivo. Imaging experiments amply demonstrated that Mn3O4@PEG-RGD NPs could efficiently accumulate in gastric cancer tissues and cells via RGD mediation, and immediately significantly increased the MRI effects. Through this study, we can conclude that Mn3O4@PEG-RGD NPs have the potential to be a novel MRI contrast agent for the postoperative monitoring of gastric cancer.

This study analyzes the expression and clinical significance of long non-coding RNA (lncRNA) BM466146 in breast cancer, and explores the role of BM466146 in immune regulation. The expression of BM466146 in 89 cases of breast cancer and their corresponding non-cancerous breast tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis was applied to evaluate patient survival. EDU and CCK-8 experiments on breast cancer cells were performed to verify the function of BM466146 in vitro. The target genes of BM466146 were screened by informatics analysis to predict associated miRNAs and their corresponding mRNAs, immune genes associated with lncRNAs and chemokines associated with CD8. Immunohistochemistry was used to detect the expression of CD8, Ki-67, and CXCL-13 in the 89 breast cancer tissues. It was found that the expression of lncRNA BM466146 in breast cancer tissues was significantly lower than that in normal breast tissues (P < 0.001). In breast cancer, tissues that overexpressed BM466146 exhibited a lower Ki-67 index compared with that of low BM466146 expression (P = 0.048). Kaplan-Meier survival analysis showed that breast cancer patients with overexpression of BM466146 had longer overall survival. EDU and CCK8 experiments showed that overexpression of BM466146 inhibited the proliferation of breast cancer cells. The hsa-miR-224-3p is associated with BM466146, and its target gene might be CXCL-13. The positive CD8 cells in the BM466146 overexpression group was higher than that in the low BM466146 expression group (P=0.027), and the positive CD8 cells in the CXCL-13 positive group was higher (P=0.023) than that of the negative group. Our results indicate that the lncRNA BM466146 has the function of tumor suppressor gene. Overexpression of BM466146 is associated with better prognosis. BM466146 could regulate CXCL-13 by adsorbing hsa-miR-224-3p and inducing CD8+ T cells to accumulate in the tumor area which regulate immune response. Therefore, BM466146 could be a prognostic biomarker and a molecular immune target of breast cancer.

Neuroblastoma is the most common extracranial neuroendocrine tumor in childhood. Although many studies have tried to find effective treatments, there are still numerous limitations in current clinical targeted therapy. So, it is important to find new therapeutic targets and strategies from a new perspective. Our previous study reported that the androgen receptor (AR) promotes the growth of neuroblastoma in vitro and in vivo. Based on documentary investigation, we postulated that the AR-SCAP-SREBPs-CYP17/HMGCR axis may regulate cholesterol and androgens synthesis and form a positive enhancement loop promoting NB progression. Clinical samples and Oncomine database analysis proved the activation of AR-SCAP-SREBPs-CYP17/HMGCR axis in neuroblastoma. The combination of inhibitors of HMGCR (statins) and CYP17A1 (abiraterone acetate) showed synergistic effect that significantly inhibited the proliferation and migration with decreased expression of related genes detected in vitro and in vivo suggesting the dual-targeted therapy had the potential to inhibit the progression of neuroblastoma in spite of its MYCN status. This study provides new ideas for clinical treatment of neuroblastoma with efficacy and reduced toxicity.

Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies for nasopharyngeal carcinoma (NPC) patients. Unfortunately, resistance is a major obstacle in the clinical management of NPC patients. We prove that the expression level of high-mobility group box 1 (HMGB1) is dramatically increased in resistant NPC cells than that in sensitive cells. HMGB1 induces the expression and secretion of IL6, which leads to constitutive autocrine activation of the JAK2/STAT3 pathway and eventually contributes to chemoresistance in NPC cells. Long non-coding RNAs (lncRNAs) have been identified as key regulators involved in drug resistance. In this study, using GO analysis of the biological process and differential expression analysis, we find 12 significantly altered IncRNAs in NPC cell lines, which may be involved in regulating gene expression. Furthermore, we determine that elevated lncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of the lncRNA MIAT/HMGB1 axis, inhibition of JAK2/STAT3, or neutralization of IL6 by antibodies significantly re-sensitizes resistant NPC cells to cisplatin in resistant NPC cells. Moreover, we provide the in vivo evidence that the deficiency of HMGB1 reduces cisplatin-resistant tumor growth. Most importantly, we provide clinical evidence showing that the expression level of the lncRNA MIAT/HMGB1/IL6 axis is elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by the lncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities for lncRNA MIAT, HMGB1, and IL6 as biomarkers for chemoresistance and targets for developing novel strategies to overcome resistance in NPC patients.

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer.

Objective: To evaluate the performance of a T2-weighted image (T2WI)-based radiomics signature for differentiating between seminomas and nonseminomas. Materials and Methods: In this retrospective study, 39 patients with testicular germ-cell tumors (TGCTs) confirmed by radical orchiectomy were enrolled, including 19 cases of seminomas and 20 cases of nonseminomas. All patients underwent 3T magnetic resonance imaging (MRI) before radical orchiectomy. Eight hundred fifty-one radiomics features were extracted from the T2WI of each patient. Intra- and interclass correlation coefficients were used to select the features with excellent stability and repeatability. Then, we used the minimum-redundancy maximum-relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) algorithms for feature selection and radiomics signature development. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of the radiomics signature. Results: Five features were selected to build the radiomics signature. The radiomics signature was significantly different between the seminomas and nonseminomas (p < 0.01). The area under the curve (AUC), sensitivity, and specificity of the radiomics signature for discriminating between seminomas and nonseminomas were 0.979 (95% CI: 0.873-1.000), 90.00 (95% CI: 68.3-98.8), and 100.00 (95% CI: 82.4-100.0), respectively. Conclusion: The T2WI-based radiomics signature has the potential to non-invasively discriminate between seminomas and nonseminomas.