Krüppel-like factor 10 (KLF10) is a tumor suppressor in multiple cancers. In a murine model of spontaneous pancreatic adenocarcinoma (PDAC), additional KLF10 depletion accelerated distant metastasis. ...However, Klf10 knockout mice, which suffer from metabolic disorders, do not develop malignancy. The mechanisms of KLF10 in PDAC progression deserve further exploration. KLF10-depleted and KLF10-overexpressing PDAC cells were established to measure epithelial-mesenchymal transition (EMT), glycolysis, and migration ability. A murine model was established to evaluate the benefit of genetic or pharmacological manipulation in KLF10-depleted PDAC cells (PDACshKLF10). Correlations of KLF10 deficiency with rapid metastasis, elevated EMT, and glycolysis were demonstrated in resected PDAC tissues, in vitro assays, and murine models. We identified sirtuin 6 (SIRT6) as an essential mediator of KLF10 that modulates EMT and glucose homeostasis. Overexpressing SIRT6 reversed the migratory and glycolytic phenotypes of PDACshKLF10 cells. Linoleic acid, a polyunsaturated essential fatty acid, upregulated SIRT6 and prolonged the survival of mice injected with PDACshKLF10. Modulating HIF1α and NFκB revealed that EMT and glycolysis in PDAC cells were coordinately regulated upstream by KLF10/SIRT6 signaling. Our study demonstrated a novel KLF10/SIRT6 pathway that modulated EMT and glycolysis coordinately via NFκB and HIF1α. Activation of KLF10/SIRT6 signaling ameliorated the distant progression of PDAC.Clinical Trial Registration: ClinicalTrials.gov. identifier: NCT01666184.
Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine ...methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.
RING finger 43 (RNF43), a RING‐type E3 ubiquitin ligase, is a key regulator of WNT signaling and is mutated in 6–10% of pancreatic tumors. However, RNF43‐mediated effects remain unclear, as only a ...few in vivo substrates of RNF43 are identified. Here, it is found that RNF43‐mutated pancreatic cancer cells exhibit elevated B‐RAF/MEK activity and are highly sensitive to MEK inhibitors. The depletion of RNF43 in normal pancreatic ductal cells also enhances MEK activation, suggesting that it is a physiologically regulated process. It is confirmed that RNF43 ubiquitinates B‐RAF at K499 to promote proteasome‐dependent degradation, resulting in reduced MEK activity and proliferative ability in cancer cells. In addition, phosphorylation of B‐RAF at T491 suppresses B‐RAF ubiquitination by decreasing the interaction between RNF43 and B‐RAF. Mutations at K499 in B‐RAF are identified in various cancer types. MEK and WNT inhibitors synergistically suppress the growth of RNF43‐mutated pancreatic cancer cells in vitro and in vivo. Collectively, the research reveals a novel mechanism by which RNF43 inhibits B‐RAF/MEK signaling to suppress tumor growth and provide a new strategy for the treatment of RNF43‐inactivated pancreatic cancer.
It is demonstrated that RNF43 ubiquitinates B‐RAF at K499, promoting its degradation. This ubiquitination process is negatively regulated by phosphorylation at T491. Inactivation of RNF43 enhances sensitivity to MEK inhibitors and creates synergy between drugs targeting the WNT and MEK pathways in various RNF43‐mutated cancers.
Aims
To determine the effect of design thinking approach in interprofessional education programme of human sexuality course.
Design
A pre‐test and post‐test of single‐group quasi‐experimental study.
...Methods
The 35 nursing students and seven psychology students in their third year were selected by the computer randomly sampling through the lottery method. The course proceeded between September 2019 and January 2020. The participants had received an 8‐week, 16‐hr design thinking approach in interprofessional education programme of human sexuality course (one section per week, 2 hr per section). We used the nursing attitude toward sexual healthcare scale, nursing intervention toward sexual healthcare scale to assess students' attitude and behaviour intention toward sexual health care and competence of interprofessional education scale to assess students' competence of cooperation before and after the teaching programme. Data analysis used descriptive statistics and t‐tests. A qualitative reflection log was also provided and analysed for themes. The SQUIRE‐EDU checklist was followed.
Results
The students' attitude and behavioural intention dimension score in the post‐test is higher than those in the pre‐test and reach statistically significant differences both in total and subscale. Interprofessional core competence score of Observation Experience, Reflective Feedback, Interprofessional Cooperation, Innovative Design, and Applied Technology score in the post‐test is higher than those in the pre‐test and reach statistically significant differences both in total and subscale. Design thinking in interprofessional education programme of human sexuality course could significantly improve both nursing and psychology students' attitude, behaviour intention of providing sexual health care and competence of interprofessional cooperation.
Abstract Background and purpose Neoadjuvant concurrent chemoradiotherapy (CCRT) is a standard treatment of locally advanced colon cancer cell (CRC). In order to maximize efficacy and minimize ...toxicity, new drugs have been developed and used in combination with CCRT. Recently, it has been shown that G9a plays a role in mediating phenotypes of cancer stem cells (CSCs). This study aimed to characterize G9a as a biomarker in predicting therapy response to prevent overtreatment and adverse effects in CRC patients. Experimental design The primary tumors from 39 patients who received CCRT for rectal cancer were selected. In vivo tumor xenograft models for tumorigenic properties in immunodeficient mice were developed. In vitro stemness ability was performed by tumor-sphere assays, cell response to anti-cancer agents and stemness-related genes analysis. Results Cells survived from radiation treatment, and displayed high levels of G9a. A significantly positive correlation was shown between G9a and CSCs marker CD133 in locally advanced rectal cancer patients with CCRT. Knockdown of G9a increased the sensitivity of cells to radiation treatment and sensitized cells to DNA damage agents through PP2A-RPA axis. Conclusions Our study theorized that G9a might serve as a novel target in colon cancer, which offers exciting potential in prediction of response to preoperative chemoradiotherapy in patients with advanced CRC.
The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex play a role in silencing gene expression. CHD4, the core component of the NuRD complex, which cooperates with histone deacetylase in ...reducing tumor suppressor genes (TSGs). To dissect the mechanisms underlying cancer promotion, we clarify the role of CHD4 in cyclin-dependent kinase inhibitor protein p21. Here, our data indicates that CHD4 deficiency impairs the recruitments of HDAC1 to the p21 promoter. ~ 300bp proximal promoter region is responsible for CHD4-HDAC1 axis-mediated p21 transcriptional activity. For identifying the role of anti-cancer drug response, knockdown of p21 overcomes cisplatin and poly-(ADP-ribose) polymerase (PARP) inhibitor-mediated growth suppression in CHD4-depleted cells. Consistent with in vitro data, tissue of patients and bioinformatics approach also showed positive correlation between CHD4 and p21. Overall, our findings not only identify that CHD4 deficiency preferentially impairs cell survival via increasing the level of p21, but also establishes targeting CHD4 as a potential therapeutic implication in BRCA-proficient breast cancer treatment.
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•An epigenetic mechanism for p21WAF1 is proposed in breast cancer.•The mechanism relies on the CHD4-HDAC1 axis in controlling p21 transcripts.•CHD4 deficiency sensitizes cells to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitor in reducing cell survival.•Targeting CHD4 should provide a strategy in the development of anti-cancer agents in BRCA-proficient breast cancer.
The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date.
The ...clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth.
We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo.
Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer.
In this paper, the wireless sensor network (WSN) with the ZigBee standard is integrated with the flexible arrayed potentiometric sensor, such as flexible arrayed pH sensor and flexible arrayed ...glucose biosensor that achieve a wireless sensing system. The wireless sensing system is accomplished by the graphical language laboratory virtual instrumentation engineering workbench and the detection signals are displayed in real time in the computer. A potentiometric electrochemical method is used to measure the output signal of potential difference between the silver/silver chloride (Ag/AgCl) reference electrode and the flexible arrayed potentiometric sensor. We provide a wireless sensing system of XBee module, which has the advantages of low cost, easy operation, portable device, high accuracy, real-time monitoring, and rapid detection. According to the experimental results of flexible arrayed pH sensor and flexible arrayed glucose biosensor, the range of pH values from pH 1 to pH 13 has a good average sensitivity of 51.38 mV/pH and a linearity of 0.995, and the range of glucose solution concentration from 100 to 500 mg/dL has a good average sensitivity of 0.179 mV(mg/dL) -1 and a linearity of 0.999. The actual target in this paper is to provide a wireless sensing system for ion sensing and monitoring of human physiological data.
Background:
This study aimed to evaluate correlations between female nurses' needs satisfaction and behavioral intentions for providing sexual health care and to assess moderating effects of learning ...needs on that correlation.
Method:
A total of 300 female RNs were enrolled. Two validated instruments were used to collect information on participants' learning needs, needs satisfaction, and behavioral intentions for providing sexual health care.
Results:
Adjusted multivariable regression analysis revealed significant moderating effects of medium and low learning needs on correlations between needs satisfaction and behavioral intentions (medium learning needs: β = 0.282, 95% CI = 0.075, 0.490;
p
= .008; low learning needs: β = 0.293, 95% CI = 0.033, 0.553;
p
= .027), while no moderating effect was observed in those with high learning needs.
Conclusion:
Needs satisfaction was significantly correlated with behavioral intentions of sexual health care in medium and low learning needs groups.
J Contin Educ Nurs
. 2020;51(10):457–464.
Aim
This study evaluated the correlation between learning needs and behavioural intention of sexual health care in female Registered Nurses and to assess the moderating effect of gender role on this ...relationship.
Design
In this cross‐sectional questionnaire‐based survey, a convenience sampling of female Registered Nurses was included from Chung Shan Medical University Hospital, Taiwan.
Methods
Three questionnaires were used to obtain self‐reported data on learning needs, behavioural intention and gender role.
Results
Based on gender role scores, 11.8% of participants were feminine, 10.0% were masculine, 31.0% were androgynous and 47.2% were undifferentiated. Significant positive correlations between learning needs and behaviour intention were observed in the total population as well as in undifferentiated, feminine and androgynous nurses (all p < .05). Learning needs were positively associated with the behavioural intention of sexual health care in female nurses, which was moderated by gender role (F = 2.868, p = .036).
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