Alpelisib and radiotherapy treatment enhances Alisertib-mediated cervical cancer tumor killing

xlomafota13 shared this article with you from Inoreader Alpelisib and radiotherapy treatment enhances Alisertib-mediated cervical cancer tumor killing Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3240-3251. eCollection 2021. ABSTRACT Human papilloma virus (HPV) is the main causative agent in cervical cancers. High-risk HPV cancers, including cervical cancer, are driven by major HPV oncogene, E6 and E7, which promote uncontrolled cell growth and genomic instability. We have previously shown that the presence of HPV E7 sensitizes cells to inhibition of aurora kinases (AURKs), which regulates the control of cell entry into and through mitosis. Such treatment is highly effective at eliminating early tumors and reducing large, late tumors. In addition, the presence of HPV oncogenes also sensitizes cells to inhibition of phosphoinositide 3-kinases (PI3Ks), a family of enzymes involved in cellular functions such as cell growth and proliferation. Using MLN8237 (Alisertib), an oral, selective inhibitor of AURKs, we investigated whether Alisertib treatment can improve tumor response when combined with e ither radiotherapy (RT) treatment or with a PI3K inhibitor, BYL719 (Alpelisib). Indeed, both RT and Alpelisib significantly improved Alisertib-mediated tumor killing, and the promising achieved results warrant further development of these combinations, and potentially translating them to the clinics. PMID:34249458 | PMC:PMC8263691 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

IL-17 signaling pathway plays a key role in laryngeal squamous cell carcinoma with ethnic specificity

xlomafota13 shared this article with you from Inoreader IL-17 signaling pathway plays a key role in laryngeal squamous cell carcinoma with ethnic specificity Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2684-2695. eCollection 2021. ABSTRACT Laryngeal squamous cell carcinoma (LSCC) is a common aggressive head and neck squamous cell carcinoma (HNSCC) and racial disparities have been reported to exist in it. However, its molecular mechanism and associated ethnic specificity are still unclear. Here, we leveraged mRNA expression data from 2 gene expression omnibus datasets (GSE142083 & GSE117005) of Chinese samples and the cancer genome atlas (TCGA) datasets of Caucasian samples to demonstrate the expression signature of LSCC. The GSE142083 dataset was used as the discovery set since it had 53 pairs of LSCC tissues and matched adjacent normal tissues, and the GSE117005 dataset was treated as the validation set with 5 pairs of tissues. Differential gene expression analysis and enrichment pathway analysis were performed. Besides, we employed weighted gene co-expression network analysis to identify hub g enes in validated pathways. The TCGA datasets were used to evaluate ethnic specificity. Immunohistochemistry (IHC) was employed to further validate the hub gene. Overall, the IL-17 signaling pathway was significantly enriched for upregulated genes in two Chinese datasets while not in TCGA datasets; and IL17RC, MAPK3, S100A8, MMP3, CXCL8, and TNFA1P3 were hub genes regulating such pathway. Therein, IL17RC might be the most important one and the IHC results displayed that the IL17RC gene upregulated in the LSCC tissue. IL-17 signaling pathway has an ethnicity-specific effect in LSCC where it is upregulated in the Chinese while not in the Caucasians and IL17RC might play a key role. Targeting genes located in the IL-17 signaling pathway may be beneficial for Chinese LSCC patients. PMID:34249422 | PMC:PMC8263688 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genetic variants of EML1 and HIST1H4E in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival

xlomafota13 shared this article with you from Inoreader Genetic variants of <em>EML1</em> and <em>HIST1H4E</em> in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3252-3262. eCollection 2021. ABSTRACT Both in vivo and in vitro evidence has supported a key role of myeloid cells in immune suppression in melanoma and in promoting melanocytic metastases. Some single-nucleotide polymorphisms (SNPs) have been shown to predict cutaneous melanoma-specific survival (CMSS), but the association between genetic variation in myeloid cell-related genes and cutaneous melanoma (CM) patient survival remains unknown. METHODS: we investigated associations between SNPs in myeloid cell-related pathway genes and CMSS in a discovery dataset of 850 CM patients and replicated the findings in another dataset of 409 CM patients. RESULTS: we identified two SNPs (EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.56 (95% confidence interval =1.19-2.05, P=0 .001) and 1.66 (1.22-2.26, P=0.001), respectively; so were their combined unfavorable alleles in a dose-response manner in both discovery and replication datasets (P trend<0.001 and 0.002, respectively). Additional functional analysis revealed that both EML1 rs10151787 G and HIST1H4E rs2069018 C alleles were associated with elevated mRNA expression levels in normal tissues. CONCLUSIONS: Our findings suggest that EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C are independent prognostic biomarkers for CMSS. PMID:34249459 | PMC:PMC8263692 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Prognostic stratification based on a novel nomogram for left-sided pancreatic adenocarcinoma after surgical resection: a multi-center study

xlomafota13 shared this article with you from Inoreader Prognostic stratification based on a novel nomogram for left-sided pancreatic adenocarcinoma after surgical resection: a multi-center study Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2754-2768. eCollection 2021. ABSTRACT Left-sided pancreatic adenocarcinoma (LPAC) has a poorer prognosis and has some distinct features compared to cancer of pancreatic head. A reliable model to predict the prognosis of LPAC following surgery is needed in clinical practice. Our study included 231 patients with resected LPAC from 3 Chinese pancreatic disease centers. Cox-regression analysis was conducted to identify independent risk factors of LAPC. Then we established a nomogram and performed C-index, receiver operating characteristic curve, calibration plot and decision curve analysis to assess its discrimination and calibration. As a result, CA19-9, surgical margin, tumor differentiation, lymph node metastasis, and postoperative adjuvant chemotherapy were identified as significant prognostic factors. Based on these predictors, a novel nomogram was constructed. The nomogram achieved high C-indexes in the training cohort (0.805) and validation cohort (0.719), which were superior than the AJCC-8 staging system and other nomograms. The area under curve of the nomogram for predicting patients survival at 1-, 2-, and 3-year in training cohort were more than 0.8. Kaplan-Meier survival curve for the subgroups stratified based on the nomogram showed a better separation than the AJCC-8 stage I, II, III, indicating a superior ability of risk stratification for our model. In summary, we constructed a nomogram which showed a better predictive ability for patients' survival with LPAC after surgical resection than the AJCC staging system and other predictive models. Our model would be helpful to discriminate high-risk LPAC and facilitate clinical decision making. PMID:34249426 | PMC:PMC8263662 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Deletion of Foxa1 in the mouse mammary gland results in abnormal accumulation of luminal progenitor cells: a link between reproductive factors and ER-/TNBC breast cancer?

xlomafota13 shared this article with you from Inoreader Deletion of Foxa1 in the mouse mammary gland results in abnormal accumulation of luminal progenitor cells: a link between reproductive factors and ER-/TNBC breast cancer? Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3263-3270. eCollection 2021. ABSTRACT In humans, parity without breastfeeding increases risk of estrogen receptor-negative (ER-) breast cancer and is associated with hypermethylation of FOXA1, a pioneer factor regulating lineage commitment of mammary gland luminal progenitor cells. We postulate that pregnancy-associated repression of FOXA1 results in the accumulation of aberrant, differentiation-arrested luminal progenitor cells which, following additional genetic and epigenetic insults, may give rise to ER- tumors. Consistent with this hypothesis, we show that deletion of Foxa1 in the mouse mammary gland results in a two-fold increase in the proportion of luminal progenitor cells and a reduction in mammary gland epithelial cells that stain positive for ER. These results provide compelling support for the notion that reduced Foxa1 expression is sufficient to alter mammary g land luminal cell fate determination in vivo, which could be a mechanism linking parity with ER- breast cancer. PMID:34249460 | PMC:PMC8263678 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Differential molecular response of larynx cancer cell lines to combined VPA/CDDP treatment

xlomafota13 shared this article with you from Inoreader Differential molecular response of larynx cancer cell lines to combined VPA/CDDP treatment Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2821-2837. eCollection 2021. ABSTRACT Successful treatment of advanced larynx squamous cell carcinoma (LSCC) remains a challenge, mainly due to limited response to chemotherapy and the phenomenon of the drug resistance. Therefore, new chemotherapeutic solutions are needed. The aim of this study was to explore benefit of combined cisplatin (CDDP) and valproic acid (VPA) therapy in patients' derived LSCC cell lines. Cell viability assay was used to establish cellular response to the drug by isobolography followed by RNA sequencing (RNAseq) analysis. Danio rerio were used for in vivo studies. Depending on the cell line, we found that the combinations of drugs resulted in synergistic or antagonistic pharmacological interaction, which was accompanied by significant changes in genes expression profiles. The presented therapeutic scheme efficiently blocked tumor growth in an in vivo mode l, corresponding to the in vitro performed studies. Interestingly the RK5 cell line, upon the combined treatment acquired a molecular profile typically associated with epithelial to mesenchymal transition (EMT). Hence, our studies demonstrates that patient-specific personalized therapy of larynx cancer should be considered and the combination of cisplatin and valproic acid should be explored as a potential therapeutic strategy in the treatment of larynx cancer. PMID:34249430 | PMC:PMC8263637 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development

xlomafota13 shared this article with you from Inoreader Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3271-3284. eCollection 2021. ABSTRACT Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the MDM2 and CDK4 genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies ta rgeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarco mas. PMID:34249461 | PMC:PMC8263664 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.