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PURPOSE Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)–expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1–expressing ESCC remains debatable. METHODS Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1–expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1–expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.

Dysregulated cholesterol metabolism is a hallmark of colorectal cancer (CRC). However, the usage of cholesterol-lowering agents seemed to have no benefit in CRC patients. In this study, we focused on the cholesterol-nuclear receptors (NRs) axis as a strategy. Cholesterol and its derivatives work as ligands for different nuclear receptors, thus promoting cancer progression. The key NR downstream of cholesterol in CRC is unknown. Here, we treated CRC cells with a cholesterol-lowering agent and lipoprotein-depleted conditioned medium, and then detected the change of the putative NRs. The results revealed that RORα/γ (Retinoic acid receptor-related Orphan Receptor α/γ) levels exhibited the most obvious increases in CRC cells subjected them to cholesterol deprivation. RORα/γ agonists significantly inhibited CRC cells proliferation and migration in vitro and in vivo. Also, RORα/γ overexpression repressed CRC cells proliferation and migration in vitro and in vivo and RORα/γ knockdown promoted it. Mechanistically, RORα/γ agonists promoted c-myc degradation by activating the transcription of the ubiquitinase NEDD4. Intriguingly, the combination of RORα/γ agonists and atorvastatin had a synergistic effect on inhibiting CRC cells. These findings demonstrate that the cholesterol- RORα/γ axis is important for maintaining c-myc protein levels. Combination therapy with atorvastatin and RORα/γ agonist is a promising therapeutic strategy for CRC.

Post-translational modifications (PTMs) are critical molecular mechanisms that regulate protein functions temporally and spatially in various organisms. Since most PTMs are dynamically regulated, quantifying PTM events under different states is crucial for understanding biological processes and diseases. With the rapid development of high-throughput proteomics technologies, massive quantitative PTM proteome datasets have been generated. Thus, a comprehensive one-stop data resource for surfing big data will benefit the community. Here, we updated our previous phosphorylation dynamics database qPhos to the qPTM (http://qptm.omicsbio.info). In qPTM, 11 482 553 quantification events among six types of PTMs, including phosphorylation, acetylation, glycosylation, methylation, SUMOylation and ubiquitylation in four different organisms were collected and integrated, and the matched proteome datasets were included if available. The raw mass spectrometry based false discovery rate control and the recurrences of identifications among datasets were integrated into a scoring system to assess the reliability of the PTM sites. Browse and search functions were improved to facilitate users in swiftly and accurately acquiring specific information. The results page was revised with more abundant annotations, and time-course dynamics data were visualized in trend lines. We expected the qPTM database to be a much more powerful and comprehensive data repository for the PTM research community.

Background Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past. Methods Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals. Results We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient. Conclusions Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.

ObjectiveMethionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined.DesignThe antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated.ResultsWe found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients.ConclusionsMethionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.

Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.

Tumor-associated macrophages (TAM) are among the most abundant immune cells in the tumor microenvironment and are important mediators of tumor development and progression. Here, we identified a macrophage-associated long noncoding RNA (lncRNA), MALR, that facilitates progression of esophageal squamous cell carcinoma (ESCC). TAM-mediated secretion of TNFα drove MALR upregulation in ESCC cells. MALR promoted aerobic glycolytic activity and facilitated angiogenesis by activating the HIF1α signaling pathway. Mechanistically, MALR bound the dsRBD1 domain of interleukin enhancer-binding factor 3 (ILF3), promoting ILF3 protein stability and ILF3-mediated liquid–liquid phase separation (LLPS), thereby enhancing HIF1α mRNA stability by preventing PARN-mediated degradation. Loss of MALR suppressed cell line–based and patient-derived xenograft tumor growth. Clinically, high expression of MALR positively correlated with HIF1α target gene expression and indicated poor prognoses for patients with esophageal cancer. Overall, this study uncovers the physiologic roles of MALR/ILF3-mediated LLPS in tumor microenvironment remodeling, highlighting the MALR–ILF3–HIF1α axis as a potential target for cancer therapy.Significance:Secretion of TNFα by tumor-associated macrophages stimulates cancer cells to upregulate lncRNA MALR, which induces ILF3 liquid–liquid phase separation and activation of HIF1α signaling to promote cancer progression.

Supplementary Table 2

Supplementary Methods

Supplementary Figures

Supplementary Table 1

Supplementary Figure from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Supplementary Data from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Supplementary tables S1-S4 show analytic details of the ENCODE ChIP-Seq data and TCGA RNA-Seq data, together with primer sequences used in this study.

Supplemental Figure S1. The over-expression of CBX4, but not of other CBX members, suppresses the migration of DLD1 cells. Supplementary Figure S2. The knockdown of CBX4 enhances migration and invasion of CRC cells. Supplementary Figure S3. The over-expression of CBX4 inhibits the cell migration and invasion of CRC cells. Supplementary Figure S4. CBX4 represses the liver metastasis of HCT116 cells. Supplementary Figure S5. CBX4 is negatively related to the Runx2 expression in CRC cell lines. Supplementary Figure S6. The knockdown of Runx2 decreases the expression of Slug. Supplementary Figure S7. The promotion of cell migration and invasion after CBX4 knockdown primarily depends on Runx2. Supplementary Figure S8. The knockdown of Slug also reverses the promotion of cell migration and invasion after CBX4 knockdown. Supplementary Figure S9. IHC antibodies specifically recognized CBX4 or Runx2 protein. Supplementary Figure S10. The ΔSIM1/2 and CDM mutations marginally affect the functions of CBX4 in CRC. Supplementary Figure S11. CBX4 strongly binds with HDAC1, HDAC2, HDAC3 and HDAC9. Supplementary Figure S12. HDAC1, HDAC2, and HDAC3, but not HDAC9, are expressed in the tested CRC cell lines. Supplementary Figure S13. The ΔSIM1/2 and CDM mutations marginally affect the interaction of CBX4 with HDAC3. Supplementary Figure S14. The binding affinity of HDAC3 with the Runx2 promoter was dependent on CBX4. Supplementary Figure S15. The knockdown of HDAC3 abrogates the functions of CBX4 in CRC. Supplementary Figure S16. Determination of CBX4 fragments interacting with HDAC3. Supplementary Figure S17. The C-terminal 10 amino acids of CBX4 are responsible for its interaction with Bmi1. Supplementary Figure S18. The ΔDM1-CBX4 and ΔTM-CBX4 mutations, but not the deltaC-CBX4 mutation, abolish the inhibition of cell migration and invasion by CBX4.

The transcriptome analysis of HCT116 cells transfected with scrambled or CBX4 shRNA.

Table S1 is the correlation between CBX4 expression and Runx2 expression of CRC patients, Table S2 is correlation between CBX4 expression and clinicopathologic characteristics of CRC patients, and Table S3 is univariate and multivariate analysis for overall survival.

Purpose: Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients.Experimental Design: We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS).Results: One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients.Conclusion: Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients. Clin Cancer Res; 17(2); 382–90. ©2011 AACR.

Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.

Supplementary Table from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo. Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft–based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.Significance: These findings reveal the role of malic enzyme in growth and metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg. Cancer Res; 78(8); 1972–85. ©2018 AACR.

Figure legends for Figure S1-7.

PDF file 59K, Clinicopathological characteristics of patient samples and expression of Bmal1 in colorectal cancer

Supplementary Data from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Addtional information on shRNA sequences, qRT-PCR primers, promoter cloning primers, antibodies and ChIP-qPCR primers used in this study.

Supplementary Figure S1. SMAD4 and ME2 copy number are frequently altered in human malignancies. Supplementary Figure S2. ME1 maintains cell survival during glucose deprivation. Supplementary Figure S3. Effects of ME1 on epithelial mesenchymal transition in gastric cancer. Supplementary Figure S4. Simultaneous knockdown of ME1 and ME2 in HGC27 cells significantly suppressed tumor growth in vivo. Supplementary Figure S5. Immunoblots show increased ME1 and decreased ME2 expression in the tumor tissues compared with corresponding normal tissues of PDX models. Supplementary Figure S6. ETV4 regulates ME1 expression in gastric cancer. Supplementary Figure S7. Clinical significance of ETV4/ME1 axis in gastric cancer.

Purpose: The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer.Experimental Design: Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens.Results: Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P = 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2–M arrest by activating the ATM pathway.Conclusion: Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer. Clin Cancer Res; 20(4); 1042–52. ©2013 AACR.

PDF file 38K, The specific Bmal1 protein expression by Western blotting for each transformed cell line compared with its control cell line

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics.Significance:A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657

Table S1. Primers sequence for qPCR Table S2. The correlation between clinicopathological parameters and ME1 expression Table S3. Univariate and multivariate analyses of various potential prognostic factors in GC patients

PDF file 18K, Bmal1 overexpression in the HCT116 and THC8307 cells after 30 generations of cell culture

Supplementary Figure from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Purpose:To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.Patients and Methods:In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.Results:Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively.Conclusions:Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

PDF file 287K, Bmal1 overexpression increases apoptosis in HCT116 (A), THC8307 (B) and HT29 (C) cells after 48 h oxaliplatin treatment

Supplementary Table S1.

Supplementary Figures S1-S6 describe additional data to support the EZH2-FBP1 feedback circuitry in hepatic and renal cells upon genotoxin-induced tumorigenesis. Supplementary Materials and Methods provide experimental details on standard assays using commercial reagents and kits.

PDF file 17K, Bmal1 protein expression in different CRC cell lines

With the recent progress in scientific research, the combination of chemotherapy and PD-1 blockade has become the new standard-of-care first-line treatment for patients with advanced esophageal squamous cell carcinoma. This short review highlights the recent important findings and challenges regarding the optimal chemotherapy backbone in combination with PD-1 blockade, biomarkers for predicting the efficacy of chemo-immunotherapy, treatment strategies beyond chemo-immunotherapy, and secondary resistance to chemo-immunotherapy in advanced esophageal squamous cell carcinoma.

Purpose: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. Conclusions: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

In China, it has been well recognized that some female patients with esophageal squamous cell carcinoma (ESCC) have different overall survival (OS) time, even with the same tumor-node-metastasis (TNM) stage, challenging the prognostic value of the TNM system alone. An effective predictive model is needed to accurately evaluate the prognosis of female ESCC patients.To construct a novel prognostic model with clinical and reproductive data for Chinese female patients with ESCC, and to assess the incremental prognostic value of the full model compared with the clinical model and TNM stage.A new prognostic nomogram incorporating clinical and reproductive features was constructed based on univariatie and Cox proportional hazards survival analysis from a training cohort (A clinical-reproductive model including incidence area, age, tumor differentiation, lymph node metastasis (N) stage, estrogen receptor alpha (ESR1) and beta (ESR2) expression, menopausal age, and pregnancy number was constructed to predict OS in female ESCC patients. Compared to the clinical model and TNM stage, the time-dependent ROC and C-index of the clinical-reproductive model showed a good discriminative ability for predicting 1-, 3-, and 5-years OS in the primary training, internal and external validation sets. Based on the optimal cut-off value of total prognostic scores, patients were classified into high- and low-risk groups with significantly different OS. The estrogen response was significantly associated with p53 and apoptosis pathways in esophageal cancer.The clinical-reproductive prognostic nomogram has an incremental prognostic value compared with the clinical model and TNM stage in predicting OS in Chinese female ESCC patients.

BackgroundThe impact of hospital volume on the long-term survival of esophageal squamous cell carcinoma (ESCC) has not been well assessed in China, especially for stage I–III stage ESCC. We performed a large sample size study to assess the relationships between hospital volume and the effectiveness of ESCC treatment and the hospital volume value at the lowest risk of all-cause mortality after esophagectomy in China.AimTo investigate the prognostic value of hospital volume for assessing postoperative long-term survival of ESCC patients in China.MethodsThe date of 158,618 patients with ESCC were collected from a database (1973–2020) established by the State Key Laboratory for Esophageal Cancer Prevention and Treatment, the database includes 500,000 patients with detailed clinical information of pathological diagnosis and staging, treatment approaches and survival follow-up for esophageal and gastric cardia cancers. Intergroup comparisons of patient and treatment characteristics were conducted with the X2 test and analysis of variance. The Kaplan-Meier method with the log-rank test was used to draw the survival curves for the variables tested. A Multivariate Cox proportional hazards regression model was used to analyze the independent prognostic factors for overall survival. The relationship between hospital volume and all-cause mortality was assessed using restricted cubic splines from Cox proportional hazards models. The primary outcome was all-cause mortality.ResultsIn both 1973-1996 and 1997-2020, patients with stage I-III stage ESCC who underwent surgery in high volume hospitals had better survival than those who underwent surgery in low volume hospitals (both PConclusionHospital volume can be used as an indicator to predict the postoperative survival of ESCC patients. Our results suggest that the centralized management of esophageal cancer surgery is meaningful to improve the survival of ESCC patients in China, but the hospital volume should preferably not be higher than 1027 cases/year.Core tipHospital volume is considered to be a prognostic factor for many complex diseases. However, the impact of hospital volume on long-term survival after esophagectomy has not been well evaluated in China. Based on a large sample size of 158,618 ESCC patients in China spanning 47 years (1973-2020), We found that hospital volume can be used as a predictor of postoperative survival in patients with ESCC, and identified hospital volume thresholds with the lowest risk of death from all causes. This may provide an important basis for patients to choose hospitals and have a significant impact on the centralized management of hospital surgery.

BackgroundThis study was intended to construct a brand new prognostic nomogram after combine clinical and pathological characteristics to increases prognostic value in patients with esophageal squamous cell carcinoma.MethodsA total of 1,634 patients were included. Subsequently, the tumor tissues of all patients were prepared into tissue microarrays. AIPATHWELL software was employed to explore tissue microarrays and calculate the tumor-stroma ratio. X-tile was adopted to find the optimal cut-off value. Univariate and multivariate Cox analyses were used to screen out remarkable characteristics for constructing the nomogram in the total populations. A novel prognostic nomogram with clinical and pathological characteristics was constructed on the basis of the training cohort (n=1,144). What’s more performance was validated in the validation cohort (n=490). Clinical-pathological nomogram were assessed by concordance index, time-dependent receiver operating characteristic, calibration curve and decision curve analysis.ResultsThe patients can divide into two groups with cut-off value of 69.78 for the tumor-stroma ratio. It is noteworthy that the survival difference was noticeable (PPConclusionsAs evidently revealed by the research findings, tumor-stroma ratio is an independent prognostic factor in patients with esophageal squamous cell carcinoma. The clinical-pathological nomogram has an incremental value compared TNM stage in predicting overall survival.

Background Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer. Methods A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays. Results circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy. Conclusions Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.

Immunotherapy plays a compelling role in cancer treatment and has already made remarkable progress. However, many patients receiving immune checkpoint inhibitors fail to achieve clinical benefits, and the response rates vary among tumor types. New approaches that promote anti-tumor immunity have recently been developed, such as small molecules, bispecific antibodies, chimeric antigen receptor T cell products, and cancer vaccines. Small molecule drugs include agonists and inhibitors that can reach the intracellular or extracellular targets of immune cells participating in innate or adaptive immune pathways. Bispecific antibodies, which bind two different antigens or one antigen with two different epitopes, are of great interest. Chimeric antigen receptor T cell products and cancer vaccines have also been investigated. This review explores the recent progress and challenges of different forms of immunotherapy agents and provides an insight into future immunotherapeutic strategies.