A review of gliomas-related proteins. Characteristics of potential biomarkers

xlomafota13 shared this article with you from Inoreader A review of gliomas-related proteins. Characteristics of potential biomarkers Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3425-3444. eCollection 2021. ABSTRACT Brain tumors are one of the most commonly diagnosed cancers of the central nervous system. Of all diagnosed malignant tumors, 80% are gliomas. An unequivocal diagnosis of gliomas is not always simple, and there is a great need for research to find new treatment options and diagnostic approaches. This paper is focused on the glioma-related protein profiles as compared to healthy brain tissue, which is reflected in multiple correlations between biological aspects that influence proliferation, apoptosis evasion and the invasiveness of neoplastic cells. The work presents the possibilities of facilitating clinical practice with proteomic biomarkers, which offer a wider diagnostic spectrum and reduce the margin of mistake in histopathological or imaging diagnostic methods. In fact, many changes in the body's homeostasis can be overlooked due to the lack of symptoms or t heir non-specificity. Nevertheless, a single marker has limited reliability in distinguishing a particular tumor subtype, since the increased or decreased level of the protein of interest may differ between the stages or locations of the tumor. Moreover, the correlations between proposed proteins - presented in this paper - may help clinicians to choose the most optimal therapy, and estimate its effectiveness, or indicate new therapeutic targets affecting disrupted biochemical pathways. PMID:34354853 | PMC:PMC8332856 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A novel five-gene score to predict complete pathological response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer

xlomafota13 shared this article with you from Inoreader A novel five-gene score to predict complete pathological response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3611-3627. eCollection 2021. ABSTRACT Neoadjuvant Chemotherapy (NAC) is not frequently used in ER-positive/HER2-negative breast cancer (BC) because around 10% patients achieve pathological complete response (pCR). Since NAC can result in cancer downstaging both in the breast and axilla and prevent a morbid surgery, thus a score to predict pCR in this population will be crucial to identify patients who can benefit from this approach. A total of 4038 patients from cohorts; GSE25066, GSE20194, Hess, GSE20181, TCGA-BRCA and METBRIC were analyzed. The score was generated by the 5 most highly expressed genes in the Hallmark E2F targets gene set amongst patients in the GSE25066 cohort with ER-positive/HER2-negative BC who achieved pCR. The area under the curve was significantly higher in the score than that for the E2F targets score. High score ER-positive/HER2-negative BCs were significantly associated with higher Nottingham pathological grade, AJCC cancer stage, MKI67 expression levels, intratumor heterogeneity, homologous recombination defects, mutation burden, neoantigen load, and infiltration of anti-cancer immune cells (CD4+, T helper type1, plasmacytoid dendritic cells, M1 macrophages). They also expressed lower abundance of stromal cells including fibroblasts, lymphatic endothelial cells, pericytes and adipocytes consistently in GSE25066, TCGA and METABRIC cohorts. All cell proliferation-related gene sets, G2M checkpoint, E2F targets, MYC targets v1 and v2, Mitotic Spindle, were strongly enriched in high score BCs consistently in 3 cohorts. The gene score was significantly associated with high pCR rate consistently in the GSE25066 (38%, P < 0.001), GSE20194 (16%, P = 0.006), and Hess cohort (23%, P = 0.037). In conclusion, the 5-gene score reflects cancer cell proliferation and immune cell infiltration, and predicts pCR after NAC in ER- positive/HER2-negative breast cancer. PMID:34354863 | PMC:PMC8332850 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Management of hepatotoxicity of chemotherapy and targeted agents

xlomafota13 shared this article with you from Inoreader Management of hepatotoxicity of chemotherapy and targeted agents Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3461-3474. eCollection 2021. ABSTRACT Hepatotoxicity of chemotherapeutic agents such as methotrexate, oxaliplatin, and irinotecan have been well documented and characterized allowing for careful management by oncologists during administration. However, the rapid advance of the field of oncology and introduction of new classes of therapies such as small molecule inhibitors and immunotherapies have introduced new hepatotoxicity challenges and management strategies. This work is a compilation of the hepatotoxicity and recommended management of various chemotherapies and targeted agents, with a focus on the newer classes of targeted anticancer agents. PMID:34354855 | PMC:PMC8332851 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer

xlomafota13 shared this article with you from Inoreader Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3628-3644. eCollection 2021. ABSTRACT Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival. PMID:34354864 | PMC:PMC8332854 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Epimedokoreanin C, a prenylated flavonoid isolated from Epimedium koreanum, induces non-apoptotic cell death with the characteristics of methuosis in lung cancer cells

xlomafota13 shared this article with you from Inoreader Epimedokoreanin C, a prenylated flavonoid isolated from Epimedium koreanum, induces non-apoptotic cell death with the characteristics of methuosis in lung cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3496-3514. eCollection 2021. ABSTRACT Methuosis is a novel type of non-apoptotic cell death characterized by accumulation of cytoplasmic vacuoles. Identification of molecules that induce methuosis may provide alternative therapeutics for cancers that are refractory to apoptosis. Epimedokoreanin C (EKC) is a prenylated flavonoid isolated from a Chinese herb Epimedium koreanum. In this article, we described that EKC reduced cell viability accompanied by extreme vacuolation in human lung cancer cells. The EKC-induced cell death was clarified as non-apoptosis based on the absence of apoptotic changes. The vacuoles stimulated by EKC were supposed to be derived from macropinocytosis based on the engulfment of extracellular fluid tracer, Lucifer Yellow. The vacuoles acquired some characteristics of late endosomes supported that EKC-induced cell death could be described as methuosis. Rac1 and Arf6 were found to be regulated inversely after EKC treatment. Blocking Rac1 activation with the specific Rac1 inhibitor EHT 1864 prevented the accumulation of vacuoles induced by EKC markedly, suggested that the regulation of Rac1 and Arf6 was at least partial mechanism involved in EKC induced methuosis. EKC synergized the effects of doxorubicin and etoposide, demonstrating the effectiveness of using EKC to synergize conventional chemotherapy. Collectively, EKC was demonstrated as a methuosis-like cell death inducer in lung cancer NCI-H292 and A549 cells. It has the potential to be used as an attractive prototype for developing drugs that could kill apoptosis-resistant cancer cells. PMID:34354857 | PMC:PMC8332866 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity

xlomafota13 shared this article with you from Inoreader A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3645-3659. eCollection 2021. ABSTRACT AST-3424/OBI-3424 (denoted by 3424) is a novel prodrug bis-alkylating agent activated by AKR1C3. AKR1C3 is overexpressed in many types of cancer, particularly in liver, non-small cell lung, gastric, renal and CRPC cancer. Currently 3424 is being studied in phase 1/2 clinical trials for the treatment of solid and hematologic cancers, and it represents potentially a novel, selective anti-cancer agent for multiple indications. In this study, AKR1C3-dependent activation of 3424 was investigated in vitro using recombinant human AKR1C3. AKR1C3-dependent cytotoxicity of 3424 was determined in a wide range of human cancer cell lines with different AKR1C3 expression levels. In addition, anti-tumor activity of 3424 was also investigated in a broad panel of CDX and PDX models. AKR1C3-dependent activation of prodrug 3424 was evident by monitoring the decrease of 3424 a nd generation of the active form, 2660. Kinetic analysis indicated that AKR1C3 exhibited higher catalytic efficiency towards 3424 compared to the physiological substrates. There was a strong correlation between 3424 cytotoxic potency and AKR1C3 expression. The racemic mixture induced DNA cross-linking in a concentration dependent manner. Tumor growth inhibition of 3424 was shown to be better than or comparable to the standard of care chemotherapy at clinically achievable doses as a single agent in various CDX models with high expression of AKR1C3, including liver HepG2, lung H460, castration-resistant prostate VCaP, gastric SNU-16, and kidney A498 cancer cell lines. The excellent anti-tumor efficacy of 3424 was further demonstrated in PDX models which have high level of AKR1C3 expression, but not in a model with low level of AKR1C3 expression. In the combination therapy, we showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models. The result s described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancers and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424. PMID:34354865 | PMC:PMC8332853 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

SIKs suppress tumor function and regulate drug resistance in breast cancer

xlomafota13 shared this article with you from Inoreader SIKs suppress tumor function and regulate drug resistance in breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3537-3557. eCollection 2021. ABSTRACT Salt-inducible kinases (SIKs), belonging to an AMP-activated kinase (AMPK) family, have an evolving role in tumourigenesis and metastasis in many solid tumours. However, the function of SIKs in breast cancer is not fully established. Here, we systematically elucidated the function of SIK family members in breast cancer. In clinical cohort of breast cancer, the expression of SIK1, SIK2 and SIK3 increased expression of SIKs was associated with good clinical outcome in breast cancer cohort. In vitro, reduced expression of SIK2 and SIK3, by way of knockdown increased the proliferation of breast cancer cells. However, SIK2 and SIK3 had contrasting effects on adhesion in breast cancer cells. Knockdown of SIK2 only enhanced the adhesion of triple negative breast cancer cell, while knockdown of SIK3 can decrease the adhesion of both MDA-MB-231 and MCF-7 cells. Inte restingly, knockdown of SIK1 and SIK3 was seen to increase the invasion of MDA-MB-231 cells. Furthermore, reduced SIKs, even triple knockdown of SIK1, SIK2 and SIK3 rendered the breast cancer cells to confer chemoresistance to paclitaxel and cisplatin. Collectively, the study reports that SIKs are actively involved in regulating the aggressive functions of breast cancer cells and influence the clinical course of the patients with breast cancer that they molecules are potential prognostic factors and chemotherapy biomarkers. PMID:34354859 | PMC:PMC8332863 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.