G2M checkpoint pathway alone is associated with drug response and survival among cell proliferation-related pathways in pancreatic cancer

xlomafota13 shared this article with you from Inoreader G2M checkpoint pathway alone is associated with drug response and survival among cell proliferation-related pathways in pancreatic cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3070-3084. eCollection 2021. ABSTRACT Given the severe side effects of the treatments and poor survival, prognostic and predictive biomarkers to guide management of pancreatic cancer are in critical need. We hypothesized that cell proliferation-related pathways are associated with drug response and survival in pancreatic cancer. Six Hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis were evaluated in 3 independent cohorts- TCGA-PAAD (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). G2M and E2F, as well as Mitotic and p53 pathway correlated highly with other gene sets. All pathways were significantly correlated with MKI67 expression and its proliferation score, but none with cytolytic activity and the rate of pathologically complete resection (R0). All pathways were significantly associated with high alteration and expression of KRAS gene except for MYC v1. G2M, E2F, and p53 pathway were significantly associated with high alteration of TP53 gene. Interestingly, different pathways correlated with the AUC of different cancer therapeutics, such as Gemcitabine (Mitotic: r = 0.706 [P = 0.01]), Paclitaxel (MYC v2: r = -0.636 [P < 0.05]), Apatinib (Mitotic: r = -0.556 [P = 0.03]), Palbociclib (E2F: r = 0.675 [P < 0.01]), and Sorafenib (G2M: r = -0.593 [P = 0.03]). Among all six pathways, only G2M was consistently associated with worse patient survival in all three cohorts. In conclusion, each cell proliferation-related pathway was predictive of a unique agent, and the G2M score alone predicts survival in pancreatic cancer. PMID:34249445 | PMC:PMC8263638 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

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.

Integrative multiplatform-based molecular profiling of human colorectal cancer reveals proteogenomic alterations underlying mitochondrial inactivation

xlomafota13 shared this article with you from Inoreader Integrative multiplatform-based molecular profiling of human colorectal cancer reveals proteogenomic alterations underlying mitochondrial inactivation Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2893-2910. eCollection 2021. ABSTRACT Mitochondria play leading roles in initiation and progression of colorectal cancer (CRC). Proteogenomic analyses of mitochondria of CRC tumor cells would likely enhance our understanding of CRC pathogenesis and reveal new independent prognostic factors and treatment targets. However, comprehensive investigations focused on mitochondria of CRC patients are lacking. Here, we investigated global profiles of structural variants, DNA methylation, chromatin accessibility, transcriptome, proteome, and phosphoproteome on human CRC. Proteomic investigations uncovered greatly diminished mitochondrial proteome size in CRC relative to that found in adjacent healthy tissues. Integrated with analysis of RNA-Seq datasets obtained from the public database containing mRNA data of 538 CRC patients, the proteomic analysis indicated that proteins encoded by 45.5% of identified progno stic CRC genes were located within mitochondria, highlighting the association between altered mitochondrial function and CRC. Subsequently, we compared structural variants, DNA methylation, and chromatin accessibility of differentially expressed genes and found that chromatin accessibility was an important factor underlying mitochondrial gene expression. Furthermore, phosphoproteomic profiling demonstrated decreased phosphorylation of most mitochondria-related kinases within CRC versus adjacent healthy tissues, while also highlighting MKK3/p38 as an essential mitochondrial regulatory pathway. Meanwhile, systems-based analyses revealed identities of key kinases, transcriptional factors, and their interconnections. This research uncovered a close relationship between mitochondrial dysfunction and poor CRC prognosis, improve our understanding of molecular mechanism underlying mitochondrial linked to human CRC, and facilitate identifies of clinically relevant CRC prognostic factors and drug targets. PMID:34249434 | PMC:PMC8263689 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A phase 1, multicenter study evaluating the safety and efficacy of KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma

xlomafota13 shared this article with you from Inoreader A phase 1, multicenter study evaluating the safety and efficacy of KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3285-3293. eCollection 2021. ABSTRACT Despite advances in treatment, most patients with multiple myeloma (MM) will relapse, and long-term survival remains poor. B-cell maturation antigen (BCMA) is an ideal therapeutic target as it is expressed throughout the disease course with normal tissue expression limited to plasma and some B-cell lineages. This phase 1, multicenter, first-in-human study evaluated the safety and efficacy of KITE-585, an autologous anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory MM (RRMM). Key eligibility criteria included measurable MM and progression, defined by the International Myeloma Working Group Consensus Criteria within 60 days of the last treatment. Patients underwent leukapheresis and subsequently received a 3-day conditioning therapy regimen (cyclophosphamide [300 mg/m2/day] and fludarabine [30 mg/m2/ day]). Patients then received a flat dose of 3 × 107 to 1 × 109 KITE-585 CAR T cells in a 3+3 dose-escalation design. The primary endpoint was incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs). Key secondary and exploratory endpoints included efficacy outcomes, incidence of AEs, levels of KITE-585 in blood, serum cytokines, and incidence of anti-BCMA CAR antibodies. Seventeen patients were enrolled, and 14 received KITE-585 with a median follow-up of 12.0 months. The median age of patients was 56 years, 41.2% had an Eastern Cooperative Oncology Group performance status of 1, 92.9% had baseline BCMA expression on plasma cells, and median number of prior therapies was 5.5. No patients experienced a DLT, all patients experienced ≥ 1 grade ≥ 3 treatment-emergent AE (TEAE), and no grade 5 TEAEs were observed. There were no grade ≥ 3 events of cytokine release syndrome, neurologic events, or infections; all were grade 1 or 2, and ea ch occurred in 21.4% of patients. Among all patients infused with KITE-585, 1 patient who received 3 × 107 anti-BCMA CAR T cells experienced a partial response. Median peak CAR T-cell expansion was low (0.98 cells/μL), as were median peak serum levels of CAR-associated cytokines, including interferon-γ (61.45 pg/mL) and interleukin-2 (0.9 pg/mL). KITE-585 demonstrated a manageable safety profile; however, the limited CAR T-cell expansion and associated lack of anti-tumor response in patients with RRMM treated with KITE-585 is consistent with the minimal CAR T-cell activity observed. PMID:34249462 | PMC:PMC8263642 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2960-2974. eCollection 2021. ABSTRACT Apatinib is an oral tyrosine kinase inhibitor that targets VEGFR2 signaling and shows potent antitumor effects in various cancers. In this study, we explored the efficacy of apatinib against oral squamous cell carcinoma (OSCC). The relationships between VEGFR2 protein expression and clinical variables were investigated in OSCC patients. OSCC tissues had higher VEGFR2 levels than paracancerous tissues. Compared to patients with low VEGFR2 expression, patients with high VEGFR2 expression had poorer overall survival (OS) and disease-free survival (DFS). Apatinib significantly induced G0/G1 phase arrest and apoptosis, inhibited cell growth and colony formation ability, and blocked autophagic flux by downregulating p-AKT and p-mTOR signaling via the VEGFR2/AKT/mTOR pathway in vitro. Moreover, the inhibition of ERK phosphorylation increased apatinib-induced apoptosis in vitro and in vivo. Apatinib synergized with SCH772984 to achieve a more significant suppression of tumor growth than individual treatment, suggesting the combination of apatinib and SCH772984 as a potent OSCC therapy. PMID:34249438 | PMC:PMC8263641 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.