Sex-specific implications of inflammation in covert cerebral small vessel disease.

BACKGROUND: The relationship between inflammation and covert cerebral small vessel disease (SVD) with regards to sex difference has received limited attention in research. We aim to unravel the intricate associations between inflammation and covert SVD, while also scrutinizing potential sex-based differences in these connections. METHODS: Non-stroke/dementia-free study population was from the I-Lan longitudinal Aging Study. Severity and etiology of SVD were assessed by 3T-MRI in each participant. Systemic and vascular inflammatory-status was determined by the circulatory levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine, respectively. Sex-specific multivariate logistic regression to calculate odds ratios (ORs) and interaction models to scrutinize women-to-men ratios of ORs (RORs) were used to evaluate the potential impact of sex on the associations between inflammatory factors and SVD. RESULTS: Overall, 708 participants (62.19 ± 8.51 years; 392 women) were included. Only women had significant associations between homocysteine levels and covert SVD, particularly in arteriosclerosis/lipohyalinosis SVD (ORs[95%CI]: 1.14[1.03-1.27] and 1.15[1.05-1.27] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively). Furthermore, higher circulatory levels of homocysteine were associated with a greater risk of covert SVD in women compared to men, as evidenced by the RORs [95%CI]: 1.14[1.01-1.29] and 1.14[1.02-1.28] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively. No significant associations were found between circulatory hsCRP levels and SVD in either sex. CONCLUSION: Circulatory homocysteine is associated with covert SVD of arteriosclerosis/lipohyalinosis solely in women. The intricacies underlying the sex-specific effects of homocysteine on SVD at the preclinical stage warrant further investigations, potentially leading to personalized/tailored managements. TRIAL REGISTRATION: Not applicable.

Why Do We Not Wear Masks Anymore during the COVID-19 Wave? Vaccination Precludes the Adoption of Personal Non-Pharmaceutical Interventions: A Quantitative Study of Taiwanese Residents.

Background and Objectives: This study examined whether the decline in people's adoption of personal NPIs (e.g., mask wearing) results from the preclusion by vaccination. This study also incorporates the concepts of risk perception and the risk-as-feelings model to elucidate the possible mechanisms behind this preclusion. Materials and Methods: Two cross-sectional surveys (N = 462 in Survey 1 and N = 505 in Survey 2) were administered before and during the first outbreak of COVID-19 in Taiwan. The survey items were designed to measure participants' perceived severity of COVID-19, worry about COVID-19, intention to adopt personal NPIs, and attitudes toward COVID-19 vaccines. Utilizing the risk perception framework, we conducted multigroup SEM (Structural Equation Modeling) to construct the optimal structural model for both samples. Results and Conclusions: The multigroup SEM results showed that worry (i.e., the emotional component of risk perception) fully mediates the influence of the perceived severity of COVID-19 (i.e., the cognitive component of risk perception) on the intention to adopt NPIs in both surveys [z = 4.03, p < 0.001 for Survey 1 and z = 2.49, p < 0.050 for Survey 2]. Before the outbreak (i.e., Survey 1), people's attitudes toward COVID-19 vaccines showed no significant association with their worry about COVID-19 [z = 0.66, p = 0.508]. However, in Survey 2, following the real outbreak of COVID-19, people's attitudes toward COVID-19 vaccines negatively predicts their worry about COVID-19 [z = -4.31, p < 0.001], indirectly resulting in a negative effect on their intention to adopt personal NPIs. This suggests the occurrence of the Peltzman effect. That is, vaccination fosters a sense of safety, subsequently diminishing alertness to COVID-19, and thus reducing the intention to adopt personal NPIs.

Correction: First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies.

Correction for 'First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies' by Po-Yuan Wang et al., Phys. Chem. Chem. Phys., 2022, 24, 24166-24172, https://doi.org/10.1039/D2CP03384D.

Study of photo-ionization and thermal effects on the interaction of a nanosecond extreme ultraviolet laser with copper.

The damage mechanism of a nanosecond extreme ultraviolet (EUV) laser with solid targets is complex and involves thermal and nonthermal effects. In this study, the interaction process of a nanosecond 46.9 nm laser with copper was investigated. A Faraday cup was used to measure the electron signals induced by the laser irradiation. The photo-ionization and thermal effects in the interaction process are discussed according to the results.

Meis1, Hi1α, and GATA1 are integrated into a hierarchical regulatory network to mediate primitive erythropoiesis.

During development, erythroid cells are generated by two waves of hematopoiesis. In zebrafish, primitive erythropoiesis takes place in the intermediate cell mass region, and definitive erythropoiesis arises from the aorta-gonad mesonephros. TALE-homeoproteins Meis1 and Pbx1 function upstream of GATA1 to specify the erythroid lineage. Embryos lacking Meis1 or Pbx1 have weak gata1 expression and fail to produce primitive erythrocytes. Nevertheless, the underlying mechanism of how Meis1 and Pbx1 mediate gata1 transcription in erythrocytes remains unclear. Here we show that Hif1α acts downstream of Meis1 to mediate gata1 expression in zebrafish embryos. Inhibition of Meis1 expression resulted in suppression of hif1a expression and abrogated primitive erythropoiesis, while injection with in vitro-synthesized hif1α mRNA rescued gata1 transcription in Meis1 morphants and recovered their erythropoiesis. Ablation of Hif1α expression either by morpholino knockdown or Crispr-Cas9 knockout suppressed gata1 transcription and abrogated primitive erythropoiesis. Results of chromatin immunoprecipitation assays showed that Hif1α associates with hypoxia-response elements located in the 3'-flanking region of gata1 during development, suggesting that Hif1α regulates gata1 expression in vivo. Together, our results indicate that Meis1, Hif1α, and GATA1 indeed comprise a hierarchical regulatory network in which Hif1α acts downstream of Meis1 to activate gata1 transcription through direct interactions with its cis-acting elements in primitive erythrocytes.

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.

First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies.

Vacancy sites, e.g., S-vacancies, are essential for the performance of MoS2 catalysts. As earlier studies have revealed that the size and shape of the S-vacancies may affect the catalytic activity, we have studied the behavior and mobility of such vacancies on MoS2 using DFT calculations and kinetic Monte-Carlo (kMC) simulations. The diffusion barriers for the S-vacancies are highly dependent on the immediate environment: isolated single S-vacancies are found to be immobile. In contrast, small nS-vacancies formed from n = 2 to 5 neighboring S-vacancies are often highly dynamic systems that can move within a confined area. Large extended nS-vacancies are generally unstable and transform quickly into alternating patterns of S-atoms and vacancy sites. These results illustrate the importance of recognizing MoS2 (but also other catalysts) as dynamic structures when trying to tune their catalytic performances by introducing specific defect structures.

Molecular characteristics and in vitro effects of antimicrobial combinations on planktonic and biofilm forms of Elizabethkingia anophelis.

OBJECTIVES: To investigate the in vitro activity of antibiotics against clinical Elizabethkingia anophelis isolates and to find a suitable antibiotic combination with synergistic effects to combat antibiotic-resistant E. anophelis and its associated biofilm. METHODS: E. anophelis isolates were identified by 16S rRNA sequencing; 30 strains with different pulsotypes were identified and the MIC, antibiotic resistance mechanism, antibiotic combination activity and killing effects of antimicrobial agents on biofilms of these strains were determined. RESULTS: All E. anophelis isolates were susceptible to minocycline and cefoperazone/sulbactam (1:1). More than 90% of clinical isolates were susceptible to cefoperazone/sulbactam (1:0.5), piperacillin/tazobactam and rifampicin. Some novel mutations, such as gyrA G81D, parE D585N and parC P134T, that have never been reported before, were identified. The synergistic effect was most prominent for the combination of minocycline and rifampicin, with 93.3% of their FIC index values ≤0.5, and no antagonism was observed using the chequerboard method. This synergistic effect between minocycline and rifampicin was also observed using time-killing methods for clinical E. anophelis isolates at both normal inoculum and high inoculum. Twenty-nine isolates tested positive for biofilm formation. Minocycline remained active against biofilm-embedded and biofilm-released planktonic E. anophelis cells; however, the enhanced effect of minocycline by adding rifampicin was only observed at 24 h (not at 72 and 120 h). CONCLUSIONS: Although E. anophelis was resistant to many antibiotics and could exhibit biofilm formation, minocycline showed potent in vitro activity against this pathogen and its associated biofilm.

High Resistance Index in the Feeding Arteries of Indirect Carotidcavernous Fistulae: A Diagnostic Pitfall.

Carotid-cavernous fistulae (CCFs) are classified into the direct and indirect types, which can be attributed to trauma, atherosclerosis, hypertension, diabetes mellitus, pregnant or postmenopausal status(1). Cerebral angiography is the gold standard for the diagnosis of CCFs. Doppler ultrasound, which typically reveals increased blood flow velocity and decreased resistance index (RI) in the feeding arteries, can assist in the diagnosis(2-3). We herein report a case of indirect CCF presenting with high RI in the feeding arteries, which is mainly attributed to the generalized atherosclerotic change, and is regarded as a diagnostic pitfall of the CCFs.

Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer.

Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.

Yes-associated protein/TEA domain family member and hepatocyte nuclear factor 4-alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice.

Great progress has been achieved in the study of Hippo signaling in regulating tumorigenesis; however, the downstream molecular events that mediate this process have not been completely defined. Moreover, regulation of Hippo signaling during tumorigenesis in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we systematically investigated the relationship between Yes-associated protein/TEA domain family member (YAP-TEAD) and hepatocyte nuclear factor 4-alpha (HNF4α) in the hepatocarcinogenesis of HCC cells. Our results indicated that HNF4α expression was negatively regulated by YAP1 in HCC cells by a ubiquitin proteasome pathway. By contrast, HNF4α was found to directly associate with TEAD4 to compete with YAP1 for binding to TEAD4, thus inhibiting the transcriptional activity of YAP-TEAD and expression of their target genes. Moreover, overexpression of HNF4α was found to significantly compromise YAP-TEAD-induced HCC cell proliferation and stem cell expansion. Finally, we documented the regulatory mechanism between YAP-TEAD and HNF4α in rat and mouse tumor models, which confirmed our in vitro results. CONCLUSION: There is a double-negative feedback mechanism that controls TEAD-YAP and HNF4α expression in vitro and in vivo, thereby regulating cellular proliferation and differentiation. Given that YAP acts as a dominant oncogene in HCC and plays a crucial role in stem cell homeostasis and tissue regeneration, manipulating the interaction between YAP, TEADs, and HNF4α may provide a new approach for HCC treatment and regenerative medicine. (Hepatology 2017;65:1206-1221).

Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma.

BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied. RESULTS: In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment. CONCLUSION: This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment. GENERAL SIGNIFICANCE: PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.

OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors.

BACKGROUND & AIMS: Activation of WNT signaling promotes the invasive activities of several types of cancer cells, but it is not clear if it regulates the same processes in colorectal cancer (CRC) cells, or what mechanisms are involved. We studied the expression and function of OVOL2, a member of the Ovo family of conserved zinc-finger transcription factors regulated by the WNT signaling pathway, in intestinal tumors of mice and human beings. METHODS: We analyzed the expression of OVOL2 protein and messenger RNA in CRC cell lines and tissue arrays, as well as CRC samples from patients who underwent surgery at Xiamen University in China from 2009 to 2012; clinical information also was collected. CRC cell lines (SW620) were infected with lentivirus expressing OVOL2, analyzed in migration and invasion assays, and injected into nude mice to assess tumor growth and metastasis. Tandem affinity purification was used to purify the OVOL2-containing complex from CRC cells; the complex was analyzed by liquid chromatography, tandem mass spectrometry, and immunoprecipitation experiments. Gene promoter activities were measured in luciferase reporter assays. We analyzed mice with an intestine-specific disruption of Ovol2 (Ovol2(flox/+) transgenic mice), as well as Apc(min/+) mice; these mice were crossed and analyzed. RESULTS: Analysis of data from patients indicated that the levels of OVOL2 messenger RNA were significantly lower in colon carcinomas than adenomas, and decreased significantly as carcinomas progressed from grades 2 to 4. Immunohistochemical analysis of a tissue array of 275 CRC samples showed a negative association between tumor stage and OVOL2 level. Overexpression of OVOL2 in SW620 cells decreased their migration and invasion, reduced markers of the epithelial-to-mesenchymal transition, and suppressed their metastasis as xenograft tumors in nude mice; knockdown of OVOL2 caused LS174T cells to transition from epithelial to mesenchymal phenotypes. OVOL2 bound T-cell factor (TCF)4 and ß-catenin, facilitating recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex; this inhibited expression of epithelial-to-mesenchymal transition-related genes regulated by WNT, such as SLUG, in CRC cell lines. OVOL2 was a downstream target of WNT signaling in LS174T and SW480 cells. The OVOL2 promoter was hypermethylated in late-stage CRC specimens from patients and in SW620 cells; hypermethylation resulted in OVOL2 down-regulation and an inability to inhibit WNT signaling. Disruption of Ovol2 in Apc(min/+) mice increased WNT activity in intestinal tissues and the formation of invasive intestinal tumors. CONCLUSIONS: OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex. Strategies to increase levels of OVOL2 might be developed to reduce colorectal tumor progression and metastasis.

A Dual Conductance Sensor for Simultaneous Measurement of Void Fraction and Structure Velocity of Downward Two-Phase Flow in a Slightly Inclined Pipe.

In this study, a new and improved electrical conductance sensor is proposed for application not only to a horizontal pipe, but also an inclined one. The conductance sensor was designed to have a dual layer, each consisting of a three-electrode set to obtain two instantaneous conductance signals in turns, so that the area-averaged void fraction and structure velocity could be measured simultaneously. The optimum configuration of the electrodes was determined through numerical analysis, and the calibration curves for stratified and annular flow were obtained through a series of static experiments. The fabricated conductance sensor was applied to a 45 mm inner diameter U-shaped downward inclined pipe with an inclination angle of 3° under adiabatic air-water flow conditions. In the tests, the superficial velocities ranged from 0.1 to 3.0 m/s for water and from 0.1 to 18 m/s for air. The obtained mean void fraction and the structure velocity from the conductance sensor were validated against the measurement by the wire-mesh sensor and the cross-correlation technique for the visualized images, respectively. The results of the flow regime classification and the corresponding time series of the void fraction at a variety of flow velocities were also discussed.

Wernicke's Encephalopathy after Bariatric Surgery with Atypical Magnetic Resonance Imaging: A Case Report.

Wernicke's encephalopathy (WE) is a disease caused by thiamine deficiency related to alcoholism, hyperemesis, or thiamine malabsorption. The clinical manifestations of WE are mental change, ataxia, and ophthalmoplegia. The typical magnetic resonance imaging (MRI) findings of WE are symmetrical involvement of medial thalamus, periventricular region of the third ventricle, periaqueductal area, and mammillary body. The atypical MRI findings are more common in nonalcoholic WE. Since the increasing population of obesity and the preference of weight loss surgery, the risk of developing thiamine deficiencies associated with weight loss surgery has become a considerable etiology of WE. We herein reported a case reminds clinicians that WE can be a possible diagnosis in patient who developed acute altered mental status with atypical MRI lesion involving bilateral centrum semiovale and corona radiata after receiving bariatric surgery.

Depletion of UBA protein 2-like protein inhibits growth and induces apoptosis of human colorectal carcinoma cells.

Ubiquitin-proteasome system regulates cell proliferation, apoptosis, angiogenesis, and motility, which are processes with particular importance for carcinogenesis. UBA protein 2-like protein (UBAP2L) was found to be associated with proteasome; however, its biological function is largely unknown. In this study, the mRNA levels of UBAP2L in human normal and colorectal carcinoma tissues were analyzed using the datasets from the publicly available Oncomine database ( www.oncomine.org ) and found UBAP2L was overexpressed in colorectal carcinoma tissues. Furthermore, we elucidated the role of UBAP2L in human colorectal cancer via an RNA interference lentivirus system in three colorectal carcinoma cell lines HCT116, SW1116, and RKO. Knockdown of UBAP2L led to suppressed cell proliferation and impaired colony formation. UBAP2L depletion in HCT116 and RKO cells also induced cell cycle arrest as well as apoptosis. Moreover, the phosphorylation of PRAS40, Bad, and the cleavage of PARP were remarkably increased after UBAP2L knockdown by Intracellular signaling array and also the activation of P38 was obviously decreased and the cleavage of Caspase 3 and Bax were increased after UBAP2L silencing by western blot assay, indicated that UBAP2L might be involved in the cell growth by the regulation of apoptosis-related proteins. Our findings indicated that UBAP2L may be essential for colorectal carcinoma growth and survival. Lentivirus-mediated small interfering RNA against UBAP2L might serve as a potential therapeutic approach for the treatment of colorectal cancer.

The Wnt-ß-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.

Wnt signalling through ß-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-ß-catenin pathway. Expression studies indicated that the Wnt-ß-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-ß-catenin pathway. Loss of function of Lin28 impairs Wnt-ß-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-ß-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-ß-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-ß-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-ß-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-ß-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.

A double-negative feedback loop between Wnt-ß-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma.

Wnt-ß-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4α is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4α maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-ß-catenin signaling and HNF4α in the EMT process of HCC cells. Our results indicated that HNF4α expression was negatively regulated during Wnt-ß-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4α was found to directly associate with TCF4 to compete with ß-catenin but facilitate transcription co-repressor activities, thus inhibiting expression of EMT-related Wnt-ß-catenin targets. Moreover, HNF4α may control the switch between the transcriptional and adhesion functions of ß-catenin. Overexpression of HNF4α was found to completely compromise the Wnt-ß-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-ß-catenin signaling and HNF4α in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-ß-catenin signaling and HNF4α expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-ß-catenin signaling or restoring HNF4α expression to prevent EMT.

Clinical research of intraperitoneal implantation of sustained-release 5-fluorouracil in advanced colorectal cancer.

BACKGROUND: The objective of this study was to investigate the safety and long-term clinical effect of intraperitoneal implantation of sustained-release 5-fluorouracil in patients with advanced colorectal cancer during radical resection. METHODS: A total of 202 patients with advanced colorectal cancer undergoing radical operations were randomly divided into an experimental group (98 cases, intraoperative intraperitoneal implantation of sustained-release 5-fluorouracil 600 mg as local chemotherapy) and a control group (104 cases, without local chemotherapy). The clinical data of the two groups was compared including toxicity, complications, local recurrence rate, distant metastasis, disease-free survival, and 1-, 3-, and 5-year survival rates. RESULTS: Both groups of patients were followed up for more than 5 years, the longest follow-up time was 7.5 years. Bone marrow suppression, hepato-renal function, postoperative anastomotic leakage, pelvic effusion, incision infection, the incidence of intestinal obstruction, venting time, and hospital stay after operation (days) between two groups had no statistical significant difference. Locoregional recurrence and liver metastasis rate were decreased significantly in experimental group (P = 0.04 and 0.04). Extensive peritoneal metastasis and other organ metastasis rates had no significant difference between two groups. In the experimental group, 1-, 3-, and 5-year survival rates were higher than in the control group (95.92 vs 87.50 %, 77.55 vs 64.42 %, and 56.12 vs 40.38 %), which had significant difference. Disease-free survival (DFS) of the experimental group was higher than that of the control group (χ (2) = 5.00, P = 0.025). CONCLUSIONS: Intraperitoneal implantation of sustained-release 5-fluorouracil is safe for advanced colorectal cancer during radical resection, which can reduce locoregional recurrence rate and liver metastasis rate. The long-term efficacy was reliable, and long-term survival and disease-free survival rate can be improved.

Myotubularin-related phosphatase 3 promotes growth of colorectal cancer cells.

Due to changes in lifestyle, particularly changes in dietary habits, colorectal cancer (CRC) increased in recent years despite advances in treatment. Nearly one million new cases diagnosed worldwide and half a million deaths make CRC a leading cause of cancer mortality. In the present study, we aimed to investigate the role of myotubularin-related phosphatase 3 (MTMR3) in CRC cell growth via lentivirus-mediated small interfering RNA (siRNA) transduction in human colon cancer cell lines HCT116 and SW1116. The effect of MTMR3 knockdown on cell growth was evaluated by MTT, colony formation, and flow cytometry assays. The effect of MTMR3 knockdown on cell apoptosis was evaluated by flow cytometry with Annexin V/7-AAD double staining. The activation of apoptotic markers, Bad and PARP, was detected using Intracellular Signaling Array. Knockdown of MTMR3 resulted in a significant reduction in cell proliferation in both HCT116 and SW1116 cells. Moreover, knockdown of MTMR3 led to S phase cell cycle arrest. Furthermore, knockdown of MTMR3 induced cell apoptosis via phosphorylation of Bad and cleavage of PARP. These results indicate that MTMR3 may play an important role in the progression of CRC and suggest that siRNA mediated silencing of MTMR3 could be an effective tool in CRC treatment.