In the United States, lung cancer is the second most common cancer in men and women. In 2017, 222,500 new cases and 155,870 deaths from lung cancer are estimated to have occurred. A tyrosine kinase receptor, epidermal growth factor receptor (EGFR), is over expressed or mutated in non-small cell lung cancer (NSCLC) resulting in increased cell proliferation and survival. Tyrosine kinase inhibitors (TKIs) are currently being used as therapy for NSCLC patients, however, they have limited efficacy in NSCLC patients due to acquisition of resistance. This study investigates the role of epithelial-mesenchymal transition (EMT) in the development of resistance against TKIs in NSCLC. Currently, the role of p120-catenin, Kaiso factor and PRMT-1 in reversal of EMT in T790M mutated and TKI-resistant NSCLC cells is a new line of study. In this investigation we found upregulation of cytoplasmic p120-catenin, which was co-localized with Kaiso factor. In the nucleus, binding of p120-catenin to Kaiso factor initiates transcription by activating EMT-transcription factors such as Snail, Slug, Twist, and ZEB1. PRMT-1 was also found to be upregulated, which induces methylation of Twist and repression of E-cadherin activity, thus promoting EMT. We confirmed that TKI-resistant cells have mesenchymal cell type characteristics based on their cell morphology and gene or protein expression of EMT related proteins. EMT proteins, Vimentin and N-cadherin, displayed increased expression, whereas E-cadherin expression was downregulated. Finally, we found that the knockdown of p120-catenin and PRMT-1 by siRNA or use of a PRMT-1 inhibitor Furamidine increased Erlotinib sensitivity and could reverse EMT to overcome TKI resistance.
The vast majority of EVAR were successfully performed under RA, involved mild blood loss, involved infrequent need for conversion to GA, and resulted in brief in-hospital length of stay and low mortality rate.
Background: EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation have been individually associated with more aggressive disease and characterized as potential prognostic markers for lung cancer patients. Methods: Tumors obtained from 109 participants with stage I–IV non-small cell lung cancer (NSCLC) were studied for EGFR/c-Met co-localization as well as for total and active forms of EGFR, c-Met, mTOR, S6K, beta-catenin, and Axin2. Slides were graded by two independent blinded pathologists using a validated scoring system. Protein expression profile correlations were assessed using Pearson correlation and Spearman’s rho. Prognosis was assessed using Kaplan–Meier analysis. Results: Protein expression profile analysis revealed significant correlations between EGFR/p-EGFR ( p = 0.0412) and p-mTOR/S6K ( p = 0.0044). Co-localization of p-EGFR/p-c-Met was associated with increased p-mTOR ( p = 0.0006), S6K ( p = 0.0018), and p-S6K ( p < 0.0001) expression. In contrast, active beta-catenin was not positively correlated with EGFR/c-Met nor any activated proteins. Axin2, a negative regulator of the Wnt pathway, was correlated with EGFR, p-EGFR, p-mTOR, p-S6K, EGFR/c-Met co-localization, and p-EGFR/p-c-Met co-localization (all p-values <0.03). Kaplan–Meier analysis revealed shorter median survival in participants with high expression of Axin2, total beta-catenin, total/p-S6K, total/p-mTOR, EGFR, and EGFR/c-Met co-localization compared with low expression. After controlling for stage of disease at diagnosis, subjects with late-stage disease demonstrated shorter median survival when exhibiting high co-expression of EGFR/c-Met (8.1 month versus 22.3 month, p = 0.050), mTOR (6.7 month versus 22.3 month, p = 0.002), and p-mTOR (8.1 month versus 25.4 month, p = 0.004) compared with low levels. Conclusions: These findings suggest that increased EGFR/c-Met signaling is correlated with upregulated mTOR/S6K signaling, which may in turn be associated with shorter median survival in late-stage NSCLC.
Exertional heat stroke (EHS) is a serious illness and a common occurrence for military personnel, athletes, and occupational workers. Innate immunity is vital for cell survival and tissue repair needed for recovery following EHS. Previously, our group revealed a unique cytokine response to EHS where circulating interleukin‐6 (IL‐6) peaked at 0.5 h post EHS; however, little is known about the acute phase response, a subsequent response to IL‐6 signaling. Therefore, we hypothesized that EHS would induce an acute phase response that would be observed in skeletal muscles, hepatocytes, and in the circulation.PurposeTo determine if acute phase proteins (APPs), fibrinogen, lipocalin, and serum amyloid A1 (SAA1) are expressed in liver and skeletal muscle following EHS and whether these result in their accumulation in the circulation.MethodsMice were subject to a standardized EHS protocol using a forced running wheel. While running, the mice experienced environmental temps of 37.5 (EHS) or 22.5 (exercise control) until they experienced loss of consciousness (at a core temperature of ~42.2). The tibialis anterior, soleus, liver, and plasma were collected from the mice (n = 8/group) at 0.5, 3, 24, 96, 216, or 336 h post‐EHS. Tissue samples from exercise controls were retrieved at 3 and 96 h post exercise.ResultsUsing protein immunoblots, a significant increase of SAA1 was observed in liver at 3 h of recovery and peaked at 24 h when compared to the exercise control (2.4 ± 1.2*, 2.5 ± 1.4* vs. 0.1 ± 0.1 AU/total protein; respectively). Moreover, circulating SAA1 was observed at the 3 h time point (5.0 ± 3.8 AU/TP). No difference for SAA1 was observed for any other time points when compared to the control. In the liver, fibrinogen, and lipocalin were undetectable for any of the recovery timepoints. No acute phase proteins were detected in skeletal muscle; although, preliminary data revealed that SAA1 expression is elevated in skeletal muscle during sepsis.ConclusionA single episode of EHS alters the expression of SAA1 in mouse liver and plasma. This observation is consistent with an acute phase response to thermal damage, in response to IL‐6 signaling, initiating cell survival and tissue repair pathways needed for recovery.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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One of the consequences of exposure to exertional heat stroke (EHS) is marked damage to the GI tract. GI damage is believed to promote EHS‐induced activation of the immune system and to be a major contributor to the morbidity and mortality of EHS. We hypothesized that the use of non‐steroidal anti‐inflammatory drugs (NSAIDS), so commonly used in exercising humans, would amplify this damage, make subjects more susceptible to EHS and result in greater GI damage and inflammation. We also hypothesized that the use of next generation NSAIDs containing a hydrogen sulfide (H2S) donor, shown to protect the GI tract, would suppress the damaging effects of unmodified NSAIDs. In this study we focus on the impact of both forms of NSAIDs on immune cell populations in the blood following EHS. To test this, we utilized a preclinical mouse model of EHS in mice, previously developed in our laboratory.METHODSC57BL6/J male mice were implanted with temperature telemetry devices. The mice were exercise trained for 3 weeks prior to undergoing a forced running wheel EHS protocol at 37.5°C. The EHS endpoint was loss of consciousness, occurring at core temperatures of ~42.2°C. During 48 hours prior to the EHS protocol, the animals were given ad libitum access to a chow embedded with analgesic doses Ibuprofen (IBU), Diclofenac (DC), or Diclofenac + H2S (HS) (i.e. ATB‐337, Antibe Corp) or placebo (PL). Three hours post‐EHS, the mice were sacrificed and blood was collected for hematological analyses.RESULTSTotal white blood cell count was lower in the DC and IBU groups compared to the control group (p=0.0079, p=0.0011 respectively). There was no difference detected between the control and the HS group. Lower monocyte (p=0.0017, p=0.0032) and neutrophil counts (p=0.0076, p= 0.0002) were observed in the DC and IBU groups compared to controls. No differences in monocyte or neutrophil counts were observed between the control and HS groups. EHS decreased mean corpuscular volume (MCV), presumably due to hemoconcentration during heat exposure. Treatment with IBU and DC attenuated this decrease in MCV compared to both PL and HS donor.DISCUSSIONThe data are consistent with the hypothesis that, following EHS, there is a greater migration of circulating monocytes and neutrophils from the blood into damaged organs such as the GI tract. With the NSAID‐H2S donor, this effect was attenuated. Previous studies have shown that IBU and DC directly interact with RBC membranes, altering their morphology such that the RBCs resemble stomatocytes. The H2S donor appears to prevent this change. Overall, the H2S donor blocks the hematological associated‐effects of traditional NSAIDs on the responses to EHS. These data suggest that the H2S donors may prevent some negative impacts of heat related injury created by use of traditional NSAIDs during EHS. Author's Views not official US Army or DoD Policy.Support or Funding InformationSupported by the DoD W81XWH‐15‐2‐0038This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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