Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis.

KDM6A (lysine demethylase 6A) has been reported to undergo inactivating mutations in colorectal cancer, but its function in the progression of colorectal cancer has not been evaluated using animal models of colorectal cancer. In this study, we found that knocking out KDM6A expression in mouse intestinal epithelium increased the length of villus and crypt, promoting the development of AOM (azoxymethane)/DSS (dextran sulfate sodium salt)-induced colorectal cancer. On the other hand, knocking down KDM6A expression promoted the growth of colorectal cancer cells. In molecular mechanism studies, we found that KDM6A interacts with HIF-1α; knocking down KDM6A promotes the binding of HIF-1α to the LDHA promoter, thereby promoting LDHA expression and lactate production, enhancing glycolysis. Knocking down LDHA reversed the malignant phenotype caused by KDM6A expression loss. In summary, this study using animal models revealed that KDM6A loss promotes the progression of colorectal cancer through reprogramming the metabolism of the colorectal cancer cells, suggesting that restoring the function of KDM6A is likely to be one of the strategies for colorectal cancer treatment.

A simple polarimetric measurement based on a computational algorithm.

A simple and compact polarimeter comprising two electrically controlled liquid-crystal variable retarders (LCVRs) and a linear polarizer is demonstrated, which is enabled by analyzing the intensity variation of the modulated output light based on a computational algorithm. A proof-of-concept prototype is presented, which is mounted onto a power meter or a CMOS camera for the intensity data collection. The polarimetric measurement for the spatial variant polarization states of light is also verified, indicating the possibility of achieving a resolution-lossless polarimeter. Thus, our proposed method shows a cost-effective way to realize a compact polarimeter in polarization optics.

Swift Assembly of Adaptive Thermocell Arrays for Device-Level Healable and Energy-Autonomous Motion Sensors.

The evolution of wearable technology has prompted the need for adaptive, self-healable, and energy-autonomous energy devices. This study innovatively addresses this challenge by introducing an MXene-boosted hydrogel electrolyte, which expedites the assembly process of flexible thermocell (TEC) arrays and thus circumvents the complicated fabrication of typical wearable electronics. Our findings underscore the hydrogel electrolyte's superior thermoelectrochemical performance under substantial deformations and repeated self-healing cycles. The resulting hydrogel-based TEC yields a maximum power output of 1032.1 nW under the ΔT of 20 K when being stretched to 500% for 1000 cycles, corresponding to 80% of its initial state; meanwhile, it sustains 1179.1 nW under the ΔT of 20 K even after 60 cut-healing cycles, approximately 92% of its initial state. The as-assembled TEC array exhibits device-level self-healing capability and high adaptability to human body. It is readily applied for touch-based encrypted communication where distinct voltage signals can be converted into alphabet letters; it is also employed as a self-powered sensor to in-situ monitor a variety of body motions for complex human actions. The swift assembly approach, combined with the versatile functionality of the TEC device, paves the way for future advancements in wearable electronics targeting at fitness monitoring and human-machine interfaces.

Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth.

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and sirt1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy.

lncRNA PCAT1 might coordinate ZNF217 to promote CRC adhesion and invasion through regulating MTA2/MTA3/Snai1/E-cadherin signaling.

LncRNA prostate cancer-associated transcript 1 (PCAT1) is a well-known oncogene, but the mechanisms of exosomes PCAT1 in colorectal cancer (CRC) remain largely unknown. Thus, the mechanisms of exosomes lncRNA PCAT1 were investigated. The expressions of exosomes lncRNA PCAT1 in tissues from stage 0-I and stage II-III CRC patients, and intestinal epithelial cell line FHC and two CRC cell lines, HT29 and HCT8 were measured by real-time quantitative PCR. The effects of lncRNA PCAT1 on adhesion and invasion of two CRC cell lines were investigated by cell-matrix adhesion and transwell assays. In addition, the target of PCAT1 (ZNF217) was validated using an RNA immune precipitation assay. Finally, the protein levels of MTA2, MTA3, SNAI1, and E-cadherin in normal participants, stage 0-I and stage II-III CRC patients, as well as two cell lines with stable ZNF217 knockdown were investigated by western blotting. The plasma exosomal lncRNA PCAT1 was found to be significantly increased in the CRC tissues and cell lines. In addition, lncRNA PCAT1 knockdown significantly inhibited the adhesion and invasion of HT29 and HCT8 cells. RIP assay results showed lncRNA PCAT1 could target ZNF217, and downregulation of lncRNA PCAT1 could decrease the protein expressions of ZNF217 in two CRC cells lines. Moreover, ZNF217 knockdown significantly decreased MTA2, MTA3, and SNAI1 expressions, but increased E-cadherin expressions in both CRC cells lines. Exosomal lncRNA PCAT1 can promote the adhesion and invasion of CRC cells, and PCAT1 overexpression may lead to ZNF217 upregulation that regulates EMT-related MTA2/MTA3/Snai1/E-cadherin signaling.

TFCP2 Overcomes Senescence by Cooperating With SREBP2 to Activate Cholesterol Synthesis in Pancreatic Cancer.

KRAS mutation is very common in pancreatic cancer. How pancreatic cancer cells overcome oncogene-induced senescence is not fully understood. Our previous studies showed that up-regulation of TFCP2 (transcription factor CP2) in pancreatic cancer promoted the growth and metastasis of pancreatic cancer cells. However, whether TFCP2 plays an important role in pancreatic cancer cell senescence is not clear. In this study, we found upregulation of TFCP2 expression in pancreatic cancer was associated with KRAS mutation. Overexpression of TFCP2 inhibited cell senescence. Knockdown of TFCP2 promoted cell senescence. Mechanistically, the interaction between TFCP2 and SREBP2 (sterol regulatory element binding transcription factor 2) synergistically activated the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis, and statins could reverse the inhibitory effect of TFCP2 on senescence. In conclusion, our study reveals a new mechanism underlying the TFCP2 regulation of pancreatic cancer cell senescence, providing a new target for the treatment of pancreatic cancer.

Mediating different-diameter Aß nerve fibers using a biomimetic 3D TENS computational model.

BACKGROUND: Significant progress has been made over the last 50 years in the design, development and testing of transcutaneous electrical nerve stimulation (TENS) in mediating different levels of tactile sensations. However, without knowing how best to stimulate the nerve fibers, the elicited sensation quality will always remain poor and unnatural. NEW METHOD: A new biomimetic 3D TENS computational model is developed to quantify the neural activation mechanism with varied surface electrodes. This model includes seven-layered anatomical structure of the forearm and biophysically-detailed myelinated Aß fibers. The Aß-fiber diameters from 1.5 - 7.5 µm were randomly distributed beneath the skin to mimic the physiologically-realistic fiber population. The arithmetic averaging algorithm and Gaussian filter were adopted to identify the sensation center and to quantify sensation intensities under different stimulation conditions. RESULTS: Fibers larger than 4.5 µm can usually be activated producing tactile sensations such as light touch, pressure, buzz, and vibration. While, fibers with diameters of 3.5 and 3 µm can only be excited at uncomfortable numb and pain sensations. The resulted modelling predictions match the recent psychophysical experimental data. COMPARISON WITH EXISTING METHOD(S): The new TENS model is more physiologically-realistic by introducing a detailed morphological information and key ionic mechanisms in nerve fibers. CONCLUSIONS: Our results indicate that TENS may be a promising method to target functionally-distinct neural pathways in an effort to improve the elicited tactile sensations quality with electrical stimulation. This work provides a promising platform of discovering neural mechanisms under TENS.

The association of miR-27a rs895819 polymorphism with colorectal cancer risk in Chinese population.

BACKGROUND: Besides environment and living habits, such as a sedentary lifestyle, smoking and drinking, genetic variation also plays an important role in the development of colorectal cancer (CRC). This study was aimed to investigate the role of miR-27a rs895819 polymorphism on CRC risk in Chinese population. METHODS: In a case-control study including 208 CRC and 312 age- and gender-matched healthy control subjects, the rs895819 polymorphism was genotyped using the TaqMan allelic discrimination assay. Furthermore, a pooled analysis based on eligible studies was performed by using the STATA software. RESULTS: Logistic regression analysis showed that the rs895819 polymorphism was not associated with CRC risk. However, a pooled analysis based on five studies from Chinese population showed a statistically significant association between the rs895819 polymorphism and CRC risk (GG vs AA: OR = 1.56, 95% CI = 1.27-1.92, Pz < .01; (AG + GG) vs AA: OR = 1.14, 95% CI = 1.01-1.30, Pz = .04; GG vs (AG + AA): OR = 1.54, 95% CI = 1.27-1.88, Pz < .01; G vs A: OR = 1.20, 95% CI = 1.09-1.33, Pz < .01). CONCLUSION: Our study suggests that miR-27a rs895819 polymorphism plays an important role in CRC risk in Chinese population and may serve as a valuable biomarker for predicting an individual's susceptibility to CRC.

Association between an indel polymorphism within the distal promoter of EGLN2 and cancer risk: An updated meta-analysis.

BACKGROUND: The association between a 4-bp indel polymorphism (rs10680577) within the distal promoter of EGLN2 and cancer risk has been investigated by several case-control studies in recent years, but investigation results were inconsistent. Thus, a systematic assessment of the association was performed based on a literature review and pooled analysis. METHODS: Two investigators independently retrieved relevant studies from PubMed, Chinese National Knowledge Infrastructure (CNKI), Embase, and Google Scholar. The fixed or random effects model was selected to calculate odds ratios (ORs) with 95% confidence intervals (CIs) based on heterogeneity level. All analyses including heterogeneity assessment, subgroup analysis, sensitivity analysis, and publication bias assessment were performed using RevMan 5.3 software and Stata 12.0 software. RESULTS: A total of six relevant studies with 3,406 cases and 5,147 controls were included in the final analysis. The overall pooled analysis showed that EGLN2 rs10680577 polymorphism was significantly associated with cancer risk under all genetic models. However, subgroup analysis based on cancer type showed that the polymorphism was significantly associated with the risk of digestive system cancer under all genetic models, and with the risk of lung cancer under dominant model, heterozygote comparison model, and allele comparison model. Subgroup analysis based on population sources showed a significant association in Chinese population under all genetic models. CONCLUSION: The present result suggests that EGLN2 rs10680577 polymorphism is associated with cancer risk, and may act as a promising predictive biomarker for cancer risk, especially in Chinese population. However, further well-designed studies are warranted to confirm these results.

A 3D Computational Model of Transcutaneous Electrical Nerve Stimulation for Estimating Aß Tactile Nerve Fiber Excitability.

Tactile sensory feedback plays an important role in our daily life. Transcutaneous electrical nerve stimulation (TENS) is widely accepted to produce artificial tactile sensation. To explore the underlying mechanism of tactile sensation under TENS, this paper presented a novel 3D TENS computational model including an active Aß tactile nerve fiber (TNF) model and a forearm finite element model with the fine-layered skin structure. The conduction velocity vs. fiber diameter and strength-duration relationships in this combined TENS model matched well with experimental data. Based on this validated TENS model, threshold current variation were further investigated under different stimulating electrode sizes with varied fiber diameters. The computational results showed that the threshold current intensity increased with electrode size, and larger nerve fibers were recruited at lower current intensities. These results were comparable to our psychophysical experimental data from six healthy subjects. This novel 3D TENS model would further guide the floorplan of the surface electrodes, and the stimulating paradigms for tactile sensory feedback.