Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by radical surgery has been a common practice for patients with locally advanced rectal cancer, but the response rate varies among patients. This study aimed to develop a ResNet-Vision Transformer based magnetic resonance imaging (MRI)-endoscopy fusion model to precisely predict treatment response and provide personalized treatment. METHODS: In this multicenter study, 366 eligible patients who had undergone neoadjuvant chemoradiotherapy followed by radical surgery at eight Chinese tertiary hospitals between January 2017 and June 2024 were recruited, with 2928 pretreatment colonic endoscopic images and 366 pelvic MRI images. An MRI-endoscopy fusion model was constructed based on the ResNet backbone and Transformer network using pretreatment MRI and endoscopic images. Treatment response was defined as good response or non-good response based on the tumor regression grade. The Delong test and the Hanley-McNeil test were utilized to compare prediction performance among different models and different subgroups, respectively. The predictive performance of the MRI-endoscopy fusion model was comprehensively validated in the test sets and was further compared to that of the single-modal MRI model and single-modal endoscopy model. RESULTS: The MRI-endoscopy fusion model demonstrated favorable prediction performance. In the internal validation set, the area under the curve (AUC) and accuracy were 0.852 (95% confidence interval [CI]: 0.744-0.940) and 0.737 (95% CI: 0.712-0.844), respectively. Moreover, the AUC and accuracy reached 0.769 (95% CI: 0.678-0.861) and 0.729 (95% CI: 0.628-0.821), respectively, in the external test set. In addition, the MRI-endoscopy fusion model outperformed the single-modal MRI model (AUC: 0.692 [95% CI: 0.609-0.783], accuracy: 0.659 [95% CI: 0.565-0.775]) and the single-modal endoscopy model (AUC: 0.720 [95% CI: 0.617-0.823], accuracy: 0.713 [95% CI: 0.612-0.809]) in the external test set. CONCLUSION The MRI-endoscopy fusion model based on ResNet-Vision Transformer achieved favorable performance in predicting treatment response to neoadjuvant chemoradiotherapy and holds tremendous potential for enabling personalized treatment regimens for locally advanced rectal cancer patients.
Humans ; Rectal Neoplasms/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Male ; Female ; Middle Aged ; Neoadjuvant Therapy/methods* ; Aged ; Adult ; Chemoradiotherapy/methods* ; Endoscopy/methods* ; Treatment Outcome

The deubiquitinases (DUBs), as the crucial peptidohydrolases in the ubiquitin system, can reverse and strictly regulate ubiquitination and play key roles in various biological processes, including the regulation of protein stability, cell signal transduction. Ubiquitin-specific protease 28 (USP28) involves multiple cancer-related signaling pathways by enhancing the stability of various cancer-related proteins, and is closely associated with the progression of colorectal, breast cancer, lung carcinomas, and pancreatic cancer. USP28 has been considered as a promising drug target in anticancer therapy, and the development of USP28 inhibitors has made some progress. In this article, we review the structure of USP28 and its interaction with substrates, discuss the research progress of USP28 in cancers and summarize the development of USP28 inhibitors.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective To explore the role pathway and pattern of the myeloma cancer gene (MYC) and its mRNA interaction with the microRNAs(miRNAs) and circular RNA(circRNAs) at hour 0, hour 6 and hour 72 in the rat liver regeneration. Methods The rat 2/3 hepatectomy (PH) model was prepared as described by Higgins, the hepatocytes were isolated according to the method of Smedsrod et al. The expression changes of mRNA, miRNA and circRNA [together named as competing endogenous RNA (ceRNA)] were detected by the large-scale quantitative detection technology, the interaction network of ceRNA was constructed by Cytoscape 3.2 software, and their correlation in expression and role were analyzed by ceRNA comprehensive analysis. Results It was found that at hour 0 and hour 6 after PH, the ratio value of MYC mRNA showed 0.15±0.03 and 2.36±0.20, miR-134-5p indicated 3.22±0.61 and 0.08±0.02, circRNA_12112 displayed 0.68±0.21 and 13.35±3.53. At the same time, the cell cycle initiation-related genes ras association domain family member 1 (RASSF1), cyclin dependent kinase 2 (CDK2), superoxide dismutase 2 (SOD2), which were promoted in expression by MYC, were down-regulated at hour 0 after PH, but the cell cycle initiation-related genes nestin (NES), RAD21 cohesin complex component (RAD21), CUE domain containing 2 (CUEDC2), which are inhibieted in expression by MYC, had no meaningful express changes at hour 0 after PH. On the other hand, the cell cycle initiation-related gene SOD2, which was promoted in expression by MYC, was up-regulated at hour 6 after PH, but the cell cycle initiation-related genes NES, RAD21, CUEDC2, which are inhibieted in expression by MYC, were down-regulated at hour 6 after PH. In contrary, at hour 72 after PH, the ratio value of MYC mRNA showed 2.36±0.20, miR-880-3p indicated 0.54±0.01, circRNA_09599 displayd 0.54±0.16. At the same time, the cell cycle termination-related gene hepatocyte growth factor (HGF), which is promoted in expression by MYC, was up-regulated 72 hours after PH, the cell cycle termination-related genes MET proto-oncogene receptor tyrosine kinase (MET) and cyclin dependent kinase inhibitor 1A (CDKN1A), which are inhibieted in expression by MYC, were down-regulated 72 hours after PH. Conclusion The correlation in expression and role of the miRNAs, which are inhibited by circRNAs, MYC, its mRNA is inhibited by miRNAs, and the cell cycle initiation-related and cell cycle termination-related genes, which are regulated by MYC, are helpful for the hepatocyte to be in cell cycle initiation state at hour 6 after PH and to be in cell cycle termination state at hour 72 after PH.

[ Abstract] Objective To explore the role pathway and pattern of the Kruppel-like factor 4 (KLF4) and its mRNA interaction with microRNA (miRNAs) and circular RNA (circRNAs) at 0 hour and the 120 th hour in the rat liver regeneration. Methods The rat 2 / 3 hepatectomy (partial hepatectomy, PH) model was prepared as described by Higgins, the hepatocytes were isolated according to the method of Smedsrod et al, the expression changes of mRNA, miRNA and circRNA together named as competing endogenous RNA (ceRNA) were detected by the large-scale quantitative detection technology, the interaction network of ceRNA was constructed by Cytoscape 3. 2 software, and their correlation in expression and role were analyzed by ceRNA comprehensive analysis. Results It was found that at the 0 hour and the 120th hour PH, the ratio value of KLF4 mRNA showed 1. 00±0. 16 and 3. 14±0. 27, miR-881-3p displays 18. 30±1. 44 and 0. 47±0. 02, circRNA_20298 indicated 0. 32±0. 10 and 4. 24±0. 22, circRNA_14826 showed 0. 42±0. 13 and 0. 61±0. 08. At the same time, the four kinds of cell apoptosis-related genes adrenoceptor beta 2 (ADRB2), dimethylarginine dimethylaminohydrolase 2 (DDAH2), annexin A5 (ANXA5), ect, which were promoted in expression by KLF4, were down-regulated at 0 hour after PH, but the cell apoptosis-related genes synuclein gamma (SNCG), glutathione-disulfide reductase (GSR), FYVE, RhoGEF and PH domain containing 4 (FGD4), ect, which were inhibited in expression by KLF4, were up-regulated at 0 hour after PH. On the other hand, the cell apoptosis-related genes ANXA5 and thymosin beta 10 (TMSB10), which are promoted in expression by KLF4, were up-regulated at the 120th hour after PH, but the cell apoptosis-related genes chloride intracellular channel 4 (CLIC4) and ataxin 3 (ATXN3), ect, which were inhibited in expression by KLF4, were down-regulated at the 120th hour after PH. Conclusion The correlation in expression and role of the miRNAs, which are inhibited by circRNAs, KLF4, its mRNA is inhibited by miRNAs, and the cell apoptosis-related genes, which are regulated by KLF4, are helpful for the hepatocyte to be in active state 0 hour after PH and to be in apoptotic state 120-hour after PH.

Objective To explore the role pathway and pattern of the sex determining region box transcription factor 2 (SOX2) and its mRNA interaction with microRNA(miRNAs, miR) and circular RNA(circRNA) at 0 hour and 2 hours in the rat liver regeneration. Methods The rat 2/3 hepatectomy (partial hepatectomy, PH) model was prepared as described by Higgins, the hepatocytes were isolated according to the method of Smedsrod et al, the expression changes of mRNA, miRNA and circRNA [together named as competing endogenous RNAs(ceRNA)] were detected by the large-scale quantitative detection technology, the interaction network of ceRNA was constructed by Cytoscape 3.2 software, and their correlation in expression and role were analyzed by ceRNA comprehensive analysis. Results It was found that at the 0 hour and 2 hours after PH, the ratio value of SOX2 mRNA shows 1.00±0.09 and 2.15±0.48, miR-3558-3p displays 4.53± 0.10 and 0.81±0.16, circRNA_18404 shows 1.24±0.04 and 11.10±0.57, circRNA_18045 displays 1.97±0.47 and 4.44± 0.23. At the same time, the eight kinds of cell dedifferentiation-related genes AT-rich interaction domain 5A (ARID5A), activating transcription factor 3 (ATF3), BTG anti-proliferation factor 2 (BTG2), etc, which are prometed in expression by SOX2, were down-regulated at 0 h after PH, but the cell differentiation-related genes interferon regulatory factor 6 (IRF6) and somatostatin (SST), which are inhibited in expression by SOX2, were up-regulated at 0 hour after PH. On the other hand, the eight kinds of cell dedifferentiation-related genes ARID5A, ATF3, BTG2, etc, which are promoted in expression by SOX2, were up-regulated at 2 hours after PH, but the cell differentiation-related gene SST, which is inhibited in expression by SOX2, was down-regulated, and IRF6 had no meaningful changes in expression at 2 hours after PH. Conclusion The correlation in expression and role of the miRNA, which are inhibited by circRNA, SOX2, its mRNA is inhibited by miRNA, and the cell stem-related genes, which are regulated by SOX2, are helpful for the hepatocyte to be in differentiation state at 0 hour after PH and to be in stem state at 2 hours after PH.

Objective To explore the role pathway and pattern of the transcription factor myeloma cancer gene (MYC) and its mRNA interaction with microRNA(miRNA, miR) and ciccular RNA(circRNAs) at 0 hour and 6 hour in the rat liver regeneration. Methods The rat 2/3 hepatectomy (partial hepatectomy，PH) model was prepared as described by Higgins, the expression changes of mRNA, miRNA and circRNA together named as competing endogenous RNAs(ceRNA) of remnant liver were detected by the large-scale quantitative detection technology, the interaction network of ceRNA was constructed by Cytoscape 3.2 software, and their correlation in expression and role were analyzed by ceRNA comprehensive analysis. Results It was found that at 0 hour and 6 hours after PH, the ratio value of MYC mRNA showed 0.15±0.03 and 2.36±0.20, miR-540-3p displays 3.00±0.43 and 0.79±0.01, circRNA_04996 showed 1.43±0.43 and 3.14±0.94. At the same time, the four kinds of inflammatory reaction-related genes plasminogen activator urokinase receptor (PLAUR), tumor necrosis factor (TNF), interleukin 1 receptor type 2 (IL1R2), ect, which were prometed in expression by MYC, were down-regulated at 0 hour after PH, but the inflammatory reaction-related genes natriuretic peptide A (NPPA), nuclear receptor subfamily O group B member 2 (NROB2) and peroxisome proliferator activated receptor alpha (PPARA), which were inhibited in expression by MYC, were up-regulated at 0 hour after PH. On the other hand, the three kinds of inflammatory reaction-related genes PLAUR, TNF, IL1R2, ect, which are prometed in expression by MYC, were up-regulated at 6 hours after PH, but the inflammatory reaction-related genes NPPA, NROB2 and PPARA, which were inhibited in expression by MYC, were down-regulated at 6 hours after PH. Conclusion The correlation in expression and role of the miRNA, which are inhibited by circRNAs, MYC, its mRNA is inhibited by miRNAs, and the inflammatory reaction-related genes, which are regulated by MYC, and are helpful for the hepatocyte to be in non-inflammatory reaction state at 0 hour after PH and to be in inflammatory reaction state at 6 hours after PH.