Enhancing cisplatin drug sensitivity through PARP3 inhibition: The influence on PDGF and G-coupled signal pathways in cancer.

Drug resistance poses a significant challenge in cancer treatment despite the clinical efficacy of cisplatin. Identifying and targeting biomarkers open new ways to improve therapeutic outcomes. In this study, comprehensive bioinformatic analyses were employed, including a comparative analysis of multiple datasets, to evaluate overall survival and mutation hotspots in 27 base excision repair (BER) genes of more than 7,500 tumors across 23 cancer types. By using various parameters influencing patient survival, revealing that the overexpression of 15 distinct BER genes, particularly PARP3, NEIL3, and TDG, consistently correlated with poorer survival across multiple factors such as race, gender, and metastasis. Single nucleotide polymorphism (SNP) analyses within protein-coding regions highlighted the potential deleterious effects of mutations on protein structure and function. The investigation of mutation hotspots in BER proteins identified PARP3 due to its high mutation frequency. Moving from bioinformatics to wet lab experiments, cytotoxic experiments demonstrated that the absence of PARP3 by CRISPR/Cas9-mediated knockdown in MDA-MB-231 breast cancer cells increased drug activity towards cisplatin, carboplatin, and doxorubicin. Pathway analyses indicated the impact of PARP3 absence on the platelet-derived growth factor (PDGF) and G-coupled signal pathways on cisplatin exposure. PDGF, a critical regulator of various cellular functions, was downregulated in the absence of PARP3, suggesting a role in cancer progression. Moreover, the influence of PARP3 knockdown on G protein-coupled receptors (GPCRs) affects their function in the presence of cisplatin. In conclusion, the study demonstrated a synthetic lethal interaction between GPCRs, PDGF signaling pathways, and PARP3 gene silencing. PARP3 emerged as a promising target.

[Sinomenine inhibits PDGF/PDGFR signaling pathway to reduce RA-FLS migration induced by NETs].

This study aims to decipher the mechanism of sinomenine in inhibiting platelet-derived growth factor/platelet-derived growth factor receptor(PDGF/PDGFR) signaling pathway in rheumatoid arthritis-fibroblast-like synoviocyte(RA-FLS) migration induced by neutrophil extracellular traps(NETs). RA-FLS was isolated from the synovial tissue of 3 RA patients and cultured. NETs were extracted from the peripheral venous blood of 4 RA patients and 4 healthy control(HC). RA-FLS was classified into control group, HC-NETs group, RA-NETs group, RA-NETs+sinomenine group and RA-NETs+sinomenine+CP-673451 group. RNA-sequencing(RNA-seq) was conducted to identify the differentially expressed genes between HC-NETs and RA-NETs groups. Sangerbox was used to perform the Gene Ontology(GO) function and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape was employed to build the protein-protein interaction(PPI) network. AutoDock Vina and PyMOL were used for molecular docking of sinomenine with PDGFß and PDGFRß. The cell proliferation and migration were determined by the cell counting kit-8(CCK-8) and cell scratch assay, respectively. Western blot was employed to determine the protein level of PDGFRß. Real-time quantitative polymerase chain reaction(RT-qPCR) was carried out to determine the mRNA levels of matrix metalloproteinases(MMPs). The results revealed that neutrophils in RA patients were more likely to produce NETs. Compared with HC-NETs group, RA-NETs group showed up-regulated expression of PDGFß and PDGFRß. Compared with control group, RA-NETs group showed increased cell proliferation and migration and up-regulated protein level of PDGFRß and mRNA levels of PDGFß, PDGFRß, MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs group, RA-NETs+sinomenine group presented decreased cell proliferation and migration and down-regulated protein and mRNA level of PDGFRß and mRNA levels of MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs+sinomenine group, the proliferation ability of RA-NETs+sinomenine+CP-673451 group decreased(P<0.05). The findings prove that sinomenine reduces the RA-NETs-induced RA-FLS migration by inhibiting PDGF/PDGFR signaling pathway, thus mitigating RA.

The role of THBS1 and PDGFD in the immune microenvironment of Helicobacter pylori-associated gastric cancer.

BACKGROUND AND STUDY AIMS: Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric cancer. However, there is still a need to identify potential immunotherapy targets. MATERIAL AND METHODS: We used the GSE116312 dataset of Helicobacter pylori-associated gastric cancer to identify differentially expressed genes, which were then overlapped with immune genes from the ImmPort database. The identified immune genes were used to classify gastric cancer samples and evaluate the relationship between classification and tumor mutations, as well as immune infiltration. An immune gene-based prognostic model was constructed, and the expression levels of the genes involved in constructing the model were explored in the tumor immune microenvironment. RESULTS: We successfully identified 60 immune genes and classified gastric cancer samples into two subtypes, which showed differences in prognosis, tumor mutations, immune checkpoint expression, and immune cell infiltration. Subsequently, we constructed an immune prognostic model consisting of THBS1 and PDGFD, which showed significant associations with macrophages and fibroblasts. CONCLUSION: We identified abnormal expression of THBS1 and PDGFD in cancer-associated fibroblasts (CAFs) within the tumor immune microenvironment, suggesting their potential as therapeutic targets.

Identification of a novel mutation of Platelet-Derived Growth Factor-C (PDGFC) gene in a girl with Non-Syndromic cleft lip and palate.

BACKGROUND: Cleft lip with or without cleft palate (CL/CP) is a prevalent congenital malformation. Approximately 16 candidate loci for CL/CP have been identified in both animal models and humans through association or genetic linkage studies. One of these loci is the platelet-derived growth factor-C (PDGFC) gene. In animal models, a mutation in the PDGFC gene has been shown to lead to CL/CP, with PDGF-C protein serving as a growth factor for mesenchymal cells, playing a crucial role in embryogenesis during the induction of neural crest cells. In this study, we present the identification of a novel frameshift mutation in the PDGFC gene, which we hypothesize to be associated with CL/CP, within a consanguineous Iranian family. CASE PRESENTATION: The proband was a 3-year-old girl with non-syndromic CL/CP. A history of craniofacial clefts was present in her family. Following genetic counseling, karyotype analysis and whole-exome sequencing (WES) were performed. Cytogenetic analysis revealed normal results, while WES analysis showed that the proband carried a homozygous c.546dupA (p.L183fs) mutation in the PDGFC gene. Sanger sequencing confirmed that her parents were carriers of the mutation. CONCLUSION: The c.546dupA (p.L183fs) mutation of PDGFC has not been previously reported and was not found in human genome databases. We speculate that the c.546dupA mutation of the PDGFC gene, identified in the Iranian patient, may be responsible for the phenotype of non-syndromic CL/CP (ns-CL/CP). Further studies are warranted to explore the specific pathogenesis of the PDGFC mutation in ns-CL/CP.

Role of Platelet-Derived Growth Factor-mediated signaling in carcinogenesis and metastasis.

Platelet-Derived Growth Factor (PDGF) mediated signaling has emerged as one of the most extensively studied cascades in cancer development and progression. Overwhelmingly increasing data obtained from preclinical and clinical studies has helped us to develop a near-complete resolution of PDGF/PDGFR signaling landscape. Phenotype- and genotype-driven studies have provided proof-of-concept that therapeutic targeting of PDGF/PDGFR signaling axis is necessary to improve clinical outcome.   Kinase inhibitor drug discovery programmes have broadened their focus to include a wide variety of kinase targets. Based on the insights gleaned from previously published high-impact research, it is clear that different transduction cascades crosstalk with PDGF/PDGFR signaling during primary tumor invasion, dissemination and ultimate metastasis of cancer cells. In this commentary, we will focus on involvement of PDGF/PDGFR signaling in different cancers and how pharmacological targeting of this signaling cascade inhibits cancer progression.

Las obsesiones antes de Freud: historia y clínica / Obsessions before Freud: history and clinical practice

Se analiza el significado del concepto de “obsesión” en el alienismo del siglo XIX. Desde el punto de vista clínico, la descripción de Esquirol fue completada por otros autores (Jules Falret, Legrand du Saulle). En el ámbito de la reflexión psicopatológica, el alienismo francés, con el delirio emotivo de Morel o la psicastenia de Janet, defendió la teoría emocional, frente al trastorno intelectual propuesto por los médicos alemanes. Finalmente, se insiste en la importancia del marco cultural en la aparición de los síntomas obsesivos y de su interpretación. En este sentido, se estudian las relaciones de los escrúpulos religiosos con la melancolía o la aparición de categorías diagnósticas sometidas a los códigos y mentalidades fin-de-siècle.

The article analyses the significance of the concept of “obsession” in nineteenth-century alienism. From a clinical point of view, Esquirol’s description was completed by other authors (Jules Falret, Legrand du Saulle). In the area of psychopathological studies, French alienism, with Morel’s emotional delirium or Janet’s psychasthenia, defended the emotional theory, as opposed to the intellectual disorder proposed by German doctors. Lastly, the importance of the cultural framework is stressed in the appearance of obsessive symptoms and their interpretation. Along these lines, the article discusses the relationship of religious scruples to melancholy or the appearance of diagnostic categories subject to fin de siècle codes and mentalities.

Polyomavirus-induced malignant transformation: comparative analysis of wild type and mutant middles T-overexpressing cell lines

Polyomavirus, a DNA tumor virus, expresses three viral oncoproteins (large, middle and small T antigens), causes malignant transformation in cell culture and induces multiple tumors in vivo. The middle T (MT) antigen seems to play an essential role in transformation and tumori-genicity. The observation that MT-overexpressing cell lines are able to grow in the absence of PDGF (platelet-derived growth factor) led several laboratories to study the mechanism underlying MT-induced growth deregulation and the signal transduction pathway used by this viral oncoprotein. A number of cellular proteins were shown to be common to both the normal PDGF mitogenic pathway and the MT transforming pathway. The expression of some PDGF primary response genes (fos, jun, myc, JE, KC) was shown to be rendered constitutive by MT overexpression. Using MT mutants, important domains for binding and activation of cytoplasmic proteins were mapped. Wild type and mutant MT cell lines are used in our laboratory to analyze the expression and activity of the PDGF early response genes during cell transformation and correlate them with activation of specific cytoplasmic proteins. In addition to abrogating the PDGF requirement for growth, activation of cellular proteins caused by MT results in cell lines that have an altered morphology and are able to form colonies in agarose. These changes may be due to alterations in connexin 43 and other cell surface proteins.