Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Role of epithelial cell-mesenchymal transition regulators in molecular typing and prognosis of colon cancer.

Background: Despite advances in colon cancer screening, diagnosis, chemotherapy, and targeted therapy, the prognosis remains poor once colon cancer develops distant metastasis or local recurrence. To further improve the prognosis of colon cancer patients, researchers or clinicians may need to identify new indicators for predicting the prognosis and treatment of colon cancer. Methods: In order to discover the new mechanism of epithelial-mesenchymal transition (EMT) promoting tumor progression and to find new indicators of colon cancer diagnosis, targeted therapy and prognosis, this study conducted The Cancer Genome Atlas (TCGA) analysis, differential gene analysis, prognostic analysis, protein-protein interaction (PPI), enrichment analysis, molecular typing, and a machine algorithm were combined with data from TCGA and Gene Expression Omnibus (GEO) databases and EMT-related genes. Results: Our study identified 22 EMT-related genes with clinical prognostic value in colon cancer. On the basis of 22 EMT-related genes, we divided colon cancer into 2 different molecular subtypes by non-negative matrix factorization (NMF) model using 14 differentially expressed genes (DEGs), and the DEGs were enriched in multiple signaling pathways related to tumor metastasis process. Further analysis of EMT DEGs revealed that the PCOLCE2 and CXCL1 genes were characteristic genes for clinical prognosis of colon cancer. Conclusions: In this study, 22 prognostic genes were screened out from 200 EMT-related genes, and then the PCOLCE2 and CXCL1 molecules were finally focused on through the combination of the NMF molecular typing model and machine learning screening feature genes, suggesting that PCOLCE2 and CXCL1 may have good application potential. The findings provide a theoretical basis for the next clinical transformation in the treatment of colon cancer.

Silencing TRPM2 enhanced erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins.

Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. Cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival. Our bioinformatic analysis revealed that TRPM2 is associated with cellular responses to chemical stimulus and oxidative stress, implying the potential role of TRPM2 in ferroptosis. Gastric cancer cells were treated with the ferroptosis-inducer, Erastin and RSL3. siRNA transfection was used to silence TRPM2. The levels of GSH, Fe2+, ROS and lipid peroxidation, and the activity of GPx activity were evaluated by flow cytometry and spectrophotometer. The effect of TRPM2 on ubiquitination of HIF-1α and Nrf2 were evaluated by co-immunoprecipitation. Erastin and RSL3 induced the up-regulation of TRPM2 in gastric cancer cell lines, especially in SGC7901 and MGC803. These two cells also showed stronger resistance to Erastin and RSL3 than the other cell lines. TRPM2 knockdown reduced the concentration of GSH and GPx activity, but enhanced the concentration of Fe2+, ROS and lipid peroxidation, which are significant indicators of ferroptosis. Importantly, silencing TRPM2 enhanced the inhibitory effects of Erastin and RSL3 on gastric cancer cell viability, migration, and invasion. TRPM2 stabilized and finally elevated the abundance of HIF-1α and Nrf2 in SGC7901 and MGC803 cells upon Erastin and RSL3. Activation of HIF-1α impaired Erastin- and RSL3-induced ferroptosis after TRPM2 knockdown. Collectively, silencing TRPM2 enhanced Erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-022-00545-z.

Shikonin induces cell autophagy via modulating the microRNA -545-3p/guanine nucleotide binding protein beta polypeptide 1 axis, thereby disrupting cellular carcinogenesis in colon cancer.

Shikonin (SHK), a major component of shiverweed, was provided with anti-tumor effects via multiple targets and signal pathways. Nevertheless, the specific mechanism of its function in colorectal cancer (CRC) still needed to be further explored. The study was designed to examine the role of SHK in CRC and its specific mechanism on the cell tumor behavior of CRC. Collection of clinical samples was performed, and test of microRNA (miR)-545-3p and guanine nucleotide-binding protein beta polypeptide 1 (GNB1) in the samples was conducted; Selection of CRC cell line was exerted, and examination of miR-545-3p and GNB1 was performed; After treatment of shikonin (SHK), correlated plasmids were transfected, test of cell advancement was performed. Test of the protein of autophagy-correlated proteins light chain 3-II/light chain 3I and p63 was performed. The interaction of miR-545-3p with GNB1 was explored, and the action of SHK in vivo was tested. SHK repressed the advancement of SW480 cells with elevated apoptosis and autophagy and the cells quantities in G0/G1 phase. MiR-545-3p was elevated in CRC. SHK boosted miR-545-3p, repression of miR-545-3p or augmentation of GNB1 was able to turn around the function of SHK on CRC, and GNB1 was the target gene of miR-545-3p.All in all, SHK stimulates apoptosis and autophagy in CRC via miR-545-3p/GNB1 signaling axis, firstly demonstrating the regulatory mechanism of SHK in CRC via miR-545-3p/GNB1 axis.

Clinical Effectiveness of Neoadjuvant Chemotherapy in Gastric Carcinoma and Exploration of Perioperative Imaging Assessment Parameters.

BACKGROUND AND AIMS: Due to the difficulty in clinical staging, a simple and feasible perioperative assessment approach for guiding personalized neoadjuvant chemotherapy (NAC) is lacking. We investigated the clinical value of NAC in advanced gastric carcinoma (GC) and the concordance between perioperative imaging and postoperative pathological assessments. METHODS: This study included 62 patients with advanced GC who received NAC between January 2012 and December 2018. The preoperative and postoperative T stages, postoperative pathological tumor regression grade (TRG), and changes in computed tomography (CT) values after NAC were assessed. Follow-ups were conducted to obtain the median survival time (MST), and Kaplan-Meier survival curves were plotted. RESULTS: The T stages significantly differed between before and after NAC (p = 0.001). The MST of patients in the TRG0 group was significantly different from that of patients in the TRG1+2 and TRG3 groups (p = 0.223). The percentages of positive lymph nodes were 0%, 24.17%, and 27.64% in the TRG0, TRG1+2, and TRG3 groups, respectively. TRG was correlated with changes in CT values before and after NAC, and the extent of change was associated with patient prognosis. CONCLUSIONS: Perioperative imaging can be used to assess the short-term effectiveness of NAC for patients with GC.

Long non-coding RNA GATA6-AS inhibits gastric cancer cell proliferation by downregulating microRNA-25-3p.

The abnormal growth of endothelial cells is involved in several types of diseases, including gastric cancer. The long non-coding RNA GATA6-AS is a key regulator of endothelial cell growth and may therefore also play an important role in gastric cancer. In the present study it was found that GATA6-AS was downregulated in tumor tissues compared with adjacent normal tissues. Moreover, plasma levels of GATA6-AS were linearly associated with GATA6-AS expression levels in tumor tissues and not in normal tissues. MicroRNA (miR)-25-3p was upregulated in tumor tissues compared with adjacent normal tissues and was inversely associated with GATA6-AS in tumor tissues only. The overexpression of miR-25-3p in gastric cancer cells resulted in no significant changes in the expression levels of GATA6-AS, whereas overexpression of GATA6-AS led to significantly downregulated miR-25-3p levels. Furthermore, overexpression of GATA6-AS inhibited cancer cell proliferation, with no effect on migration and invasion. The overexpression of miR-25-3p resulted in increased proliferation of cancer cells and attenuated the effects of GATA6-AS overexpression. Thus, it is postulated that GATA6-AS inhibits proliferation of gastric cancer cells by downregulating miR-25-3p.

MicroRNA­25/ATXN3 interaction regulates human colon cancer cell growth and migration.

The present study aimed to investigate the function of microRNA­25 (miR­25) in human colon cancer cell viability and migration in addition to the underlying possible mechanisms. miR­25 expression was upregulated in patients with colon cancer compared with the control group. Reverse transcription­quantitative polymerase chain reaction and gene chip technology were used to analyze the alterations of miR­25 in patients with colon cancer. Cell viability and cell migration were analyzed using MTT and wound healing assays, respectively, apoptosis was analyzed using flow cytometry, and western blot analysis was conducted to determine the protein expression of ataxin­3 (ATXN3), apoptosis regulator Bax (Bax) and cyclin D1. Overexpression of miR­25 increased cell viability and migration, decreased apoptosis, decreased caspase­3/9 activity level in addition to decreased Bax protein expression, and increased cyclin D1 protein expression in colon cancer cells. Furthermore, miR­25 was demonstrated to target ATXN3 and suppress ATXN3 protein expression. Downregulation of miR­25 induced apoptosis of colon cancer cells via increased expression ATXN3. Small interfering­ATXN3 inhibited the anti­cancer effects of miR­25 downregulation in colon cancer. Collectively, the present results demonstrated that miR­25 promoted human colon cancer cell viability and migration by regulating ATXN3 expression.

Design of a Measurement System for Six-Degree-of-Freedom Geometric Errors of a Linear Guide of a Machine Tool.

This paper proposes a system utilizing a Renishaw XL80 positioning error measuring interferometer and sensitivity analysis design to measure six-degree-of-freedom (6 DOF) geometric errors of a machine tool's linear guide. Each error is characterized by high independence with significantly reduced crosstalk, and error calculations are extremely fast and accurate. Initially, the real light path was simulated using Zemax. Then, Matlab's skew ray tracing method was used to perform mathematical modeling and ray matching. Each error's sensitivity to the sensor was then analyzed, and curve fitting was used to simplify and speed up the mathematical model computations. Finally, Solidworks was used to design the set of system modules, bringing the proposed system closer to a product. This system measured actual 6 DOF geometric errors of a machine tool's linear guide, and a comparison is made with the Renishaw XL-80 interferometer measurements. The resulting pitch, yaw, horizontal straightness, and vertical straightness error deviation ranges are ±0.5 arcsec, ±3.6 arcsec, ±2.1 µm, and ±2.3 µm, respectively. The maximum repeatability deviations for the measured guide's pitch, yaw, roll, horizontal straightness, vertical straightness, and positioning errors are 0.4 arcsec, 0.2 arcsec, 4.2 arcsec, 1.5 µm, 0.3 µm, and 3 µm, respectively.

Evolution of Slow Magnetic Relaxation: from Diamagnetic Matrix Y(OH)CO3 to Dy(0.06)Y(0.94)(OH)CO3 with High Spin-Reversal Barrier and Blocking Temperature.

A stable Dy(III)-dispersed compound with single-molecule magnet behavior, Dy(0.06)Y(0.94)(OH)CO3, was isolated by a general strategy targeted at the doping of paramagnetic Dy(3+) into a diamagnetic 3D inorganic network of Y(OH)CO3. The single-ion origin of slow magnetic relaxation was gradually released as variations of the dysprosium/yttrium ratio and finally gave a relatively large spin-reversal barrier around 200 K and high hysteresis temperature of 8 K. This study opens up new opportunities to investigate the slow magnetic relaxation and magnetostructural correlation by choosing a suitable inorganic architecture with strong axial anisotropy.