Background: Conventional methods for predicting treatment response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) are limited. Methods: This study retrospectively recruited 134 LARC patients who underwent standard nCRT followed by total mesorectal excision surgery in our institution. Based on pre-operative axial T2-weighted images, machine learning radiomics was performed. A receiver operating characteristic (ROC) curve was performed to test the efficiencies of the predictive model. Results: Among the 134 patients, 32 (23.9%) achieved pathological complete response (pCR), 69 (51.5%) achieved a good response, and 91 (67.9%) achieved down-staging. For prediction of pCR, good-response, and down-staging, the predictive model demonstrated high classification efficiencies, with an AUC value of 0.91 (95% CI: 0.83–0.98), 0.90 (95% CI: 0.83–0.97), and 0.93 (95% CI: 0.87–0.98), respectively. Conclusion: Our machine learning radiomics model showed promise for predicting response to nCRT in patients with LARC. Our predictive model based on the commonly used T2-weighted images on pelvic Magnetic Resonance Imaging (MRI) scans has the potential to be adapted in clinical practice. Novelty and Impact Statements: Methods for predicting the response of the locally advanced rectal cancer (LARC, T3-4, or N+) to neoadjuvant chemoradiotherapy (nCRT) is lacking. In the present study, we developed a new machine learning radiomics method based on T2-weighted images. As a non-invasive tool, this method facilitates prediction performance effectively. It achieves a satisfactory overall diagnostic accuracy for predicting of pCR, good response, and down-staging show an AUC of 0.908, 0.902, and 0.930 in LARC patients, respectively.
Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2‐(anaphthoyl)ethyl‐trimethylammonium iodide (α‐NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin‐d (GSDMD)/caspase‐4 pathway. Furthermore, Cell Counting Kit‐8 fluorescence‐activated cell sorting analysis showed that α‐NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with α‐NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. α‐NETA also significantly increased expression of pyroptosis‐associated molecules including caspase‐4 and GSDMD in EOC cells. Knockdown of either caspase‐4 or GSDMD in ovarian cancer cells strongly interfered with α‐NETA cell‐killing activity, indicating that α‐NETA acts through the pyroptosis pathway. In vivo, α‐NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that α‐NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy.—Qiao, L., Wu, X., Zhang, J., Liu, L., Sui, X., Zhang, R., Liu, W., Shen, F., Sun, Y., Xi, X. α‐NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase‐4 pathway. FASEB J. 33, 12760–12767 (2019). http://www.fasebj.org
Previous studies reported that Follistatin-like 3 (FSTL3) is abundantly expressed in several solid tumors and participate in the regulation of cell metabolism. However, the clinico-pathological significance, biological role and molecular mechanism of FSTL3 in colorectal cancer (CRC) is still unclear. Here we report that the expression level of FSTL3 in colon cancer specimens was significantly higher, compared to normal tissue and interestingly, the expression of FSTL3 was related to lymph node metastasis, tumor stage, tumor size, and intravascular emboli (IVE). As an upstream molecular event, we found that transcriptional regulation of FSTL3 was highly dependent on YAP1 de-phosphorylation events and that increased FSTL3 expression readily activated the β-Catenin pathway, which is a well-known signaling hub that promotes EMT processes and aerobic glycolysis in cancer cells. We found that elevated FSTL3 expression strongly promotes migration, invasion and metastatic formation of CRC cells by directly activating β-Catenin -mediated EMT and aerobic glycolysis. In the xenograft mouse model, FSTL3 expression was linked to increased metastatic formation of CRC cells. Together, the activation of YAP1 induces FSTL3 expression. FSTL3-mediated β-Catenin pathway activation promotes EMT and aerobic glycolysis and therefore affecting the invasive and metastatic capacity of CRC cells. The abundant FSTL3 expression is a poor prognostic factor and pharmacological targeting of YAP1 can counteract FSTL3 expression, suggesting a promising therapeutic target for anti-metastatic strategies in patients suffering from CRC.
Among the gynaecological cancers, epithelial ovarian cancer (EOC) has the highest lethality because of the high incidence of tumour progression and metastasis. Exploration of the detailed mechanisms underlying EOC metastasis and the identification of crucial targets is important to better estimate the prognosis and improve the treatment of this disease. The present study aimed to identify the role of miR-520h in the prognosis of patients with EOC, and the mechanisms of its involvement in EOC progression. We showed that miR-520h was upregulated in 116 patients with EOC, especially in those with advanced-stage disease, and high miR-520h expression predicted poor outcome. Furthermore, ectopic expression of miR-520h enhanced EOC cell proliferation, migration and invasion, and induced epithelial–mesenchymal transition in vitro and in vivo. miR-520h promoted EOC progression by downregulating Smad7, and subsequently activating the TGF-β signalling pathway. Most importantly, TGF-β1 stimulation increased miR-520h expression in EOC cells by upregulating its transcription factor c-Myb. In conclusion, we described the role of the TGF-β1/c-Myb/miR-520h/Smad7 axis in EOC metastasis, and highlighted the possible use of miR-520h as a prognostic marker for EOC.
Miscanthus, a member of the Saccharinae subtribe that includes sorghum and sugarcane, has been widely studied as a feedstock for cellulosic biofuel production. Here, we report the sequencing and assembly of the Miscanthus floridulus genome by the integration of PacBio sequencing and Hi-C mapping, resulting in a chromosome-scale, high-quality reference genome of the genus Miscanthus. Comparisons among Saccharinae genomes suggest that Sorghum split first from the common ancestor of Saccharum and Miscanthus, which subsequently diverged from each other, with two successive whole-genome duplication events occurring independently in the Saccharum genus and one whole-genome duplication occurring in the Miscanthus genus. Fusion of two chromosomes occurred during rediploidization in M. floridulus and no significant subgenome dominance was observed. A survey of cellulose synthases (CesA) in M. floridulus revealed quite high expression of most CesA genes in growing stems, which is in agreement with the high cellulose content of this species. Resequencing and comparisons of 75 Miscanthus accessions suggest that M. lutarioriparius is genetically close to M. sacchariflorus and that M. floridulus is more distantly related to other species and is more genetically diverse. This study provides a valuable genomic resource for molecular breeding and improvement of Miscanthus and Saccharinae crops.
Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a median survival of around 15 months. A potential treatment strategy involves targeting glioma stem-like cells (GSCs) that are able to initiate, maintain, and repopulate the tumor mass. Here, we identify ACT001, a parthenolide derivative, targeting GSCs through regulation of adipocyte enhancer binding protein 1 (AEBP1) signaling. Methods: The effects of ACT001 on cell survival of normal human astrocytes (NHA) and patient-derived glioma stem-like cells (GSCs) were evaluated. RNA-Seq were performed to detect differentially expressed genes. ACT001 efficacy as a single agent or in combination with SHP-2 inhibitor SHP099 was assessed using a GSC orthotopic xenograft model. Results: GSCs exhibit high response to ACT001 in compared with normal human astrocytes. AEBP1 is a putative target of ACT001 by RNA-Seq analysis, which expression associates with prognosis of GBM patients. Knockdown of AEBP1 inhibits GSC proliferation and glioma sphere formation. Treatment with ACT001 or PI3K inhibitor or AEBP1 depletion would impair AKT phosphorylation and GSC proliferation, whereas constitutive AKT activation rescues ACT001 treatment or AEBP1 depletion-inhibited cell proliferation. Moreover, ACT001 blocks TGF-β-activated AEBP1/AKT signaling in GSCs. ACT001 exhibits antitumor activity either as a single agent or in combination with SHP099, which provides significant survival benefits for GSC tumor xenograft-bearing animals. Conclusions: Our data demonstrate AEBP1 as a new druggable target in GBM and ACT001 as a potential therapeutic option for improving the clinical treatment of GBM in combination with SHP099.
Background: There is no conclusion about the most important contributor to the upswing of locally advanced colorectal cancer (LACRC) survival. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database was extracted to identify colorectal adenocarcinoma cancer patients at stage II and III diagnosed in the two periods 1989–1990 and 2009–2010. The statistical methods included Pearson’s chi-squared test, log-rank test, Cox regression model and propensity score matching. Results: The Cox regression model showed that hazard ratio (HR) of non-surgery dropped from 11.529 to 3.469 in right colon cancer (RCC), 5.214 to 2.652 in left colon cancer (LCC) and 3.275 to 3.269 in rectal cancer (RC) from 1989–1990 to 2009–2010. The 95% confidence intervals (CIs) for surgical resection in 2009–2010 were narrower than those in 1989–1990. HR became greater in LACRC without chemotherapy (from 1.337 to 1.779 in RCC, 1.269 to 2.017 in LCC, 1.317 to 1.811 in RC). There was no overlapping about the 95% CI of chemotherapy between the two groups. The progress of surgery was not linked to the improvement of overall survival (OS) of RCC ( p = 0.303) and RC ( p = 0.660). Chemotherapy had a significant association with OS of all colorectal cancer (CRC) patients ( p = 0.017 in RCC; p = 0.006 in LCC; p = 0.001 in RC). Conclusions: Advancements in chemotherapy regimen were the main contributor to the upswing of CRC survival. The improvements in surgery had a limited effect on improvements in CRC survival.
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