Paracrine production of IL-6 promotes a hypercoagulable state in pancreatic cancer

xlomafota13 shared this article with you from Inoreader Paracrine production of IL-6 promotes a hypercoagulable state in pancreatic cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):5992-6003. eCollection 2021. ABSTRACT Venous thromboembolism is the most common complication and the secondary cause of death in pancreatic cancer. Moreover, the hypercoagulable state induces microcirculation dysfunction, acidosis and hypoxia, and further enhances tumor immune evasion, tumor growth and metastasis. Numerous studies have revealed that patients with malignant tumors have high levels of IL-6, which stimulates hepatocytes to synthesize thrombopoietin, causing an increase in platelets. This study found that the concentration of IL-6 in pancreatic cancer patient sera was higher than that in healthy donors, while pancreatic cancer cells had low expression levels of IL-6, which was different from other types of cancer. This contradictory result prompted us to uncover the underlying mechanism. Our data revealed that pancreatic cancer enhanced IL-6 production in fibroblasts via the Jagged/Notch axis, while IL-6 further elevated Jagged-1/2 expression in a paracrine positive feedback loop in pancreatic cancer. Inhibition experiments and RNAi studies demonstrated that IL-6-induced Jagged-1/2 production in pancreatic cancer depended on STAT3 and that Jagged-1/2 enhanced IL-6 mRNA expression in HSFs through the NF-κB pathway. Finally, the animal study showed that knockdown of Jagged-1/2 or blockade of the Jagged/Notch pathway by Nirogacestat could alleviate pancreatic cancer-induced hypercoagulability. Accordingly, our findings clarified the key role of the Jagged/Notch/IL-6/STAT3 feedback loop in the development of a hypercoagulable state in pancreatic cancer, which also provides new therapeutic strategies for pancreatic cancer patients who suffer from hypercoagulability. PMID:35018238 | PMC:PMC8727799 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions

xlomafota13 shared this article with you from Inoreader Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):5762-5781. eCollection 2021. ABSTRACT Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers. The p53-MDM2-MDMX pathway provides multiple molecular targets for small molecule screening as potential therapies for wild-type p53. As a result of its effect on molecular carcinogenesis, a personalized therapeutic approach based on the wild-type and mutant p53 protein is desirable. We highlighted the implications of p53 mutations in cancer, p53 ubiquitination mechanistic details, targeting p53-MDM2/MDMX interactions, significant discoveries related to MDM2 inh ibitor drug development, MDM2 and MDMX dual target inhibitors, and clinical trials with p53-MDM2/MDMX-targeted drugs. We also investigated potential therapeutic repurposing of selective estrogen receptor modulators (SERMs) in targeting p53-MDM2/MDMX interactions. Molecular docking studies of SERMs were performed utilizing the solved structures of the p53/MDM2/MDMX proteins. These studies identified ormeloxifene as a potential dual inhibitor of p53/MDM2/MDMX interaction, suggesting that repurposing SERMs for dual targeting of p53/MDM2 and p53/MDMX interactions is an attractive strategy for targeting wild-type p53 tumors and warrants further preclinical research. PMID:35018225 | PMC:PMC8727821 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Surgical resection of brain metastases prolongs overall survival in non-small-cell lung cancer

xlomafota13 shared this article with you from Inoreader Surgical resection of brain metastases prolongs overall survival in non-small-cell lung cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):6160-6172. eCollection 2021. ABSTRACT It remains unclear whether surgical resection of brain metastases prolongs overall survival in patients with non-small-cell lung cancer (NSCLC). A retrospective study was designed to evaluate the benefits of surgical resection for 296 patients with NSCLC and brain metastases. Patients were grouped into those who underwent craniotomy (brain surgery group) and those who did not (non-surgery group). Characteristics, survival, and EGFR mutation status were compared between the two groups. We found that the clinical characteristics were similar between the two groups. However, patients in the brain surgery group had metastases of larger diameters (3.67 cm vs. 2.06 cm, P<0.001) and a lower rate of extracranial metastasis (8.7% vs. 45.5%, P=0.001). Overall survival was significantly longer for those who underwent brain surgery (40.3 months vs. 8.4 months, P< ;0.001). The adjusted hazard ratio of craniotomy was 0.30 (95% confidence interval [CI], 0.15-0.62). The survival benefit of brain surgery was observed in both EGFR mutation-positive and EGFR mutation-negative sub-populations; the adjusted hazard ratios [aHRs] were 0.34 [95% CI, 0.11-1.00] and 0.26 [95% CI, 0.09-0.73] for EGFR mutation-positive and mutation-negative sub-populations, respectively. We concluded that for patients with NSCLC and brain metastases, surgical resection of brain metastases improved overall survival. This survival benefit was particularly evident in cases with large-sized metastases limited to the brain. PMID:35018249 | PMC:PMC8727818 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Calcitriol induces estrogen receptor alpha expression through direct transcriptional regulation and epigenetic modifications in estrogen receptor-negative breast cancer cells

xlomafota13 shared this article with you from Inoreader Calcitriol induces estrogen receptor alpha expression through direct transcriptional regulation and epigenetic modifications in estrogen receptor-negative breast cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):5951-5964. eCollection 2021. ABSTRACT Patients with estrogen receptor (ER) α-negative breast tumors have a poor prognosis and are not suitable for hormone therapy. Previously, we demonstrated that calcitriol, the active metabolite of vitamin D, induces ERα expression and re-establishes the response to antiestrogens in ER-negative breast cancer cells. However, the mechanisms involved in this process have not been elucidated. Therefore, the present study was undertaken to investigate the mechanisms implicated in the calcitriol-induced ERα expression in ER-negative breast cancer cells. Using EMSA and ChIP assays, we found that the calcitriol/vitamin D receptor (VDR)/retinoic X receptor (RXR) complex binds to putative vitamin D response elements (VDREs) in the ERα gene promoter region. In addition, we established by a fluorometric assay that calcitriol decreased DNA-methyltransferase and histone deac etylase activities. Flow cytometry and qPCR analyses showed that co-treatment of calcitriol with inhibitors of the histone deacetylase and DNA methyltransferase, and genistein significantly increased ERα expression, compared to that observed with the compounds alone. In conclusion, the calcitriol-dependent ERα induction in ER-negative breast cancer cells results from binding of the VDR-RXR complex to VDREs in the ERα gene promoter region, including the downregulation of enzymes with chromatin-remodeling activities. These results may bring forth novel mechanistic knowledge into the actions of calcitriol in ERα-negative breast cancer. PMID:35018235 | PMC:PMC8727803 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Factors associated with colorectal cancer screening intent and uptake among adult Non-Hispanic Black men

xlomafota13 shared this article with you from Inoreader Factors associated with colorectal cancer screening intent and uptake among adult Non-Hispanic Black men Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):6200-6213. eCollection 2021. ABSTRACT Non-Hispanic (NH) Black men in the United States have the lowest five-year colorectal cancer (CRC) survival rate across all racial/ethnic and sex subgroups and are less likely than their NH White counterparts to complete CRC screening. We hypothesized that greater masculinity barriers to medical care (MBMC) would be negatively associated with CRC screening uptake. Employing a survey design, we examined the MBMC scale and other psychosocial factors influencing CRC screening intent and uptake in a sample of 319 NH Black men aged 45 to 75 years residing in Minnesota, Ohio, and Utah. A series of ordinary least squares and logistic regression models were run with intention and uptake as the outcome variable while controlling for various demographic characteristics. Independent variables in all models included average score on the MBMC; CRC screening knowledge, beliefs and values; and barriers to and social support for CRC screening. Social support, marital status, and age were positively associated with CRC screening intention. Increased CRC screening knowledge and older age were associated with a greater likelihood of completing a stool-based screening test for CRC. Fewer masculinity-related and CRC screening barriers were associated with a greater likelihood of undergoing a sigmoidoscopy or colonoscopy. Contrary to our primary hypothesis, lesser MBMC-related perceptions were associated with increased CRC screening uptake among NH Black men. Our findings inform future CRC promotion programs and emphasize the need for multilevel interventions tailored toward this marginalized population to reduce disparities in screening and survival. PMID:35018252 | PMC:PMC8727804 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Truncating CDKN1A mutations: an insight into the biology of urinary tract carcinomas?

xlomafota13 shared this article with you from Inoreader Truncating <em>CDKN1A</em> mutations: an insight into the biology of urinary tract carcinomas? Via American Journal of Cancer Research Am J Cancer Res. 2021 Dec 15;11(12):6214-6217. eCollection 2021. ABSTRACT A recent in silico study by Arnoff and El-Deiry found that urothelial carcinomas of the bladder and upper tract as well as chromophobe renal cell carcinoma are more likely than other malignancies to harbor alterations in the CDKN1A gene, encoding for the cyclin-dependent kinase inhibitor p21Waf1, a major target of p53 regulatory pathways. Most of these mutations were truncating and thus presumably resulting in loss of p21Waf1 function. Herein, we discuss the prognostic and therapeutic implications of these findings. PMID:35018253 | PMC:PMC8727807 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Subclinical Hypothyroidism with Negative for Thyroid Peroxidase Antibodies in Pregnancy: Intellectual Development of Offspring

xlomafota13 shared this article with you from Inoreader Subclinical Hypothyroidism with Negative for Thyroid Peroxidase Antibodies in Pregnancy: Intellectual Development of Offspring Via liebertpub1 Thyroid, Ahead of Print. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.