Roles of Tumor Suppressor Signaling on Reprogramming and Stemness Transition in Somatic Cells

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Unparticle Phenomenology -- A Mini Review

We review some collider phenomenology of unparticle physics, including real emissions and virtual exchanges of unparticle. Existing experimental constraints from collider physics as well as astrophysics are briefly discussed.Comment: 6 pages, 5 figs and 1 table. Based on invited plenary talk at the 16th International Conference on "Supersymmetry and Unification of Fundamental Interactions", at Seoul, Korea, June 16-21, 2008. More references adde

Physiological β-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma

BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/β-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological β-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of β-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells. RESULTS: Introduction of increased β-catenin signaling, haploid expression of β-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/β-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous β-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/β-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-β, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using β-catenin shRNA inhibitory assays, a dominant role for β-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres. CONCLUSIONS: Wnt/β-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/β-catenin signaling with stemness transition networks

Improving the filament weld-strength of Fused Filament Fabrication products through improved interdiffusion

Fused Filament Fabrication (FFF) is a popular additive manufacturing technique where molten polymer filament is applied in a raster pattern, layer by layer, to obtain the work piece. A necessary consequence of this method is a pronounced mechanical anisotropy of the product; the interface between the filaments is weaker compared to the filament itself. The strength of this interface is governed by the reptation theory which postulates a more efficient interpenetration of polymeric surfaces with decreasing polymer viscosity. This relationship was utilized in this work to modify a polycarbonate-acrylonitrile butadiene styrene polymer blend to produce FFF work pieces with less mechanical anisotropy, independent of printer settings. The tensile strength ratio of the printed interface to bulk tensile strength could be increased from 41% to 95%. Though the absolute bulk tensile strength decreases slightly, this method presents an easy and effective way to address the mechanical problems inherent in the FFF-method

Evidence of the neuron-restrictive silencer factor (NRSF) interaction with Sp3 and its synergic repression to the mu opioid receptor (MOR) gene

Previously, we reported that the neuron-restrictive silencer element (NRSE) of mu opioid receptor (MOR) functions as a critical regulator to repress the MOR transcription in specific neuronal cells, depending on neuron-restriction silence factor (NRSF) expression levels [C.S.Kim, C.K.Hwang, H.S.Choi, K.Y.Song, P.Y.Law, L.N.Wei and H.H.Loh (2004) J. Biol. Chem., 279, 46464–46473]. Herein, we identify a conserved GC sequence next to NRSE region in the mouse MOR gene. The inhibition of Sp family factors binding to this GC box by mithramycin A led to a significant increase in the endogenous MOR transcription. In the co-immunoprecipitation experiment, NRSF interacted with the full-length Sp3 factor, but not with Sp1 or two short Sp3 isoforms. The sequence specific and functional binding by Sp3 at this GC box was confirmed by in vitro gel-shift assays using either in vitro translated proteins or nuclear extract, and by in vivo chromatin immunoprecipitation assays. Transient transfection assays showed that Sp3-binding site of the MOR gene is a functionally synergic repressor element with NRSE in NS20Y cells, but not in the NRSF negative PC12 cells. The results suggest that the synergic interaction between NRSF and Sp3 is required to negatively regulate MOR gene transcription and that transcription of MOR gene would be governed by the context of available transcription factors rather than by a master regulator

High rate of virological failure and low rate of switching to second-line treatment among adolescents and adults living with HIV on first-line ART in Myanmar, 2005-2015.

BACKGROUND: The number of people living with HIV on antiretroviral treatment (ART) in Myanmar has been increasing rapidly in recent years. This study aimed to estimate rates of virological failure on first-line ART and switching to second-line ART due to treatment failure at the Integrated HIV Care program (IHC). METHODS: Routinely collected data of all adolescent and adult patients living with HIV who were initiated on first-line ART at IHC between 2005 and 2015 were retrospectively analyzed. The cumulative hazard of virological failure on first-line ART and switching to second-line ART were estimated. Crude and adjusted hazard ratios were calculated using the Cox regression model to identify risk factors associated with the two outcomes. RESULTS: Of 23,248 adults and adolescents, 7,888 (34%) were tested for HIV viral load. The incidence rate of virological failure among those tested was 3.2 per 100 person-years follow-up and the rate of switching to second-line ART among all patients was 1.4 per 100 person-years follow-up. Factors associated with virological failure included: being adolescent; being lost to follow-up at least once; having WHO stage 3 and 4 at ART initiation; and having taken first-line ART elsewhere before coming to IHC. Of the 1032 patients who met virological failure criteria, 762 (74%) switched to second-line ART. CONCLUSIONS: We found high rates of virological failure among one third of patients in the cohort who were tested for viral load. Of those failing virologically on first-line ART, about one quarter were not switched to second-line ART. Routine viral load monitoring, especially for those identified as having a higher risk of treatment failure, should be considered in this setting to detect all patients failing on first-line ART. Strategies also need to be put in place to prevent treatment failure and to treat more of those patients who are actually failing

Long-term outcomes of second-line antiretroviral treatment in an adult and adolescent cohort in Myanmar.

BACKGROUND: Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now. OBJECTIVE: To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged ≥ 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015. DESIGN: Retrospective cohort study using routinely collected program data. RESULTS: Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes. CONCLUSIONS: Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs available after a careful cost-benefit analysis

Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 Diabetes Mellitus

<p>Abstract</p> <p>Background</p> <p>There are no risk scores available for predicting heart failure in Type 2 diabetes mellitus (T2DM). Based on the Hong Kong Diabetes Registry, this study aimed to develop and validate a risk score for predicting heart failure that needs hospitalisation in T2DM.</p> <p>Methods</p> <p>7067 Hong Kong Chinese diabetes patients without history of heart failure, and without history and clinical evidence of coronary heart disease at baseline were analyzed. The subjects have been followed up for a median period of 5.5 years. Data were randomly and evenly assigned to a training dataset and a test dataset. Sex-stratified Cox proportional hazard regression was used to obtain predictors of HF-related hospitalization in the training dataset. Calibration was assessed using Hosmer-Lemeshow test and discrimination was examined using the area under receiver's operating characteristic curve (aROC) in the test dataset.</p> <p>Results</p> <p>During the follow-up, 274 patients developed heart failure event/s that needed hospitalisation. Age, body mass index (BMI), spot urinary albumin to creatinine ratio (ACR), HbA_1c, blood haemoglobin (Hb) at baseline and coronary heart disease during follow-up were predictors of HF-related hospitalization in the training dataset. HF-related hospitalization risk score = 0.0709 × age (year) + 0.0627 × BMI (kg/m²) + 0.1363 × HbA_1c(%) + 0.9915 × Log₁₀(1+ACR) (mg/mmol) - 0.3606 × Blood Hb(g/dL) + 0.8161 × CHD during follow-up (1 if yes). The 5-year probability of heart failure = 1-S₀(5)^{EXP{0.9744 × (Risk Score - 2.3961)}}. Where S₀(5) = 0.9888 if male and 0.9809 if female. The predicted and observed 5-year probabilities of HF-related hospitalization were similar (p > 0.20) and the adjusted aROC was 0.920 for 5 years of follow-up.</p> <p>Conclusion</p> <p>The risk score had adequate performance. Further validations in other cohorts of patients with T2DM are needed before clinical use.</p