Disulfidptosis-associated long non-coding RNA signature predicts the prognosis, tumor microenvironment, and immunotherapy and chemotherapy options in colon adenocarcinoma.

BACKGROUND: Disulfidptosis is independent of apoptosis, ferroptosis, and cuproptosis and is associated with cancer progression, treatment response, and prognosis. However, the predictive potential of disulfidptosis-associated lncRNAs in colon adenocarcinoma (COAD) and their features in the tumor immune microenvironment (TIME) require further elucidation. METHODS: RNA transcriptome, clinical information, and mutation data of COAD samples were obtained from the TCGA database. The risk model was first constructed by co-expression analysis of disulfidptosis genes and lncRNAs, and prognostic lncRNAs were screened using Cox regression, followed by least absolute shrinkage and selection operator analysis. Enrichment analyses were performed to explore the underlying biological functions and signaling of model-associated differentially expressed genes (MADEGs). Moreover, TIME of MADEGs was analyzed to assess the immunotherapy. Finally, the expression levels of the lncRNAs were verified by taking specimens of patients with COAD from the Affiliated Hospital of Qingdao University. RESULTS: We constructed a prognosis-related risk model based on four disulfidptosis-associated lncRNAs (ZEB1-AS1, SNHG16, SATB2-AS1, and ALMS1-IT1). By analyzing the survival of patients in the whole, training, and test groups, we found that patients with COAD in the low-risk group had better overall survival than those in the high-risk group. Validation of the model via Cox analysis and clinical indicators demonstrated that the model had a decent potential for predicting the prognosis of patients with COAD. Enrichment analyses revealed that the MADEGs were related to disulfidptosis-associated biological functions and cancer pathways. Furthermore, patients with COAD in the high-risk group had more positive responses to immune checkpoint inhibitors (ICIs) than those in the low-risk group, as confirmed by TIME analysis. ZEB1-AS1, SNHG16, and ALMS1-IT1 were expressed at higher levels in tumor samples than those in the corresponding paracancerous samples (p < 0.05), whereas SATB2-AS1 was upregulated in the paracancerous samples (p < 0.05). CONCLUSIONS: This signature may guide prognosis, molecular mechanisms, and treatment strategies, including ICIs and chemotherapy, in patients with COAD.

Modeling of mesenchymal hybrid epithelial state and phenotypic transitions in EMT and MET processes of cancer cells.

Based on the transcriptional regulatory mechanisms between microRNA-200 and transcription factor ZEB in an individual cancer cell, a minimal dynamic model is proposed to study the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) processes of cancer cells. It is shown that each cancer cell can exit in any of three phenotypic states: the epithelial (E) state, the mesenchymal (M) state, and the epithelial/mesenchymal (E/M) hybrid state, and the state of cancer cell can interconvert between different states. The phase diagram shows that there are monostable, bistable, and tristable phenotypic states regions in a parameters plane. It is found that different pathway in the phase diagram can correspond to the EMT or the MET process of cancer cells, and there are two possible EMT processes. It is important that the experimental phenomenon of E/M hybrid state appearing in the EMT process but rather in the MET process can be understood through different pathways in the phase diagram. Our numerical simulations show that the effects of noise are opposite to these of time delay on the expression of transcription factor ZEB, and there is competition between noise and time delay in phenotypic transitions process of cancer cells.

A kinetic model of multiple phenotypic states for breast cancer cells.

Quantitative modeling of microscopic genes regulatory mechanisms in an individual cell is a crucial step towards understanding various macroscopic physiological phenomena of cell populations. Based on the regulatory mechanisms of genes zeb1 and cdh1 in the growth and development of breast cancer cells, we propose a kinetic model at the level of single cell. By constructing the effective landscape of underlying stationary probability for the genes expressions, it is found that (i) each breast cancer cell has three phenotypic states (i.e., the stem-like, basal, and luminal states) which correspond to three attractions of the probability landscape. (ii) The interconversions between phenotypic states can be induced by the noise intensity and the property of phenotypic switching is quantified by the mean first-passage time. (iii) Under certain conditions, the probabilities of each cancer cell appearing in the three states are consistent with the macroscopic phenotypic equilibrium proportions in the breast cancer SUM159 cell line. (iv) Our kinetic model involving the TGF-ß signal can also qualitatively explain several macroscopic physiological phenomena of breast cancer cells, such as the "TGF-ß paradox" in tumor therapy, the five clinical subtypes of breast cancer cells, and the effects of transient TGF-ß on breast cancer metastasis.

A van der Waals-like Transition Between Normal and Cancerous Phases in Cell Populations Dynamics of Colorectal Cancer.

Based on a deterministic continuous model of cell populations dynamics in the colonic crypt and in colorectal cancer, we propose four combinations of feedback mechanisms in the differentiations from stem cells (SCs) to transit cells (TCs) and then to differentiated cells (DCs), the four combinations include the double linear (LL), the linear and saturating (LS), the saturating and linear (SL), and the double saturating (SS) feedbacks, respectively. The relative fluctuations of the population of SCs, TCs, and DCs around equilibrium states with four feedback mechanisms are studied by using the Langevin method. With the increasing of net growth rate of TCs, it is found that the Fano factors of TCs and DCs go to a peak in a transient phase, and then increase again to infinity in the cases of LS and SS feedbacks. The "up-down-up" characteristic on the Fano factor (like the van der Waals loop) demonstrates that there exists a transient phase between the normal and cancerous phases, our novel findings suggest that the mathematical model with LS or SS feedback might be better to elucidate the dynamics of a normal and abnormal (cancerous) phases.

Synthesis, characterization, and DNA-binding studies of ruthenium complexes [Ru(tpy)(ptn)]2+ and Ru(dmtpy)(ptn)]2+.

Two ruthenium(II) polypyridyl complexes [Ru(tpy)(ptn)](2+) (1) and Ru(dmtpy)(ptn)](2+) (2) (ptn=3-(1,10-phenanthrolin-2-yl)-as-triazino[5,6-f]naphthalene, tpy=2,2':6',2"-terpyridine, dmtpy=5,5'-dimethyl-2,2':6',2"-terpyridine) have been synthesized and characterized by elemental analysis, (1)H NMR, mass spectrometry and crystal structure analysis. Spectroscopic studies together with isothermal titration calorimetry (ITC) and viscosity measurements prove that two complexes bind to DNA in an intercalative mode. ITC experiments show that the binding mode for complex 2 is entropically driven, while an entropy-driven initial binding of complex 1 is followed by an entropically and enthalpically favorable process. This difference may be attributed to the ancillary ligand effects on the DNA binding of Ru(II) complexes. Circular dichroism titrations of calf thymus DNA (CT-DNA) with Ru(II) complexes show that complexes 1 and 2 induce B to Z conformational transition of calf thymus DNA at low ionic strength (0.05 M NaCl). The induced Z-DNA conformation can revert to B form when Ru(II) complexes are displaced by ethidium bromide or at high ionic strengths ([NaCl]=0.4 M), but keeps intact with temperature ranged from 25 to 90 °C. The unique structure and characteristics of Ru(II) complexes designed in this investigation will be useful for the study of Z-DNA.