Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer.

BACKGROUND:Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. AIM/METHODS:To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/β-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. RESULTS/CONCLUSION:We report for the first time that K-Ras activation increases the CBP/β-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/β-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells

Low-cost global MPPT scheme for photovoltaic systems under partially shaded conditions

Maximum Power Point Tracking (MPPT) is a technique applied to improve the efficiency of power conversion in Photovoltaic (PV) systems. Under partially shadowed conditions, the Power-Voltage (P-V) characteristic exhibits multiple peaks and the existing MPPT methods such as the Perturb and Observe (P&O) are incapable of searching for the Global Maximum Power Point (GMPP). This paper proposes a low-cost on-line MPPT scheme to overcome this drawback. By using hybrid numerical searching process, the operating point approaches Local Maximum Power Points (LMPPs) gradually and the GMPP is caught by comparing all the LMPPs. Simulation results prove the effectiveness and correctness of the proposed method. © 2013 IEEE.published_or_final_versio

Aged garlic extract reduces low attenuation plaque in coronary arteries of patients with diabetes: A randomized, double-blind, placebo-controlled study.

Several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification and non-calcified plaque (NCP) in the general population. However, its effects on plaque progression in patients with diabetes have not yet been investigated, at least to the best of our knowledge. This study investigated whether AGE reduces the coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with diabetes mellitus (DM). A total of 80 participants with DM with a median age of 57 years were prospectively assigned to consume 2,400 mg AGE/day (after completion, 37 participants) or placebo (after completion, 29 participants) orally. Both groups underwent CCTA at baseline and follow-up 365 days apart. In total, 66 participants completed the study. Coronary plaque volume, including total plaque (TP), dense calcium (DC), fibrous, fibro-fatty and low-attenuation plaque (LAP) volumes were measured based upon pre-defined intensity cut-off values using semi-automated software (QAngio CT). Changes in various plaque types were normalized to the total coronary artery length. The non-parametric Wilcoxon rank-sum test was performed to examine the differences in plaque formation between the 2 groups. No significant differences were found in the baseline characteristics between the AGE and placebo groups. Compared with the placebo group, the AGE group exhibited a statistically significant regression in normalized LAP [median and standard deviation (SD) -0.2 (18.8) vs. 2.5 (69.3), P=0.0415]. No differences were observed in TP, fibrous, or fibrofatty plaque volumes between the AGE and placebo group. On the whole, this study indicated that the %LAP change in the AGE group was significantly greater than that in the placebo group in patients with diabetes. However, further studies are warranted to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events

Dynamics of fully coupled rotators with unimodal and bimodal frequency distribution

We analyze the synchronization transition of a globally coupled network of N phase oscillators with inertia (rotators) whose natural frequencies are unimodally or bimodally distributed. In the unimodal case, the system exhibits a discontinuous hysteretic transition from an incoherent to a partially synchronized (PS) state. For sufficiently large inertia, the system reveals the coexistence of a PS state and of a standing wave (SW) solution. In the bimodal case, the hysteretic synchronization transition involves several states. Namely, the system becomes coherent passing through traveling waves (TWs), SWs and finally arriving to a PS regime. The transition to the PS state from the SW occurs always at the same coupling, independently of the system size, while its value increases linearly with the inertia. On the other hand the critical coupling required to observe TWs and SWs increases with N suggesting that in the thermodynamic limit the transition from incoherence to PS will occur without any intermediate states. Finally a linear stability analysis reveals that the system is hysteretic not only at the level of macroscopic indicators, but also microscopically as verified by measuring the maximal Lyapunov exponent.Comment: 22 pages, 11 figures, contribution for the book: Control of Self-Organizing Nonlinear Systems, Springer Series in Energetics, eds E. Schoell, S.H.L. Klapp, P. Hoeve

Organic film thickness influence on the bias stress instability in Sexithiophene Field Effect Transistors

In this paper, the dynamics of bias stress phenomenon in Sexithiophene (T6) Field Effect Transistors (FETs) has been investigated. T6 FETs have been fabricated by vacuum depositing films with thickness from 10 nm to 130 nm on Si/SiO2 substrates. After the T6 film structural analysis by X-Ray diffraction and the FET electrical investigation focused on carrier mobility evaluation, bias stress instability parameters have been estimated and discussed in the context of existing models. By increasing the film thickness, a clear correlation between the stress parameters and the structural properties of the organic layer has been highlighted. Conversely, the mobility values result almost thickness independent

Design, analysis, tools and applications for programmable high-speed and power-aware 4G processors

Data rate traffic and communication capacity demand have been increased continuously. Therefore, a highly advanced 4G wireless system is required to meet a high demand for modern mobile terminals. For getting a further improvement for 4G communication systems, new paradigms of design, analysis tools and applications for 4G communication processors are necessary. In this paper, some of these new paradigms are discussed. Furthermore, a single-step discrete cosine transform truncation (DCTT) method is proposed for the modeling-simulation in signal integrity verification for high-speed communication processors. ©2011 IEEE.published_or_final_versio

A case of septicaemic anthrax in an intravenous drug user

<p><b>Background:</b> In 2000, Ringertz et al described the first case of systemic anthrax caused by injecting heroin contaminated with anthrax. In 2008, there were 574 drug related deaths in Scotland, of which 336 were associated with heroin and or morphine. We report a rare case of septicaemic anthrax caused by injecting heroin contaminated with anthrax in Scotland.</p> <p><b>Case Presentation:</b> A 32 year old intravenous drug user (IVDU), presented with a 12 hour history of increasing purulent discharge from a chronic sinus in his left groin. He had a tachycardia, pyrexia, leukocytosis and an elevated C-reactive protein (CRP). He was treated with Vancomycin, Clindamycin, Ciprofloxacin, Gentamicin and Metronidazole. Blood cultures grew Bacillus anthracis within 24 hours of presentation. He had a computed tomography (CT) scan and magnetic resonance imagining (MRI) of his abdomen, pelvis and thighs performed. These showed inflammatory change relating to the iliopsoas and an area of necrosis in the adductor magnus.</p> <p>He underwent an exploration of his left thigh. This revealed chronically indurated subcutaneous tissues with no evidence of a collection or necrotic muscle. Treatment with Vancomycin, Ciprofloxacin and Clindamycin continued for 14 days. Negative Pressure Wound Therapy (NPWT) device was applied utilising the Venturi™ wound sealing kit. Following 4 weeks of treatment, the wound dimensions had reduced by 77%.</p> <p><b>Conclusions:</b> Although systemic anthrax infection is rare, it should be considered when faced with severe cutaneous infection in IVDU patients. This case shows that patients with significant bacteraemia may present with no signs of haemodynamic compromise. Prompt recognition and treatment with high dose IV antimicrobial therapy increases the likelihood of survival. The use of simple wound therapy adjuncts such as NPWT can give excellent wound healing results.</p&gt