Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival

xlomafota13 shared this article with you from Inoreader Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2264-2277. eCollection 2021. ABSTRACT Although natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., DOCK2 rs261083 G>C, VAV2 rs2519996 C>T and EPHB1 rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with ad justed hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, P = 3.34×10-4), 1.28 (1.12-1.47, P = 4.57×10-4) and 0.75 (0.67-0.83, P = 1.50×10-7), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset (P trend<0.0001 and <0.0001, respectively). Moreover, the survival-associated DOCK2 rs261083 C allele had a significant correlation with reduced DOCK2 transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced EPHB1 transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that DOCK2 and EPHB1 genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes. PMID:34094683 | PMC:PMC8167686 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview

xlomafota13 shared this article with you from Inoreader Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):1873-1894. eCollection 2021. ABSTRACT Numerous prostate cancer (PC) associated genes have been reported in previous genome-wide association studies. Elucidation of prostate cancer pharmacogenomics have enhanced studies into the impact of germline genetic changes on treatment, in addition to evaluating related genomic alterations and biomarkers in prostate tumor tissues. Currently, Abiraterone (Abi) is used as one of the therapeutic options for PC. In this article, germline variants that have been associated with responses to Abi in patients with advanced PC are summarized. These include biomarker genes such as CYP17A1, AR-V7, HSD3B1, SLCO2B1, SULT1E1, and SRD5A2 that are involved in homologous recombination, as well as in gene expression mutations in important signaling pathways, such as WNT and Abi metabolic pathways. PMID:34094659 | PMC:PMC8167691 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail

xlomafota13 shared this article with you from Inoreader Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2278-2290. eCollection 2021. ABSTRACT The engagement of human angiotensin-converting enzyme 2 (hACE2) and SARS-CoV-2 spike protein facilitate virus spread. Thus far, ACE2 and TMPRSS2 expression is correlated with the epithelial-mesenchymal transition (EMT) gene signature in lung cancer. However, the mechanism for SARS-CoV-2-induced EMT has not been thoroughly explored. Here, we showed that SARS-CoV-2 induces EMT phenotypic change and stemness in breast cancer cell model and subsequently identified Snail as a modulator for this regulation. The in-depth analysis identifies the spike protein (S), but not envelope (E), nucleocapsid (N), or membrane protein (M), of SARS-CoV-2 induces EMT marker changes. Suppression of Snail expression in these cells abrogates S protein-induced invasion, migration, stemness, and lung metastasis, suggesting that Snail is required for SARS-CoV-2-mediated aggressive phenotype in cancer. This study reveals an important oncogenic role of SARS-CoV-2 in triggering breast cancer metastasis through Snail upregulation. PMID:34094684 | PMC:PMC8167694 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

ENO1 monoclonal antibody inhibits invasion, proliferation and clone formation of cervical cancer cells

xlomafota13 shared this article with you from Inoreader ENO1 monoclonal antibody inhibits invasion, proliferation and clone formation of cervical cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):1946-1961. eCollection 2021. ABSTRACT α-enolase (ENO1), highly expressing in cell membranes, cytoplasm and nuclei of cervical cancer and other tumors, acts as a plasminogen receptor and a glycolytic enzyme. ENO1 is found to be associated with tumorigenesis, invasion and migration, and proves to be an ideal target of tumor therapy. In this study, ENO1 monoclonal antibodies (ENO1mAb) was prepared to blockade ENO1 and the therapeutic role was observed in cervical cancer cells. First, ENO1mAb was prepared and screened by evaluating the inhibitory effect on migration and invasion of cervical cancer cells, which is supposed to block ENO1 expressed on cell membrane. Second, folic acid (FA) conjugated PLGA nanoparticles (FA-SS-PLGA) targeting tumor cells were prepared to mediate ENO1mAb entry into cells and its anti-tumor effects were investigated in vitro. We found that PLGA/FA-SS-PLGA nanoparticles- mediated ENO1mAb could antagonize the activity of ENO1 enzyme, significantly decreased the contents of lactic acid and pyruvate, and inhibited the proliferation, migration and clone formation of cervical cancer cells compared with the sham control (P < 0.05). In summary, ENO1mAb could specifically block ENO1 expressed on cell membrane and inhibit ENO1 glycolysis enzyme activity inside tumor cells, and plays a therapeutic role against cervical cancer cells. It suggests that ENO1mAb has promising anti-tumor effects. PMID:34094663 | PMC:PMC8167678 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Glycosylation of Siglec15 promotes immunoescape and tumor growth

xlomafota13 shared this article with you from Inoreader Glycosylation of Siglec15 promotes immunoescape and tumor growth Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2291-2302. eCollection 2021. ABSTRACT Siglec15 is a recently characterized immunosuppressive transmembrane protein, which expresses in various types of solid tumors and promotes cancer development. Several studies reported that Siglec15 is a prognostic biomarker of cancer patients, and targeting Siglec15 may be a promising strategy for cancer therapy. However, the regulation of Siglec15 function remains unclear. Here we show that the immunosuppression activity of Siglec15 is largely modulated by N-glycosylation. Through mass spectrum and site mutation analysis, we identified that Siglec15 was extensively glycosylated at N172 (N173 for mouse) in cancer cells. Meanwhile, Siglec15 N172Q had a similar molecular weight with PNGase-F-treated Siglec15, suggesting N172 as the only one glycosylation residue. In xenograft model, glycosylation deficiency of Siglec15 reduced tumor growth in C57BL/6 mice, but had no impact in nude mice, indicating the requirement of N-glycosylation for immunosuppressive function of Siglec15. Furthermore, colorectal cancer patients with high Siglec15 expression had a poor response to neoadjuvant chemo-radiotherapy and short survival time. Interestingly, removal of N-glycosylation enhances the detection of Siglec15, which may be employed in the prediction of immunotherapy response. Together, our results disclose a pivotal role of glycosylated Siglec15 in tumor immune escape, which may be a therapeutic target for cancer immunotherapy. PMID:34094685 | PMC:PMC8167674 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Trends in treatments for prostate cancer in the United States, 2010-2015

xlomafota13 shared this article with you from Inoreader Trends in treatments for prostate cancer in the United States, 2010-2015 Via American Journal of Cancer Research Am J Cancer Res. 2021 May 20;11(5):2351-2368. eCollection 2021. ABSTRACT Although annual mortality trends for prostate cancer were stabilized in recent years, understanding the exact treatment changes is necessary for optimal management. Utilization of not-otherwise specified (NOS) treatments for prostate cancer was unclear. Thus, this study aimed to analyze trends in treatment for prostate cancer in the U.S. from 2010 to 2015 and examine whether the treatment for the prostate cancer in the U.S. is compliant with clinical practice guidelines. Using joinpoint regression models, we examined trends in the rate and proportion of age-standardized utilization (ASUR and ASUP) of treatments for prostate cancer diagnosed during 2010-2015 in the U.S. based on the data from the Surveillance, Epidemiology, and End Results (SEER, 2018 data-release, with linkage to active surveillance/watchful waiting [AS/WW]) cancer registry program. Among 316,690 men with prostate cancer diagnosed during 2010-2015, ASUR and ASUP for radical prostatectomy, radiotherapy, AS/WW and NOS treatment were 32.7, 34.4, 10.0 and 40.1 per 100,000, and 27.9%, 29.3%, 8.5% and 34.2%, respectively. Trends in the overall ASUR for prostate cancer treatments differed by cancer risk group, patients' age, race/ethnicity, Gleason score, insurance status, and the average education level, average poverty-level and foreign-born person percentage of the patient's residence-county, but not by rural-urban continuum or region. ASUP of radical prostatectomy decreased from 9.8% in 2010 to 4.8% in 2015 (annual percent change [APC] = -12.0%, 95% CI, -15.9 to -7.9%), and the decrease was observed in all different risk groups. ASUP of AS/WW increased from 16.4% in 2010 to 30.2% in 2013 (APC = 22.7%, 95% CI, 4.6 to 44.0%) and then remained stable through 2013 to 2015 (APC = 1.9%, 95% CI, -24.1 to 36.9%). The increasing tendency of AS/WW only occurred in the low-risk and interm ediate-risk groups. The ASUP of NOS treatment has increased from 32.3% in 2010 to 36.8% in 2015 (P<0.01). In conclusion, ASUR and ASUP for prostate cancer treatments, including NOS treatment, had changed during 2010-2015. Their trends appeared to differ by cancer risk-group, age, race/ethnicity, Gleason score and socioeconomic factors. Future studies are warranted to understand the impacts of upward trends in ASUP of NOS treatments and AS/WW on patient survival and prostate cancer mortality. PMID:34094691 | PMC:PMC8167696 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mitochondrial structural alterations in ovarian cancer patient-derived xenografts resistant to cisplatin

xlomafota13 shared this article with you from Inoreader Mitochondrial structural alterations in ovarian cancer patient-derived xenografts resistant to cisplatin Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2303-2311. eCollection 2021. ABSTRACT Mitochondria have attracted attention in cancer research as organelles associated with tumor development and response to therapy. We recently reported acquisition of resistance to cisplatin (DDP) associated with a metabolic rewiring in ovarian cancer patient-derived xenografts (PDXs) models. DDP-resistant PDXs models were obtained mimicking the clinical setting, treating mice bearing sensitive-DDP tumors with multiple cycles of DDP until the development of resistance. To further characterize the metabolic rewiring, the present study focused on tumor mitochondria. We analysed by transmission electron microscopy the mitochondria structure in two models of DDP-resistant and the corresponding DDP-sensitive PDXs and evaluated tumor mDNA content, the expression of genes and proteins involved in mitochondria functionality, and mitochondria fitness-related processes, such as autophagy. We observed a decrease in the number of mitochondria paralleled by an increased volume in DDP-resistant versus DDP-sensitive PDXs. DDP-resistant PDXs presented a higher percentage of damaged mitochondria, in particular of type 2 (concave-shape), and type 3 (cristolysis) damage. We found no difference in the mDNA content, and the expression of genes involved in mitochondrial biogenesis was similar between the sensitive and resistant PDXs. An upregulation of some genes involved in mitochondrial fitness in DDP-R versus DDP-S PDXs was observed. At protein level, no difference in the expression of proteins involved in mitochondrial function and biogenesis, and in autophagy/mitophagy was found. We here reported that the acquisition of DDP resistance is associated with morphological alterations in mitochondria, even if we couldn't find any dysregulation in the studied genes/proteins that could explain the observed differences. PMID:34094686 | PMC:PMC8167697 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Regional lymph nodes distribution pattern in central area of right-sided colon cancer: in-vivo detection and the update on the clinical exploration

xlomafota13 shared this article with you from Inoreader Regional lymph nodes distribution pattern in central area of right-sided colon cancer: in-vivo detection and the update on the clinical exploration Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2095-2105. eCollection 2021. ABSTRACT Distribution of regional lymph nodes (LNs) is decisive for the lymphadenectomy boundary in radical resection of right-sided colon cancer (RCC). Currently, the data of LNs in central area remains ambiguous and scarce. Herein we aim to provide a more detailed anatomical research on LNs surrounding the superior mesenteric vessels for RCC and investigated the metastasis rate. In this study, Carbon Nanoparticles (CNs) and Indocyanine Green (ICG) were used for regional LNs mapping by preoperative colonoscopic tattooing (PCT) and we laparoscopically observed the stained LNs distribution pattern. Lastly, 143 RCC patients who received a "superior mesenteric artery (SMA)-oriented" hemicolectomy were included to calculate the probability of LNs metastasis in our target area. 27 patients diagnosed as RCC (mean age 58.04 years, 17 male) were included. 14 patients underwent CNs injection and 13 patients consented to the ICG, while 4 cases suffered from imaging failure. The unequal number of the regional LNs located between SMV and SMA was detected in 22 cases (81.48%), posterior to SMV area in 6 cases (22.22%), and anterior to SMA in 16 cases (59.26%), respectively. The presence of LNs posterior to SMV was associated with the crossing pattern of ileocolic artery (χ2 = 4.24, P = 0.039). The probability of LNs metastasis in the above areas (target areas) was 2.10% (3/143). In conclusion, right-hemi colon-draining lymphatic vessels anteriorly/posteriorly traversed the SMV and arrived at the surface of SMA near the middle colonic artery (MCA) level, which highlights the potential need of removing mesenteric tissue in our target area on lymphatic resection. PMID:34094671 | PMC:PMC8167669 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cumulative total S-1 dose in adjuvant chemotherapy affects the long-term outcome following curative gastrectomy for gastric cancer

xlomafota13 shared this article with you from Inoreader Cumulative total S-1 dose in adjuvant chemotherapy affects the long-term outcome following curative gastrectomy for gastric cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2312-2318. eCollection 2021. ABSTRACT A recent JCOG1104, OPAS-1 trial revealed the significance of S-1 duration. However, the significance of cumulative total S-1 dose (CTSD) remains unclear. In this study, we designed to evaluate the prognostic effect of CTSD on adjuvant chemotherapy after curative gastrectomy. We retrospectively analyzed 77 consecutive pStage II and III gastric cancer (GC) patients, who underwent curative gastrectomy followed by adjuvant S-1 chemotherapy from 2008 through 2014. CTSD of 20000 mg was the upper-limit of cut-off value to stratify the prognosis (5-year relapse free survival (RFS); CTSD < 20000 mg vs. CTSD ≥ 20000 mg: 51.9% vs. 85.1%, P = 0.004). Compared patients with CTSD more than 20000 mg, those with CTSD less than 20000 mg had a significantly higher rate of preoperative anemia (P = 0.041), low nutrition (P = 0.008) and open gastrectomy (P = 0.012). Multivariate Cox's proportional hazards model for RFS proved that CTSD less than 20000 mg was an independent prognostic factor [P = 0.031, HR 3.32 (95% CI: 1.11-11.1)] although S-1 intensity and duration were not independent prognostic factors. The cumulative total S-1 dose more than 20000 mg might contribute to better prognosis. PMID:34094687 | PMC:PMC8167698 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The role of liver sinusoidal endothelial cells in cancer liver metastasis

xlomafota13 shared this article with you from Inoreader The role of liver sinusoidal endothelial cells in cancer liver metastasis Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):1845-1860. eCollection 2021. ABSTRACT Liver sinusoidal endothelial cells (LSECs) are the gatekeeper cells in the liver, contributing critical roles in liver physiological and pathological changes. Factors such as dietary macronutrients, toxins, and aging impact LSEC fenestration. Defenestration of LSECs changes their phenotype and function. Under liver injury, capillarized LSECs promote hepatic stellate cells (HSCs) activation and fibrogenesis, while decapillarized LSECs protect the activation of HSCs and liver injury. The expression of chemokines, such as CXCL9 and CXCL16, changes and impacts the infiltration of immune cells in the liver during disease progression, including hepatocellular carcinoma (HCC). As the largest solid organ, liver is one of the most favorable organs into where tumor cells metastasize. The increased interaction and adhesion of circulating tumor cells (CTCs) with LSECs in the local microenvironment and LSEC-induced tolerance of immunity promote cancer liver metastasis. Several strategies can be applied to target LSEC to modulate their function to prevent cancer liver metastasis, including gut microbiota modulation, microRNA therapy, and medical treatment. Delivery of different treatment agents with nanoparticles may promote precise target treatment. Overall, targeting LSECs is a potential strategy for treatment of early liver diseases and prevention of cancer liver metastasis. PMID:34094657 | PMC:PMC8167702 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma

xlomafota13 shared this article with you from Inoreader Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2319-2330. eCollection 2021. ABSTRACT Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectiv ely. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort. PMID:34094688 | PMC:PMC8167682 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.