Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A.

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs

The interface between silicon and a high-k oxide

The ability to follow Moore's Law has been the basis of the tremendous success of the semiconductor industry in the past decades. To date, the greatest challenge for device scaling is the required replacement of silicon dioxide-based gate oxides by high-k oxides in transistors. Around 2010 high-k oxides are required to have an atomically defined interface with silicon without any interfacial SiO2 layer. The first clean interface between silicon and a high-K oxide has been demonstrated by McKee et al. Nevertheless, the interfacial structure is still under debate. Here we report on first-principles calculations of the formation of the interface between silicon and SrTiO3 and its atomic structure. Based on insights into how the chemical environment affects the interface, a way to engineer seemingly intangible electrical properties to meet technological requirements is outlined. The interface structure and its chemistry provide guidance for the selection process of other high-k gate oxides and for controlling their growth. Our study also shows that atomic control of the interfacial structure can dramatically improve the electronic properties of the interface. The interface presented here serves as a model for a variety of other interfaces between high-k oxides and silicon.Comment: 10 pages, 2 figures (one color

High pressure chemical reactivity and structural study of the Na-P and Li-P systems

Pressure enables the synthesis of (Na/Li)3P compounds at RT bypassing established chemical methods while at higher pressure, both undergo a pressure-induced phase transition.</p

Foot kinematics in patients with two patterns of pathological plantar hyperkeratosis

Background: The Root paradigm of foot function continues to underpin the majority of clinical foot biomechanics practice and foot orthotic therapy. There are great number of assumptions in this popular paradigm, most of which have not been thoroughly tested. One component supposes that patterns of plantar pressure and associated hyperkeratosis lesions should be associated with distinct rearfoot, mid foot, first metatarsal and hallux kinematic patterns. Our aim was to investigate the extent to which this was true. Methods: Twenty-seven subjects with planter pathological hyperkeratosis were recruited into one of two groups. Group 1 displayed pathological plantar hyperkeratosis only under metatarsal heads 2, 3 and 4 (n = 14). Group 2 displayed pathological plantar hyperkeratosis only under the 1st and 5th metatarsal heads (n = 13). Foot kinematics were measured using reflective markers on the leg, heel, midfoot, first metatarsal and hallux. Results: The kinematic data failed to identify distinct differences between these two groups of subjects, however there were several subtle (generally <3°) differences in kinematic data between these groups. Group 1 displayed a less everted heel, a less abducted heel and a more plantarflexed heel compared to group 2, which is contrary to the Root paradigm. Conclusions: There was some evidence of small differences between planter pathological hyperkeratosis groups. Nevertheless, there was too much similarity between the kinematic data displayed in each group to classify them as distinct foot types as the current clinical paradigm proposes

Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20–37 kg/m2). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min−1.m−2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR

Inadequate physician knowledge of the effects of diet on blood lipids and lipoproteins.

BACKGROUND: To assess the nutrition knowledge of physicians on the basic effects of diet on blood lipids and lipoproteins. METHODS: Anonymous mailed dietary knowledge surveys to 6000 randomly selected physicians in the United States licensed in either Internal Medicine or Cardiology. RESULTS: Response rate: 16% (n = 639). Half of the physicians did not know that canola oil and 26% did not know olive oil were good sources of monounsaturated fat. Ninety-three percent (84% of cardiologists vs. 96% of internists; p < 0.001) did not know that a low-fat diet, in general, would increase blood triglycerides. Approximately three-quarters (70% of cardiologists vs. 77% of internists; p < 0.01) did not know a low-fat diet would decrease HDL-c and almost half (45%) thought that a low-fat diet would not change HDL-c. CONCLUSIONS: If physicians are to implement dietary and cholesterol management guidelines, they will likely need to become more knowledgeable about nutrition

A 'resource allocator' for transcription based on a highly fragmented T7 RNA polymerase

Synthetic genetic systems share resources with the host, including machinery for transcription and translation. Phage RNA polymerases (RNAPs) decouple transcription from the host and generate high expression. However, they can exhibit toxicity and lack accessory proteins (σ factors and activators) that enable switching between different promoters and modulation of activity. Here, we show that T7 RNAP (883 amino acids) can be divided into four fragments that have to be co‐expressed to function. The DNA‐binding loop is encoded in a C‐terminal 285‐aa ‘σ fragment’, and fragments with different specificity can direct the remaining 601‐aa ‘core fragment’ to different promoters. Using these parts, we have built a resource allocator that sets the core fragment concentration, which is then shared by multiple σ fragments. Adjusting the concentration of the core fragment sets the maximum transcriptional capacity available to a synthetic system. Further, positive and negative regulation is implemented using a 67‐aa N‐terminal ‘α fragment’ and a null (inactivated) σ fragment, respectively. The α fragment can be fused to recombinant proteins to make promoters responsive to their levels. These parts provide a toolbox to allocate transcriptional resources via different schemes, which we demonstrate by building a system which adjusts promoter activity to compensate for the difference in copy number of two plasmids.United States. Office of Naval Research (N00014‐13‐1‐0074)National Institutes of Health (U.S.) (5R01GM095765)National Science Foundation (U.S.) (Synthetic Biology Engineering Research Center (SA5284‐11210))United States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship (NDSEG) Program))Hertz Foundation (Fellowship