Pathophysiological role of MicroRNA-29 in pancreatic ductal adenocarcinoma

Indiana University-Purdue University Indianapolis (IUPUI)Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and responds poorly to current therapies. Thus, it is imperative to develop novel treatments for PDAC. Dense fibrotic stroma associated with PDAC abrogates drug perfusion into the tumor, and pancreatic stellate cells (PSCs) are the major stromal cells responsible for fibrosis. Activated PSCs produce pro-inflammatory factors and secrete an excessive amount of extracellular matrix (ECM) proteins, the major stromal proteins in PDAC. MicroRNAs (miRNAs) are conserved small non-coding RNAs that regulate gene expression by binding to the 3′UTR of target mRNA transcripts, causing translational repression or degradation. A single miRNA regulates several targets within intracellular networks and can have a profound impact on normal physiology. miR-29 has been previously reported to have anti-fibrotic and tumor suppressive roles in various cancers. We found miR-29 expression was significantly decreased in activated PSCs and pancreatic cancer cells in vitro, in vivo models, as well as in PDAC patient biopsies. Through in vitro studies in activated PSC, we found that miR-29 inhibited the expression of ECM proteins and reduced cancer growth when co-cultured with pancreatic cancer cells. miR-29 overexpression in pancreatic cancer cells decreased their invasive potential and sensitized chemoresistant cancer cells to gemcitabine treatment by inhibiting autophagy through the direct targeting of two essential, autophagy related genes, TFEB and ATG9A. In developing therapies and for in vivo functional studies, viral-based gene delivery is a powerful tool to target the pancreas. We tested various self-complementary recombinant adeno-associated virus (scAAV) serotypes in normal mice (C57BL/6) and in a KrasG12D-driven pancreatic cancer mouse model via systemic and intraductal delivery methods. We found that retrograde intraductal delivery of scAAV6 safely targeted the pancreas/neoplasm with the greatest efficiency. Our findings provide a better understanding of miR-29 in pancreatic cancer and demonstrates its potential therapeutic use to target PDAC

A digital driving technique for an 8 b QVGA AMOLED display using modulation

Active-matrix organic LED (AMOLED) is one of the most promising contenders for next-generation displays. However, the VT-shift issue in thin-film transistors (TFT) has to be addressed to enable wide deployment. Voltage programming and current programming are well-known VT-shift-compensation techniques for analog driving. However, they all need more than 4 TFTs per pixel, which increases the panel complexity and decreases yield and aperture ratio. Recently, a VT-shift compensation technique that uses a 2TFT-1C pixel in an analog driving AMOLED has been reported. However, it requires OLED supply voltage programming, and shows a 14% variation in OLED current after VT-shift compensation, which is not enough for high-definition applications. Digital driving has been proposed as an alternative to mitigate the VT-shift issue with a simple pixel structure and to provide flexibility to the driver design. In this paper shows the pixel structures for voltage programming, current programming and digital driving. While the gate of the driving TFT (M2) is in the high state, the voltage across M2 is very small due to the large current-driving capability of a TFT as compared with an OLED. Hence, the current through the OLED is dominated by the supply voltage (PVDD), and minimally affected by the variations in TFT characteristics. Digital driving is also useful for true dark-level expression since the OLED can be completely turned off for black gray levels

Screening for Early Gastric Cancer Using a Noninvasive Urine Metabolomics Approach

The early detection of gastric cancer (GC) could decrease its incidence and mortality. However, there are currently no accurate noninvasive markers for GC screening. Therefore, we developed a noninvasive diagnostic approach, employing urine nuclear magnetic resonance (NMR) metabolomics, to discover putative metabolic markers associated with GC. Changes in urine metabolite levels during oncogenesis were evaluated using samples from 103 patients with GC and 100 age- and sex-matched healthy controls. Approximately 70% of the patients with GC (n = 69) had stage I GC, with the majority (n = 56) having intramucosal cancer. A multivariate statistical analysis of the urine NMR data well discriminated between the patient and control groups and revealed nine metabolites, including alanine, citrate, creatine, creatinine, glycerol, hippurate, phenylalanine, taurine, and 3-hydroxybutyrate, that contributed to the difference. A diagnostic performance test with a separate validation set exhibited a sensitivity and specificity of more than 90%, even with the intramucosal cancer samples only. In conclusion, the NMR-based urine metabolomics approach may have potential as a convenient screening method for the early detection of GC and may facilitate consequent endoscopic examination through risk stratification

Bone quality and growth characteristics of growth plates following limb transplantation between animals of different ages - Results of an experimental study in male syngeneic rats

<p>Abstract</p> <p>Introduction</p> <p>The purpose of this study was to identify graft osteoporosis post transplantation by micro-CT analysis, and the growth potential of growth plates in the transplanted limb.</p> <p>Methods</p> <p>Ten juvenile to juvenile and five juvenile to adult hind limb transplants were performed in male syngeneic Lewis rats. Upper tibial bone density in isochronograft and heterochronograft limbs was measured by 3D micro-CT and compared with that of the opposite non-operated limbs.</p> <p>Results</p> <p>We observed inferior bone quality (p < 0.05) in heterochronografts compared to isochronografts. After transplantation, isochronografts did not exhibit increases in tibial lengths compared to opposite juvenile non-operated tibias (p = 0.66) or heterochronograft tibias (p = 0.61). However, significant differences were observed between heterochrongraft tibial lengths when and opposite adult non operated tibial lengths (p < 0.001).</p> <p>Conclusions</p> <p>Age dependent alterations affect bone quality, resulting in post transplantation osteoporosis in heterochronografts, but not isochronografts. However, the growth plates of transplanted limbs retain their properties of longitudinal growth and continue to grow at the same rate.</p

Conformal and Ultra Shallow Junction Formation Achieved Using a Pulsed-Laser Annealing Process Integrated With a Modified Plasma Assisted Doping Method

Recently, a shallow and conformal doping profile is required for promising 3D structured devices. In this study, we deposited the dopant phosphorus (P) using modified plasma assisted doping (PaD) followed by an annealing process to electrically activate the dopants. A rapid thermal annealing process (RTP) was the first approach tested for activation but it resulted in a deep junction ( &gt; 35 nm). To reduce the junction depth, we tried the fiash lamp annealing process (FLP) to shorten the annealing time. We also predicted the annealing temperature by numerical thermal analysis, which reached 1,020 degrees C. However, the FLP resulted in a deep junction (similar to 30 nm), which was not shallow enough to suppress short channel effects. Since an even shorter annealing process was required to form a ultra-shallow junction, we tried the laser annealing process (LAP) as a promising alternative. The LAP, which had a power density of 0.3 J/cm(2), increased the surface temperature up to 1,100 degrees C with a shallow isothermal layer. Using the LAP, we achieved a USJ with an activated surface dopant concentration of 3.86 x 10(19) cm(-3) and a junction depth of 10 nm, which will allow further scaling-down of devices.1

Urine-NMR metabolomics for screening of advanced colorectal adenoma and early stage colorectal cancer

Although colorectal cancer (CRC) is considered one of the most preventable cancers, no non-invasive, accurate diagnostic tool to screen CRC exists. We explored the potential of urine nuclear magnetic resonance (NMR) metabolomics as a diagnostic tool for early detection of CRC, focusing on advanced adenoma and stage 0 CRC. Urine metabolomics profiles from patients with colorectal neoplasia (CRN; 36 advanced adenomas and 56 CRCs at various stages, n = 92) and healthy controls (normal, n = 156) were analyzed by NMR spectroscopy. Healthy and CRN groups were statistically discriminated using orthogonal projections to latent structure discriminant analysis (OPLS-DA). The class prediction model was validated by three-fold cross-validation. The advanced adenoma and stage 0 CRC were grouped together as pre-invasive CRN. The OPLS-DA score plot showed statistically significant discrimination between pre-invasive CRN as well as advanced CRC and healthy controls with a Q2 value of 0.746. In the prediction validation study, the sensitivity and specificity for diagnosing pre-invasive CRN were 96.2% and 95%, respectively. The grades predicted by the OPLS-DA model showed that the areas under the curve were 0.823 for taurine, 0.783 for alanine, and 0.842 for 3-aminoisobutyrate. In multiple receiver operating characteristics curve analyses, taurine, alanine, and 3-aminoisobutyrate were good discriminators for CRC patients. NMR-based urine metabolomics profiles significantly and accurately discriminate patients with pre-invasive CRN as well as advanced CRC from healthy individuals. Urine-NMR metabolomics has potential as a screening tool for accurate diagnosis of pre-invasive CRN.Peer reviewe

Silicon carbide-free graphene growth on silicon for lithium-ion battery with high volumetric energy density

Silicon is receiving discernable attention as an active material for next generation lithium-ion battery anodes because of its unparalleled gravimetric capacity. However, the large volume change of silicon over charge-discharge cycles weakens its competitiveness in the volumetric energy density and cycle life. Here we report direct graphene growth over silicon nanoparticles without silicon carbide formation. The graphene layers anchored onto the silicon surface accommodate the volume expansion of silicon via a sliding process between adjacent graphene layers. When paired with a commercial lithium cobalt oxide cathode, the silicon carbide-free graphene coating allows the full cell to reach volumetric energy densities of 972 and 700 Whl(-1) at first and 200th cycle, respectively, 1.8 and 1.5 times higher than those of current commercial lithium-ion batteries. This observation suggests that two-dimensional layered structure of graphene and its silicon carbide-free integration with silicon can serve as a prototype in advancing silicon anodes to commercially viable technology.

The role of Qa-2, the functional homolog of HLA-G, in a Behcet's disease-like mouse model induced by the herpes virus simplex

<p>Abstract</p> <p>Background</p> <p>It has been suggested that the HLA-G molecule is a genetic risk factor for Behcet's disease (BD). In this study, we evaluated the level of Qa-2, a murine nonclassical class I MHC molecule and possible functional homolog of HLA-G, to determine if it was associated with various symptoms of BD-like mice. In addition, we investigated siRNA (small interfering RNA) treatment to determine if it inhibited Qa-2 expression, thereby changing the symptoms of mice.</p> <p>Methods</p> <p>RNA interference (RNAi) and vector transfection were employed to manipulate gene expression <it>in vivo </it>in mice. siRNA (small interfering RNA) or Qa-2 expression vector was applied to inhibit or up-regulate Qa-2 expression, respectively.</p> <p>Results</p> <p>The Qa-2 levels in granulocytes were lower in BD-like mice than in normal controls. The silencing of Qa-2 by intravenous injection of siRNA (500 nmol/mouse, 4 times at 3-day intervals) specifically reduced the Qa-2 levels and worsened the BD-like symptoms.</p> <p>Conclusions</p> <p>Silencing Qa-2 by injecting siRNA into mice resulted in deterioration of symptoms in BD-like mice.</p