Acetylation-Mimic Mutation of TRIM28-Lys304 to Gln Attenuates the Interaction with KRAB-Zinc-Finger Proteins and Affects Gene Expression in Leukemic K562 Cells.

TRIM28/KAP1/TIF1ß is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming.

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography−mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.

Generation of TRIM28 Knockout K562 Cells by CRISPR/Cas9 Genome Editing and Characterization of TRIM28-Regulated Gene Expression in Cell Proliferation and Hemoglobin Beta Subunits.

TRIM28 is a scaffold protein that interacts with DNA-binding proteins and recruits corepressor complexes to cause gene silencing. TRIM28 contributes to physiological functions such as cell growth and differentiation. In the chronic myeloid leukemia cell line K562, we edited TRIM28 using CRISPR/Cas9 technology, and the complete and partial knockout (KO) cell clones were obtained and confirmed using quantitative droplet digital PCR (ddPCR) technology. The amplicon sequencing demonstrated no off-target effects in our gene editing experiments. The TRIM28 KO cells grew slowly and appeared red, seeming to have a tendency towards erythroid differentiation. To understand how TRIM28 controls K562 cell proliferation and differentiation, transcriptome profiling analysis was performed in wild-type and KO cells to identify TRIM28-regulated genes. Some of the RNAs that encode the proteins regulating the cell cycle were increased (such as p21) or decreased (such as cyclin D2) in TRIM28 KO cell clones; a tumor marker, the MAGE (melanoma antigen) family, which is involved in cell proliferation was reduced. Moreover, we found that knockout of TRIM28 can induce miR-874 expression to downregulate MAGEC2 mRNA via post-transcriptional regulation. The embryonic epsilon-globin gene was significantly increased in TRIM28 KO cell clones through the downregulation of transcription repressor SOX6. Taken together, we provide evidence to demonstrate the regulatory network of TRIM28-mediated cell growth and erythroid differentiation in K562 leukemia cells.

Long-Term Survival of Combined Hepatocellular-Cholangiocarcinoma: A Nationwide Study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an aggressive primary liver cancer. However, the clinical features are not clearly understood because of limited literature and the complex nature of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). METHODS: The records of 100,754 patients with newly diagnosed liver cancer between 2004 and 2013 were obtained from the Taiwan Cancer Registry. The primary outcome measures were overall survival and local recurrence-free survival. The median follow-up time was 60 months (29-120 months). RESULTS: HCC-CC tended to share some characteristics with HCC, including increased frequency of stage I cases, high individual tumor rates, and similar patterns of viral hepatitis B and hepatitis C infections. In contrast, HCC-CC showed malignant behavior similar to that of CC, as high-grade tumor cell differentiation and presentation of jaundice were predominant in HCC-CC and CC compared with HCC. Overall survival and local recurrence-free survival rates of HCC-CC were between HCC and CC rates. The mortality rate of HCC-CC was 79.2% (HCC, 77.5%; CC, 93.5%) and the local recurrence rate of HCC-CC was 65.3% (HCC, 74.6%; CC, 88.4%). Surgical treatment was an independent factor for the long-term prognosis of HCC-CC, whereas transarterial chemoembolization (TAcE) promoted survival in both surgical and nonsurgical groups. CONCLUSION: Our data confirmed that, although it reflects the malignant behavior of CC, HCC-CC should mainly be characterized as a subtype of HCC. With careful selection of patients, curative resection and TAcE might benefit the survival of patients with HCC-CC. IMPLICATIONS FOR PRACTICE: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare cancer that shares demographic characteristics, as well as survival probabilities, with both hepatocellular carcinoma and cholangiocarcinoma. It occurs frequently in patients with hepatitis B virus infection, cirrhotic liver background, and early-stage disease. Compared with 20% of initial resection rates of its counterparts, HCC-CC has higher initial resection rate (55%). Although short-term overall survival is inferior to HCC, its long-term overall survival is similar with HCC.

Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma.

This study compared the prognostic significance of staging between the American Joint Committee on Cancer 8th edition Tumor, Node, Metastasis (TNM) staging system and the Barcelona Clinic Liver Cancer (BCLC) classification in patients with hepatocellular carcinoma (HCC). The study population comprised patients with liver cancer registered in the Taiwan Cancer Database from 2007 to 2013 and was followed up until December 31, 2016. The study included patients with HCC, with known staging in both TNM and BCLC systems, and with follow-up >1 month. Primary endpoint was overall survival. Univariate and multivariate Cox proportional hazards model were constructed to investigate the significance of staging by two systems. Goodness-of-fit of model was evaluated via Akaike's information criterion (AIC), the lower the better. Among 73,136 patients with newly diagnosed liver cancer, a total of 37,062 patients with HCC (25.6% underwent surgery) were eligible. The mean age and overall survival of this cohort were 63.9 years and 27.2%, respectively. Overall survivals for stages I, II, III, and IV (the TNM system) were 54.5%, 34.9%, 10.3%, and 6.4%, respectively. Overall survivals for stages A, B, C, and D (the BCLC classification) were 54.5%, 29.2%, 9.8%, and 4.0%, respectively. The median follow-up time was 59.4 months. Multivariate Cox proportional hazards model revealed that both systems predicted overall survival, cancer-specific survival, disease-free survival, and local recurrence-free rate well. Values of ΔAIC of the BCLC classification and the TNM system were lower for the surgery group and nonsurgery group, respectively. The TNM system (8th edition) predicted long-term outcome better than the BCLC classification in patients with HCC. But in patients treated initially with surgery, the BCLC classification outperformed the 8th edition of the TNM system. IMPLICATIONS FOR PRACTICE: This work demonstrates that the Tumor, Node, Metastasis (TNM) system (8th edition) and the Barcelona Clinic Liver Cancer (BCLC) classification both predict long-term outcome significantly in patients with hepatocellular carcinoma but that the TNM system (8th edition) predicts long-term outcome better than the BCLC classification. For patients treated initially with surgery, BCLC classification outperforms in 8th edition TNM system in predicting long-term outcome.

Radiofrequency ablation versus surgical resection for the treatment of solitary hepatocellular carcinoma 2 cm or smaller: A cohort study in Taiwan.

BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) is increasingly being used instead of surgical resection for the treatment of hepatocellular carcinoma (HCC) tumor measuring ≦2 cm. However, the long-term outcomes of RFA, especially in comparison to surgical resection, are still debated. We compared the outcomes of surgical resection and RFA in patients with a solitary HCC tumor measuring ≦2 cm from a 10-year cohort study. METHODS: From Jan 2006 to Dec 2016, 156 patients with a resectable HCC measuring ≦2 cm who underwent surgical resection (n = 83) or RFA (n = 73) at the Buddhist Tzu Chi Medical Foundation were enrolled. Patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were retrospectively examined, and comparisons were made between the two groups and through subgroup analyses. RESULTS: The 1-year, 3-year, 5-year, and 7-year OS outcomes were comparable between the surgical resection group and the RFA group (P = 0.193), but the surgical resection group had significantly higher 1-year, 3-year, 5-year, 7-year, and 10-year RFS than the RFA group (P = 0.018). Multivariate analysis revealed that patients with lower age, Child-Turcotte-Pugh score, or albumin-bilirubin score before treatment had better OS, and patients with an HCV infection or receiving RFA treatment had higher HCC recurrence rates. CONCLUSION: The liver reserve determined the long-term OS of patients with an HCC tumor ≦ 2 cm, and surgical resection offered better RFS than RFA (ClinicalTrials.gov number, NCT04525833.).

Using a kinect-based game to teach oral hygiene in four elementary students with intellectual disabilities.

BACKGROUND: Individuals with intellectual disabilities (ID) may have difficulties in performing daily living tasks. Among other daily living tasks, independent oral hygiene is an essential life skill for people with ID. MATERIALS AND METHODS: Four children with intellectual disabilities (two males and two females, ages 7-11) participated in the experiment. We employed the KinectTM V2 sensor to gamify oral hygiene skill training. Specifically, a non-concurrent multiple baseline design was adopted to demonstrate the relation between game-based intervention and independent oral hygiene skills. RESULTS: All students learned how to brush their teeth independently and maintained the skill 4 weeks later with the introduction of the game-based training. Social validity results showed the teachers and parents considered the video game was useful. CONCLUSIONS: The proposed Kinect-based video game might be used for effective training of elementary students with ID to improve oral hygiene independently.

TRIM28 Regulates Dlk1 Expression in Adipogenesis.

The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.

Using an augmented reality game to teach three junior high school students with intellectual disabilities to improve ATM use.

BACKGROUND: Individuals with intellectual disabilities (ID) may have difficulties in performing daily living tasks. Among other daily living tasks, independent automated teller machine (ATM) skills are an essential life skill for people with intellectual disabilities. MATERIALS AND METHODS: Three junior high school students in a special education class participated in the experiment. We employed the augmented reality (AR) technology to gamify ATM skill training. Specifically, a multiple baseline design was adopted to demonstrate the relation between game-based intervention and using an ATM independently. RESULTS: Data showed that the percentage of correct task steps increased among all three participants. Social validity results showed the teachers considered the AR game was very useful and it had helped their students learn the ATM skills effectively. CONCLUSIONS: The proposed AR game can be used for effective training of students with intellectual disabilities using an ATM independently.

Using a motion-controlled game to teach four elementary school children with intellectual disabilities to improve hand hygiene.

BACKGROUND: Individuals with intellectual disabilities (ID) may have difficulties in performing daily living tasks. Among other daily living tasks, independent personal hygiene is an essential life skill for people with ID. MATERIALS AND METHODS: Four children in a special education class participated in the experiment. We employed the Kinect V2 sensor to gamify hand washing. Specifically, a non-concurrent multiple baseline design was adopted to demonstrate the relation between game-based intervention and washing hands independently. RESULTS: Data showed that the percentage of correct task steps increased among all four participants. Social validity results showed the parents considered the video game was very useful and it had helped their children learn the hand hygiene skills effectively. CONCLUSIONS: Although the game is a highly accepted training tool for school-use, it currently remains error-prone. A more technically robust system will likely result in higher participant motivation and task performance.

Asymmetric Low Temperature Bonding Structure with Thin Solder Layers Using Ultra-Thin Buffer Layer.

Asymmetric Cu to In/Sn bonding structure with Ni ultrathin buffer layer (UBL) on Cu side is investigated in this research. The usage of Ni UBL slows down intermetallic compound (IMC) formation during bonding. Asymmetric structure can separate electrical isolation and solder process to avoid interaction, which can prevent IMC formation during polymer curing. A well-bonded asymmetric structure can be achieved with submicron solder by 150 °C bonding for 15 min. The structure shows the potential for low temperature hybrid bonding technology in high-density three-dimensional (3D) integration.

Is vegetarian diet associated with a lower risk of breast cancer in Taiwanese women?

BACKGROUND: Studies on the relationship between vegetarian diet and breast cancer in Asian populations are limited. This study aimed to investigate the relationship between vegetarian diet, dietary patterns, and breast cancer in Taiwanese women. METHODS: This case-control study compared the dietary patterns of 233 breast cancer patients and 236 age-matched controls. A questionnaire about vegetarian diets and 28 frequently-consumed food items was administered to these 469 patients in the surgical department of Taipei Tzu Chi Hospital. Serum biochemical status was also examined. RESULTS: There were no significant differences between the two groups for age, education, family history, oral contraceptive usage, or regular exercise. However, the cancer group presented with both a higher body mass index and an older age of primiparity (P < 0.05). Two food items (shellfish and seafood) were highly correlated (correlation coefficient = 0.77), so shellfish was excluded to avoid multicollinearity. A factor analysis of 27 food items produced five dietary patterns: meat, processed meat, fruit/vegetable/soybean, dessert/sugar, and fermented food. Multivariate logistic regression showed that meat/fat and processed meat dietary patterns were associated with breast cancer risk (odds ratio (OR): 2.22, 95% CI 1.67-2.94, P < 0.001; OR: 1.49, 95% CI 1.09-2.04, P = 0.013, respectively). Vegetarian diet, high isoflavone intake, and high albumin levels were inversely associated with breast cancer risk (P < 0.05). Vegetarians had a higher daily soy isoflavone intake than non-vegetarians (25.9 ± 25.6 mg vs. 18.1 ± 15.6 mg, P < 0.001). CONCLUSIONS: Vegetarian diets show as protective role against breast cancer risk, while meat and processed meat dietary patterns are associated with a higher breast cancer risk.

Dynamic response of RNA editing to temperature in Drosophila.

BACKGROUND: Adenosine-to-inosine RNA editing is a highly conserved process that post-transcriptionally modifies mRNA, generating proteomic diversity, particularly within the nervous system of metazoans. Transcripts encoding proteins involved in neurotransmission predominate as targets of such modifications. Previous reports suggest that RNA editing is responsive to environmental inputs in the form of temperature alterations. However, the molecular determinants underlying temperature-dependent RNA editing responses are not well understood. RESULTS: Using the poikilotherm Drosophila, we show that acute temperature alterations within a normal physiological range result in substantial changes in RNA editing levels. Our examination of particular sites reveals diversity in the patterns with which editing responds to temperature, and these patterns are conserved across five species of Drosophilidae representing over 10 million years of divergence. In addition, we show that expression of the editing enzyme, ADAR (adenosine deaminase acting on RNA), is dramatically decreased at elevated temperatures, partially, but not fully, explaining some target responses to temperature. Interestingly, this reduction in editing enzyme levels at elevated temperature is only partially reversed by a return to lower temperatures. Lastly, we show that engineered structural variants of the most temperature-sensitive editing site, in a sodium channel transcript, perturb thermal responsiveness in RNA editing profile for a particular RNA structure. CONCLUSIONS: Our results suggest that the RNA editing process responds to temperature alterations via two distinct molecular mechanisms: through intrinsic thermo-sensitivity of the RNA structures that direct editing, and due to temperature sensitive expression or stability of the RNA editing enzyme. Environmental cues, in this case temperature, rapidly reprogram the Drosophila transcriptome through RNA editing, presumably resulting in altered proteomic ratios of edited and unedited proteins.

VEGF-D and A Preoperative Serum Levels Predict Nodal and Distant Metastases in Differentiated Thyroid Cancer Patients.

BACKGROUND: Preoperative tumor aggressiveness biomarkers may help surgeons decide the extent of an operation. However, whether serum angiogenetic factors can be used to predict the prognosis of patients with differentiated thyroid cancer is still unclear. METHODS: Seventy-six DTC patients were prospectively recruited. Preoperative serum samples were collected and measured for Tie-2, Ang-1, Ang-2, VEGF-A, and VEGF-D levels. The potential correlations between their serum levels and clinicopathologic features as well as their prognoses were analyzed. RESULTS: Older age (>45 years old) and higher VEGF-A serum levels were independent predictors of extrathyroidal extension. The VEGF-D serum level was an independent factor for lymph node metastases and VEGF-A was an independent factor for distant metastases. None of these serum angiogenetic factors were significantly different between patients who were disease free and those with recurrences. The presence of lymph node metastases was the only independent factor for recurrence over the 2-year follow-up. CONCLUSION: Preoperative serum VEGF-A and VEGF-D levels were significantly elevated in DTC patients with distant and lymph node metastases. These findings, when combined with other clinicopathological factors, may help in surgical decisions.

Light-activated tandem catalysis driven by multicomponent nanomaterials.

Transitioning energy-intensive and environmentally intensive processes toward sustainable conditions is necessary in light of the current global condition. To this end, photocatalytic processes represent new approaches for H2 generation; however, their application toward tandem catalytic reactivity remains challenging. Here, we demonstrate that metal oxide materials decorated with noble metal nanoparticles advance visible light photocatalytic activity toward new reactions not typically driven by light. For this, Pd nanoparticles were deposited onto Cu2O cubes to generate a composite structure. Once characterized, their hydrodehalogenation activity was studied via the reductive dechlorination of polychlorinated biphenyls. To this end, tandem catalytic reactivity was observed with H2 generation via H2O reduction at the Cu2O surface, followed by dehalogenation at the Pd using the in situ generated H2. Such results present methods to achieve sustainable catalytic technologies by advancing photocatalytic approaches toward new reaction systems.

Modified LigaSure hemorrhoidectomy for the treatment of hemorrhoidal crisis.

PURPOSE: This study aimed at reporting a modified LigaSure technique for the treatment of acute hemorrhoidal crisis. METHODS: Consecutive patients with an acute hemorrhoidal crisis received a modified LigaSure hemorrhoidectomy. After removing the hemorrhoidal tissues above the welding line, scissors were used to undermine the anoderm to excise residual thrombosed hemorrhoidal tissue. The wound was approximated with a continuous 4-0 vicryl suture. RESULTS: Forty patients (mean age, 47.5 years; range 22.0-76.0 years) were included. The mean duration of the crisis, length of the operation, and follow-up were 2.0 days (range 1.0-5.0 days), 35.6 min (range 15.0-60.0 min), and 13.2 months (range 6-24 months), respectively. At the final follow-up, all patients were continent and there were no cases with anal stenosis, recurrent bleeding, prolapse, or thrombus. The mean pain score before surgery was 8.3, and was 4.4 and 3.2 on postoperative days 1 and 7, respectively. Complications within 30 days of surgery included two cases of urine retention, two cases bleeding, one wound infection and one case of fecal impaction, which all resolved with conservative treatment. The only late complication was one case of residual skin tags. CONCLUSIONS: The modified LigaSure hemorrhoidectomy offers rapid pain relief, early recovery, and low morbidity for patients with an acute hemorrhoidal crisis.

Nitrogen Configuration Effects on Charge Carrier Dynamics in CsPbBr3/Carbon Dots S-Scheme Heterojunction for Photocatalytic CO2 Reduction.

Nitrogen-doped carbon dots (NCDs) featuring primary pyrrolic N and pyridinic N dominated configurations were prepared using hydrothermal (H-NCDs) and microwave (M-NCDs) methods, respectively. These H-NCDs and M-NCDs were subsequently applied to decorate CsPbBr3 nanocrystals (CPB NCs) individually, using a ligand-assisted reprecipitation process. Both CPB/M-NCDs and CPB/H-NCDs nanoheterostructures (NHSs) exhibited S-scheme charge transfer behavior, which enhanced their performance in photocatalytic CO2 reduction and selectivity of CO2-to-CH4 conversion, compared to pristine CPB NCs. The presence of pyrrolic N configuration at the heterojunction of CPB/H-NCDs facilitated efficient S-scheme charge transfer, leading to a remarkable 43-fold increase in photoactivity. In contrast, CPB/M-NCDs showed only a modest 3-fold enhancement in photoactivity, which was attributed to electron trapping by pyridinic N at the heterojunction. The study offers crucial insights into charge carrier dynamics within perovskite/carbon NHSs at the molecular level to advance the understanding of solar fuel generation.

Antioxidants cause rapid expansion of human adipose-derived mesenchymal stem cells via CDK and CDK inhibitor regulation.

BACKGROUND: Antioxidants have been shown to enhance the proliferation of adipose-derived mesenchymal stem cells (ADMSCs) in vitro, although the detailed mechanism(s) and potential side effects are not fully understood. RESULTS: During log-phase growth, exposure to ImF-A resulted in a higher percentage of ADMSCs in the S phase of the cell cycle and a smaller percentage in G0/G1 phase. This resulted in a significantly reduced cell-doubling time and increased number of cells in the antioxidant-supplemented cultures compared with those supplemented with FGF-2 alone, an approximately 225% higher cell density after 7 days. Western blotting showed that the levels of the CDK inhibitors p21 and p27 decreased after ImF-A treatment, whereas CDK2, CDK4, and CDC2 levels clearly increased. In addition, ImF-A resulted in significant reduction in the expression of CD29, CD90, and CD105, whereas relative telomere length, osteogenesis, adipogenesis, and chondrogenesis were enhanced. The results were similar for ADMSCs treated with antioxidants and those under hypoxic conditions. CONCLUSION: Antioxidant treatment promotes entry of ADMSCs into the S phase by suppressing cyclin-dependent kinase inhibitors and results in rapid cell proliferation similar to that observed under hypoxic conditions.

WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway.

The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40-domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle-dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1α localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1's involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA-dependent epigenetic control mechanism that sustains centromere integrity and genomic stability.

Application of the analytic hierarchy process in the performance measurement of colorectal cancer care for the design of a pay-for-performance program in Taiwan.

OBJECTIVE: To prioritize performance measures for colorectal cancer care to facilitate the implementation of a pay-for-performance (PFP) system. DESIGN: Questionnaires survey. SETTING: Medical hospitals in Taiwan. PARTICIPANTS: Sixty-six medical doctors from 5 November 2009 to 10 December 2009. INTERVENTION: Analytic hierarchy process (AHP) technique. Main outcome measure(s) Performance measures (two pre-treatment, six treatment related and three monitoring related) were used. RESULTS: Forty-eight doctors responded and returned questionnaires (response rate 72.7%) with surgeons and physicians contributing equally. The most important measure was the proportion of colorectal patients who had pre-operative examinations that included chest X-ray and abdominal ultrasound, computed tomography or MRI (global priority: 0.144), followed by the proportion of stages I-III colorectal cancer patients who had undergone a wide surgical resection documented as 'negative margin' (global priority: 0.133) and the proportion of colorectal cancer patients who had undergone surgery with a pathology report that included information on tumor size and node differentiation (global priority: 0.116). Most participants considered that the best interval for the renewal indicators was 3-5 years (43.75%) followed by 5-10 years (27.08%). CONCLUSIONS: To design a PFP program, the AHP method is a useful technique to prioritize performance measures, especially in a highly specialized domain such as colorectal cancer care.