Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer.

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

[Expression of interleukin-37, vascular endothelial growth factor A, and transforming growth factor-ß1 and their correlation with T cells in children with primary immune thrombocytopenia]. / å„¿ç«¥åŽŸå‘å ç–«æ€§è¡€å°æ¿å‡å°‘ç—‡IL-37、VEGFA、TGF-ß1çš„è¡¨è¾¾åŠå ¶ä¸ŽTç»†èƒžçš„ç›¸å ³æ€§ç ”ç©¶.

OBJECTIVES: To investigate the expression of interleukin-37 (IL-37), vascular endothelial growth factor A (VEGFA), and transforming growth factor-ß1 (TGF-ß1) in children with primary immune thrombocytopenia (ITP) and their correlation with T cells. METHODS: A retrospective analysis was conducted on 45 children with ITP (ITP group) who were admitted to Handan Central Hospital from January 2020 to April 2022, and 30 healthy children who underwent physical examination during the same period were included as the healthy control group. The mRNA expression levels of IL-37, VEGFA, and TGF-ß1 and the levels of regulatory T cells (Treg) and helper T cells 17 (Th17) were measured before and after treatment, and the correlation between the mRNA expression levels of IL-37, VEGFA, and TGF-ß1 and the levels of Treg, Th17, and Treg/Th17 ratio were analyzed. RESULTS: Compared with the healthy control group, the ITP group had a significantly higher mRNA expression level of IL-37 and a significantly higher level of Th17 before and after treatment, as well as significantly lower mRNA expression levels of VEGFA and TGF-ß1 and significantly lower levels of Treg and Treg/Th17 ratio (P<0.05). After treatment, the ITP group had significant reductions in the mRNA expression level of IL-37 and the level of Th17 and significant increases in the mRNA expression levels of VEGFA and TGF-ß1 and the levels of Treg and Treg/Th17 ratio (P<0.05). Correlation analysis showed that in the ITP group, the mRNA expression levels of IL-37 and TGF-ß1 were negatively correlated with the levels of Treg and Treg/Th17 ratio (P<0.05) and were positively correlated with the level of Th17 (P<0.05) before and after treatment; the mRNA expression level of VEGFA was positively correlated with the levels of Treg and Treg/Th17 ratio (P<0.05) and was negatively correlated with the Th17 level (P<0.05) before and after treatment. CONCLUSIONS: Abnormal expression levels of IL-37, VEGFA, and TGF-ß1 may be observed in children with ITP, which is significantly associated with the imbalance of Treg/Th17 ratio. It is speculated that the cytokines such as IL-37, VEGFA, and TGF-ß1 may be involved in the development and progression of ITP or may become important potential targets for the treatment of children with ITP. Citation:Chinese Journal of Contemporary Pediatrics, 2023, 25(11): 1131-1136.

Mineralization of cyanides via a novel Electro-Fenton system generating •OH and •O2.

Traditional methods of cyanides' (CN-) mineralization cannot overcome the contradiction between the high alkalinity required for the inhibition of hydrogen cyanide evolution and the low alkalinity required for the efficient hydrolysis of cyanate (CNO-) intermediates. Thus, in this study, a novel Electro-Fenton system was constructed, in which the free cyanides released from ferricyanide photolysis can be efficiently mineralized by the synergy of •OH and •O2-. The complex bonds in ferricyanide (100 mL, 0.25 mM) were completely broken within 80 min under ultraviolet radiation, releasing free cyanides. Subsequently, in combination with the heterogeneous Electro-Fenton process, •OH and •O2- were simultaneously generated and 92.9% of free cyanides were transformed into NO3- within 120 min. No low-toxic CNO- intermediates were accumulated during the Electro-Fenton process. A new conversion mechanism was proposed that CN- was activated into electron-deficient cyanide radical (•CN) by •OH, and then the •CN intermediates reacted with •O2- via nucleophilic addition to quickly form NO3-, preventing the formation of CNO- and promoting the mineralization of cyanide. Furthermore, this new strategy was used to treat the actual cyanide residue eluent, achieving rapid recovery of irons and efficient mineralization of cyanides. In conclusion, this study proposes a new approach for the mineralization treatment of cyanide-containing wastewater.

Systematic profiling of invasion-related gene signature predicts prognostic features of lung adenocarcinoma.

Due to the high heterogeneity of lung adenocarcinoma (LUAD), molecular subtype based on gene expression profiles is of great significance for diagnosis and prognosis prediction in patients with LUAD. Invasion-related genes were obtained from the CancerSEA database, and LUAD expression profiles were downloaded from The Cancer Genome Atlas. The ConsensusClusterPlus was used to obtain molecular subtypes based on invasion-related genes. The limma software package was used to identify differentially expressed genes (DEGs). A multi-gene risk model was constructed by Lasso-Cox analysis. A nomogram was also constructed based on risk scores and meaningful clinical features. 3 subtypes (C1, C2 and C3) based on the expression of 97 invasion-related genes were obtained. C3 had the worst prognosis. A total of 669 DEGs were identified among the subtypes. Pathway enrichment analysis results showed that the DEGs were mainly enriched in the cell cycle, DNA replication, the p53 signalling pathway and other tumour-related pathways. A 5-gene signature (KRT6A, MELTF, IRX5, MS4A1 and CRTAC1) was identified by using Lasso-Cox analysis. The training, validation and external independent cohorts proved that the model was robust and had better prediction ability than other lung cancer models. The gene expression results showed that the expression levels of MS4A1 and KRT6A in tumour tissues were higher than in normal tissues, while CRTAC1 expression in tumour tissues was lower than in normal tissues. The 5-gene signature prognostic stratification system based on invasion-related genes could be used to assess prognostic risk in patients with LUAD.

Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the surveillance, epidemiology, and end results (SEER) database.

BACKGROUND: Whether the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system (AJCC-7) is a successful revision remains debatable. We aimed to compare the predictive capacity of the AJCC-7 for colorectal cancer with the 6th edition of the AJCC TNM staging system (AJCC-6). METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) dataset consisting of 158,483 records was used in this study. We evaluated the predictive capacity of the two editions of the staging system using Harrell's C index and Bayesian Information Criterion (BIC). RESULTS: There was a significant prognostic difference between patients at stage IIB and IIC (P < 0.001). Stage III patients with similar prognoses were adequately sub-grouped in the same stage according to AJCC-7. The Harrell's C index revealed a value of 0.7692 for AJCC-7, which was significantly better than 0.7663 for AJCC-6 (P < 0.001). BIC analysis provided consistent results (P < 0.001). CONCLUSIONS: This study demonstrates that AJCC-7 is superior to the AJCC-6 staging system in predictive capacity.

Which is a more accurate predictor in colorectal survival analysis? Nine data mining algorithms vs. the TNM staging system.

OBJECTIVE: Over the past decades, many studies have used data mining technology to predict the 5-year survival rate of colorectal cancer, but there have been few reports that compared multiple data mining algorithms to the TNM classification of malignant tumors (TNM) staging system using a dataset in which the training and testing data were from different sources. Here we compared nine data mining algorithms to the TNM staging system for colorectal survival analysis. METHODS: Two different datasets were used: 1) the National Cancer Institute's Surveillance, Epidemiology, and End Results dataset; and 2) the dataset from a single Chinese institution. An optimization and prediction system based on nine data mining algorithms as well as two variable selection methods was implemented. The TNM staging system was based on the 7(th) edition of the American Joint Committee on Cancer TNM staging system. RESULTS: When the training and testing data were from the same sources, all algorithms had slight advantages over the TNM staging system in predictive accuracy. When the data were from different sources, only four algorithms (logistic regression, general regression neural network, bayesian networks, and Naïve Bayes) had slight advantages over the TNM staging system. Also, there was no significant differences among all the algorithms (p>0.05). CONCLUSIONS: The TNM staging system is simple and practical at present, and data mining methods are not accurate enough to replace the TNM staging system for colorectal cancer survival prediction. Furthermore, there were no significant differences in the predictive accuracy of all the algorithms when the data were from different sources. Building a larger dataset that includes more variables may be important for furthering predictive accuracy.

Integrated ratio of metastatic to examined lymph nodes and number of metastatic lymph nodes into the AJCC staging system for colon cancer.

OBJECTIVE: At present, only the number of metastatic lymph nodes (LNs+) is used for the pN category of AJCC TNM system for colon cancer. Recently, the ratio of metastatic to examined lymph nodes (LNR) has been reported to represent powerful independent predictive capacity in colon cancer. We sought to propose a novel category (nLN) which intergrades LNR and LNs+ into the AJCC staging system for colon cancer. DESIGN: 34476 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) dataset with stage III colon cancer were reviewed. Harrell's C statistic was used to evaluate the predictive capacity. The Cox proportional hazards model was used to construct a novel category. RESULTS: The LNR category had more predictive capacity than the pN category in whole groups of patients (Harrell's C index: 0.6194 vs 0.6113, p = 0.003). Subgroup analysis showed that the LNR category was not better than pN category in predictive capacity if the number of lymph nodes examined was more than 13. We also found that there was significant survival heterogeneity among different pN categories at the same LNR category (P<0.001). The Harrell's C index for our nLN category which intergrades LNR and LNs+ was 0.6228, which was significant higher than that of the pN category (Harrell's C index: 0.6113, P<0.001) or LNR category (Harrell's C index: 0.6194, P = 0.005), respectively. CONCLUSION: To evaluate the prognosis of colon cancer, our nLN category which intergrades LNR with LNs+ is more accurate than the pN category or LNR category, respectively.

Is the seventh edition of the UICC/AJCC TNM staging system reasonable for patients with tumor deposits in colorectal cancer?

OBJECTIVE: To assess the rationality of the seventh edition of TNM staging system on tumor deposits (TDs) and propose a novel subclassification. SUMMARY BACKGROUND DATA: The TDs had been debated for many years. The seventh edition of TNM staging system proposed a "pN1c" concept. However, the value of the modification is still debated. METHODS: A total of 1541 patients with colorectal cancer were reviewed. Overall survival rates were compared between patients without LNM but TD (+), and those who were TD (-). The TDs were stratified into the "any T + any N" category. Two-step multivariate analysis was performed to identify significant prognostic factors. Univariate analysis was used to determine whether a correlation existed between the number of TDs and prognosis. RESULTS: There was a significant prognostic difference between patients without LNM or TDs compared with those with positive TDs. Only in T3N2bM0 there was a significant prognostic difference between LNM (+), TD (+) patients and TD (-) patients. The seventh edition of TNM staging system was substituted by the novel TNM staging system in 2-step multivariate analysis. Only in T3N1cM0 there was a significant prognostic difference between patients with only 1 TD and those with more than 1 TD. CONCLUSION: The seventh edition of TNM staging system on TDs satisfactorily predicts patients' outcome for those without LNM. Patients who categorized as T3N2bM0TD (+) and T4N2bM0TD (-/+) should be reclassified as stage IV. Number of TDs was not an independent prognostic parameter in the TNM staging system.

Which is the most suitable classification for colorectal cancer, log odds, the number or the ratio of positive lymph nodes?

OBJECTIVE: The aim of the current study was to investigate which is the most suitable classification for colorectal cancer, log odds of positive lymph nodes (LODDS) classification or the classifications based on the number of positive lymph nodes (pN) and positive lymph node ratio(LNR) in a Chinese single institutional population. DESIGN: Clinicopathologic and prognostic data of 1297 patients with colorectal cancer were retrospectively studied. The log-rank statistics, Cox's proportional hazards model, the Nagelkerke R(2) index and a Harrell's C statistic were used. RESULTS: Univariate and three-step multivariate analyses identified that LNR was a significant prognostic factor and LNR classification was superior to both the pN and LODDS classifications. Moreover, the results of the Nagelkerke R(2) index (0.130) and a Harrell's C statistic (0.707) of LNR showed that LNR and LODDS classifications were similar and LNR was a little better than the other two classifications. Furthermore, for patients in each LNR classification, prognosis was homologous between those in different pN or LODDS classifications. However, for patients in pN1a, pN1b, LODDS2 and LODDS3 classifications, significant differences in survival were observed among patients in different LNR classifications. CONCLUSIONS: For patients with colorectal cancer, the LNR classification is more suitable than pN and LODDS classifications for prognostic assessment in a Chinese single institutional population.

Can lymph node ratio take the place of pN categories in the UICC/AJCC TNM classification system for colorectal cancer?

BACKGROUND: Lymph node ratio (LNR) has been reported to represent a powerful independent prognostic value in some malignancies. The significance of LNR in colorectal cancer is still under debate. METHODS: A total of 505 patients with stage III colorectal cancer were reviewed. Using running log-rank statistics, we calculated the best cutoff values for LNRs and proposed a novel rN category: rN1, 0% < LNR ≤ 35%; rN2, 35% < LNR ≤ 69%; and rN3, LNR > 69%. A Spearman's correlation coefficient test was used to assess the correlation between the number of retrieved nodes and the number of metastatic nodes, as well as the number of retrieved nodes and the LNRs. Univariate and two-step multivariate analyses were performed, respectively, to identify the significant prognostic clinicopathologic factors. RESULTS: The 5-year overall survival rate decreased significantly with increasing LNRs: rN(1) = 61% survival rate, rN(2) = 30.3% survival rate, and rN(3) = 11.2% survival rate (P < 0.001). Univariate and two-step multivariate analyses identified the rN category as a significant prognostic factor no matter whether the minimum number of LNs retrieved was met. There was a significant prognostic difference among different rN categories for any pN category, but no apparent prognostic difference was seen between different pN categories in any rN category. Moreover, marked heterogeneity could be seen within III(a-c) substages when survival was compared among rN(1-3) categories but not between pN(1-2) categories. CONCLUSIONS: rN categories have more potential for predicting patient outcomes and are superior to the UICC/AJCC pN categories. We recommend rN categories for prognostic assessment and rN categories should be reported routinely in histopathological reports.

Is pT2 subclassification feasible to predict patient outcome in colorectal cancer?

BACKGROUND: This study aimed to evaluate the prognostic impact of pT2 subclassification according to the depth of muscularis propria (MP) invasion and to explore the clinicopathologic factors correlated with lymph node metastasis (LNM) and postoperative hematogenous metastasis in pT2 colorectal cancer. METHODS: A total of 317 patients with pT2 colorectal cancer were reviewed. pT2a represents the infiltration of the inner circumferential layer of the MP, and pT2b represents the infiltration of the outer longitudinal layer of the MP. Clinicopathologic factors and overall survival rates were compared in patients with pT2a and pT2b stage cancers. Multivariate analysis was performed to identify the significantly important prognostic factors. Univariate and multivariate analyses were performed, respectively, to identify the significantly important clinicopathologic factors correlated with LNM and postoperative hematogenous metastasis in pT2 colorectal cancer. RESULTS: According to the depth of MP invasion, 107 patients were classified as pT2a and 210 patients were classified as pT2b. Among them, there were 55 patients with LNM, 34 patients with postoperative hematogenous metastasis. There was significant difference in most of clinicopathologic features between patients in the pT2a and pT2b stages. Multivariate analysis identified pN stage (P < .001) and tumor location (P = .036) were independent factors affecting the prognosis. However, no apparent difference was observed between pT2a versus pT2b cancer. Univariate and multivariate analyses uniformly identified lymphovascular invasion (P = .035) and the depth of MP invasion (P = .005) as significantly correlated with LNM. Multivariate analysis found tumor location (P = .021) and the presence or absence of LNM (P < .001) were important factors affecting postoperative hematogenous metastasis. CONCLUSIONS: In pT2 colorectal cancer treated with R0 surgery, there is a high risk of LNM in deep MP invasion versus superficial MP invasion. The pT2 subclassification system had no significant advantage in identifying a different prognosis, except for predicting the LNM before surgery. Rectal cancer and the presence of LNM were high-risk factors resulting in hematogenous metastasis postoperatively.