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Copy Number Amplification of the PIK3CA Gene Is Associated with Poor Prognosis in Non-lymph node metastatic Head and Neck Squamous Cell Carcinoma
Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC).
We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients.
We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis.
We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.2%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026)
Copy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.
Progress in genomics has led to the identification of oncogenes, and genetic mutations associated with carcinogenesis have been reported for many carcinomas. Furthermore, an increase in the gene copy number due to focal amplification or chromosomal polysomy is another major mechanism of oncogene activation
Recent studies have shown that the over expression of epidermal growth factor receptor (EGFR) is associated with a poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC)
Upon binding with a ligand, EGFR activates multiple intracellular signaling pathways, including the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which transmit extracellular signals to the nucleus to control cell growth and proliferation. In many types of malignancies, such as lung cancer and colorectal cancer, mutations in the genes encoding EGFR or downstream components of the signaling pathways are highly prevalent
In addition to gene mutations, copy number alterations of EGFR, KRAS, PIK3CA and other signaling mediators are also critical factors that drive cancer development and determine prognoses and the sensitivity to anticancer drugs. In NSCLC, EGFR gene copy amplification, as determined by FISH, was shown to likely be associated with poor prognosis and with improved survival upon treatment with EGFR tyrosine kinase inhibitors
Little is known about the frequency of mutations and copy number alterations of genes other than EGFR that encode components of the RAS and PI3K pathways in HNSCC. Herein, we present a sequence and copy number analysis of the RAS, RAF and PI3K genes in a collection of 115 clinical samples.
This prospective cohort study was approved by the Ethics Committee for Biomedical Research of the Jikei Institutional Review Board, Jikei University School of Medicine, Tokyo, Japan. All of the patients provided written informed consent. Between September 2006 and August 2009, 115 tumors were obtained from 115 HNSCC patients who underwent surgery at the Department of Head and Neck Surgery, Jikei University Hospital. And they were consecutively submitted by surgical management. Clinical information was obtained from the clinical and surgical charts. Based on the postoperative staging, the tumor-node-metastasis (TNM) classification and stage were determined according to the 6th UICC TNM classification and stage groupings
Tumor samples
In each case, the tumor samples from the primary site and surrounding normal tissue, but not the metastatic sites, were stored at −80°C after excision. The cancer tissue was divided into two specimens: one for pathological confirmation in which the sample was composed of >70% cancer cells and the other for DNA and protein extraction.
Mutation analysis
We used DNA sequencing to detect mutations in the clinical HNSCC specimens. Polymerase chain reaction (PCR) amplification of genomic DNA was performed, and the following genes were analyzed for mutations: KRAS (exons 1 and 2); BRAF (exon 15); and PIK3CA (exons 9 and 20). These regions included those with the most common mutations previously observed in human cancer. Table
Analysis of copy number by quantitative PCR
The copy number changes in KRAS, BRAF and PIK3CA were evaluated by qPCR using the qPCRTM MasterMix for SYBR Green, as previously reported
Analysis of the copy number by array CGH
For the samples with copy number amplification identified by qPCR, we performed an array comparative genomic hybridization (CGH) analysis using microarray slides that contained 180,000 probes (Agilent Technologies, Santa Clara, CA, USA)
Statistical analysis
The Student t-test, chi-squared test and Fisher test were used to evaluate differences in the patients' characteristics stratified by the copy number alternation. Disease-free survival curve's end point is defined by recurrence (local relapse, new lymph node metastasis or distant metastasis) during follow. All patients conducted observation within two month after surgery and patients were periodically (every 0.5–2 months) examined on an outpatient basis to make sure they had not relapsed. Examinations consisted of standard tests, including endoscopy and computed tomography of the chest and neck. It was defined recurrence when a carcinoma was detected again in a primary tumor and cervical lymph node or distant metastases were observed on computed tomography. Over-all survival and disease-free survival curves were generated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazard models were fitted for multivariate analysis adjusting for age, gender, smoking status, mutation status of KRAS and PIK3CA, and amplification status. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were computed. All of the statistical analyses were performed using STATA 9.1 (STATA Corp., College Station, TX). A p value < 0.05 was considered statistically significant.
Patients' characteristics
The patients ranged in age from 32 to 88 years, and there were more men than women in the cohort. Most of the patients had oropharyngeal or oral cavity cancer, and 47% had stage IV disease. The patient characteristics are listed in (Table
Mutation analysis of KRAS, BRAF and PIK3CA
We conducted a sequencing analysis to examine the frequency of mutations in the KRAS, BRAF and PIK3CA genes, and we investigated the correlations between the presence of mutations and the clinical data. Specifically, we sequenced KRAS exon 1and exon2, BRAF exon 15 and PIK3CA exon 9 and exon 20 and identified mutations in 6 of the 115 patients (5.2%). Three mutations were observed in exon 1 of KRAS, and all were the same substitution (G12A). No mutation was found in exon 2.The primary tumors included two oral cavity carcinomas and one oropharyngeal carcinoma; in terms of lifetime smoking status (pack-years), one patient had a high score (more than 30 pack-years), and the others had low scores
Copy number analysis of KRAS, BRAF and PIK3CA
We identified copy number changes in PIK3CA, K-RAS and BRAF. PIK3CA copy number amplification was found in 37 cases (32.2%), whereas only 10 cases (8.7%) were found for K-RAS and 2 cases (1.7%) for BRAF (Table
Kaplan-Meier curves of over-all survival and disease-free survival by Copy number status
Tumor recurrence and death occurred in 49 patients (42.6%) and 22 patients (19.1%), respectively during the median follow-up period of 723 days. Over-all survival and disease-free survival curves were generated using the Kaplan-Meier method, and log-rank tests were used to determine if survival was associated with the copy number status of PIK3CA. There was no significant association between the copy number status (with or without amplification) in PIK3CA and the over-all survival and disease-free survival (Log-rank test, p = 0.45 and p = 0.26) (Figure
Figure 1
115 patients with PIK3CA copy number status
115 patients with PIK3CA copy number status. Kaplan-Meier curves for disease-free survival (A) and over-all survival (B). Patients were with or without PIK3CA copy number amplification. The p-values were estimated using the log-rank test
However, after excluding the patients with lymph node metastasis, the disease-free survival curves drawn using the Kaplan-Meier method about 59 patients without lymph node metastasis (N stage = N0 patients) indicated that the patients with PIK3CA copy number amplification (n = 16) showed earlier recurrence than those without PIK3CA copy number amplification (n = 43) (log-rank test,
Figure 2
Restricting 59 patients without lymph node metastases
Restricting 59 patients without lymph node metastases. Kaplan-Meier curves for disease-free survival. Patients with or without amplification in PIK3CA, restricting to 59 patients without lymph node metastases. The p-values were estimated using the log-rank test
Cox proportional hazard models with multivariate adjustment
Cox proportional hazard models with disease-free survival were computed to determine the significance of PIK3CA amplification with adjustment for age, gender, smoking status and mutation status (Table
The overall mutation frequency of KRAS, BRAF and PIK3CA in our HNSCC samples was lower than reported for other cancers. We identified mutations in 2.6% of our samples for the KRAS gene, 2.6% for PIK3CA and 0% for BRAF. KRAS mutations are observed in approximately 45-60% of pancreatic cancers
The KRAS mutations identified in three of our tumor samples (2.6%) were identical G12A substitutions, which is a well-characterized activating mutation. The low KRAS mutation frequency in the present study is in agreement with previous small-scale studies of HNSCC that reported a mutation frequency of 2.4% (1/42 samples) in oral squamous cell carcinoma
We analyzed exon 15 of BRAF to search for a V600E substitution, the most common activating mutation of BRAF, which is observed at high frequencies in various cancers
Mutations in exons 9 and 20 of PIK3CA were found in three specimens (2.6%), and these mutations are known to be hotspot mutations that generate a constitutively active kinase in other cancers
In our analysis, an amplification of the PIK3CA copy number was found in many of the samples (32.2%). With regard to lung cancer, such amplification is more frequent in squamous cell carcinomas (33.1%) than adenocarcinomas (6.2%)
The limitations of this study include the small number of patients especially about the prognosis study by the status of the copy number and may be include the selection bias in undergoing surgery.
We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.1%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026) Copy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis.
Competing interests
No potential conflicts of interest were disclosed.
Authors' contributions
Conception/Design: TH, TS, MU Financial support: TH, YY, MU Administrative support: TH, TS, SK, YY, MU Provision of study materials: TH, TS, TK, HM Collection/assembly of data: TH, TS, MY, TK, HM, Data analysis: TH, TS, MU Manuscript writing: TH, TS, SK. All authors read and approved the final manuscript.
This research was partially supported by High Technology Research Center Project for Private University and the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Young Scientists (B).
Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines
Distinctive E-cadherin and epidermal growth factor receptor expression in metastatic and nonmetastatic head and neck squamous cell carcinoma predictive and prognostic correlation
Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma
Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study
Epidermal growth factor receptor mutations in lung cancer
DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset
K-ras mutations and benefit from cetuximab in advanced colorectal cancer
PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab
Gene status of head and neck squamous cell carcinoma cell lines and cetuximab-mediated biological activities
Mutational analyses of the BRAF, KRAS, and PIK3CA genes in oral squamous cell carcinoma
Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis
Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas
Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma
New TNM staging criteria for head and neck tumors
Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells
Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method
PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients
Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines
The use of ultra-dense array CGH analysis for the discovery of micro-copy number alterations and gene fusions in the cancer genome
Alcohol, smoking, and occupational factors in cancer of the larynx: a case–control study
BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm /carcinoma (IPMN/IPMC) of the pancreas
Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis
Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer
KRAS gene mutation in colorectal cancer is correlated with increased proliferation and spontaneous apoptosis
KRAS mutation status in primary nonsmall cell lung cancer and matched metastases
BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma
BRAF mutations in metastatic melanoma: a possible association with clinical outcome
High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma
Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia
High frequency of mutations of the PIK3CA gene in human cancers
Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma
Frequent mutation of the PIK3CA gene in ovarian and breast cancers
Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas
KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab
Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis
Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines
PIK3CA mutations in head and neck squamous cell carcinoma
Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas
PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors
PIK3CA mutations and copy number gains in human lung cancers
PIK3CA amplification is predictive of poor prognosis in Tunisian patients with nasopharyngeal carcinoma
Pre-publication history
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Abstract: Advances in swept source laser technology continues to increase the imaging speed of swept-source optical coherence tomography (SS-OCT) systems. These fast imaging speeds are ideal for microvascular detection schemes, such as speckle variance (SV), where interframe motion can cause severe imaging artifacts and loss of vascular contrast. However, full utilization of the laser scan speed has been hindered by the computationally intensive signal processing required by SS-OCT and SV calculations. Using a commercial graphics processing unit that has been optimized for parallel data processing, we report a complete high-speed SS-OCT platform capable of real-time data acquisition, processing, display, and saving at 108,000 lines per second. Subpixel image registration of structural images was performed in real-time prior to SV calculations in order to reduce decorrelation from stationary structures induced by the bulk tissue motion. The viability of the system was successfully demonstrated in a high bulk tissue motion scenario of human fingernail root imaging where SV images (512 × 512 pixels, n = 4) were displayed at 54 frames per second.
Fourier domain optical coherence tomography (FD-OCT) is becoming a well-established high-resolution biomedical imaging modality with numerous pre-clinical and clinical applications, such as real-time assessment of optimal coronary artery stent placement and as a supplement in lymph node biopsies [1–3]. Swept source OCT (SS-OCT) uses tunable lasers to sweep the wavelength of the light to interrogate the tissue, thus allowing the reconstruction of a depth-resolved axial scan (A-scan or A-line) [4]. Owing to the continuous advancement of swept source laser technology, A-scan rates exceeding multi-megahertz have been demonstrated [5]. These fast imaging speeds are beneficial for functional imaging techniques, such as speckle variance (SV) analysis for microvasculature detection, where interframe motion can cause severe imaging artifacts and loss of vascular contrast.
Speckle variance identifies microvasculature by calculating the interframe intensity variance of structural images, providing a non-invasive high sensitivity imaging technique capable of visualizing capillaries without the use of exogenous contrast agents [6]. However, practical application of using SV, including the presentation of real-time diagnostic information, is hindered by the computationally intensive signal processing required by structural and SV calculations when implemented on a serially oriented central processing unit (CPU). In comparison, commercially available graphics processing units (GPUs) are optimized for parallel data processing, and have recently been adapted to accelerate processing speeds of computationally intensive algorithms such as spectrometer-based FD-OCT [7–12]. While SV has been used to identify microvasculature for many studies, the added ability to image in real-time would open SV to assist in interventional procedures such as stroke, spinal cord injury (SCI), age-related macular degeneration (AMD) and oncology.
Here, we describe a high-speed SS-OCT imaging platform capable of real-time SV processing, display and saving at 108,000 A-scans per second. The system utilizes a polygon-based short cavity ring laser at 54 kHz, where buffering and amplification is performed to double the A-scan rate of the laser [5]. The complete SS-OCT signal processing including λ-to-k spectral resampling, fast Fourier transform (FFT), post-FFT (structural and SV) processing, and display were implemented on a GPU. In addition, subpixel image registration of structural images was performed prior to SV calculations to reduce decorrelation from stationary structures induced by the bulk tissue motion. To the best of our knowledge, this is the first demonstration of real-time high-speed functional SS-OCT, where structural images were processed and displayed at 216 (512 × 512 pixels) frames per second (fps) along with the processing and display of n = 4 averaged structural and SV images at 54 fps. This enables real-time imaging of microvasculature and allows SV to be used as an interventional guide to procedure. While the capabilities of SV OCT as an imaging tool has been demonstrated many times in the past, the added function of providing real-time information extends this technique to new applications both in preclinical and clinical settings.
Figure 1 shows the system configuration, which consists of a swept source OCT system and a custom-built personal computer. The swept source laser design employed a buffered polygon ring cavity laser. A 600 lines/mm diffraction grating (GR25-0613, Thorlabs) was selected to create the necessary dead time between laser sweeps and enabled buffering from 54kHz to 108kHz [13]. The laser had a total output power of ~50mW, a coherence length of 3mm, and an axial resolution of 9μm in tissue. A Mach-Zehnder interferometer (MZI) was used to interrogate the biological samples, while standard techniques for triggering with a fiber Bragg grating (FBG) and recalibration with a MZI clock were used in this system [14]. The laser beam scanning was implemented using a pair of galvanometer mirrors controlled by an analog output card (PXI-6259, National Instrument), where the fast-axis sweep was driven by the FBG A-scan trigger and the slow-axis sweep was controlled by the software.
A custom-built personal computer housed high-end consumer-level electronic components that were specially selected and configured to enable continuous real-time acquisition, processing, and display of both structural and speckle variance data. Recalibrated fringe data can be simultaneously saved at an A-scan rate of 108kHz, taking full advantage of the laser sweep rate. The analog signals were digitized at 250MS/s by a 12-bit data acquisition card (ATS9350, Alazartech), and transferred frame-by-frame (B-scan) to the computer memory via PCIe x8 interface. The raw and recalibrated data was copied to and from the memory of a GPU (GeForce GTX 460 1GB, NVIDIA) at 3.0GB/s over PCIe x16. The final structural and speckle variance images were rendered and displayed directly off the GPU memory. Concurrently, the recalibrated data was streamed to a solid-state drive (SSD) (RevoDrive 3 X2, OCZ) at 1.3GB/s through PCIe x4.
The custom-built software was developed with Microsoft Visual C++ 2008 and the Alazartech software development kit (SDK), OpenGL, and National Instrument NiDAQmx application programming interface for acquisition, display, and galvanometer control, respectively. For signal processing, the GPU was programmed using NVIDIA's compute unified device architecture (CUDA) toolkit and SDK 4.0 [15]. Custom CUDA kernels, in combination with built-in CUDA libraries, were used to manipulate and reconstruct structural and speckle variance OCT images on the 336 cores of the GPU. Utilizing the GPU to perform massive parallel data processing, not only dramatically enhances the data throughput when compared to processing using only the CPU, but also concurrently frees up CPU resources. Another advantage for processing data directly on the GPU is that the reconstructed OCT images can be rendered and displayed without any additional memory transactions.
To minimize dead time between frame captures, tasks were divided into four threads, as depicted in Fig. 2 , for data acquisition (Thread 1), processing and saving (Thread 2), image display (Thread 3), and slow axis galvanometer control (Thread 4). The four threads were synchronized in a cascaded producer-consumer paradigm, where Thread 1 triggered both Thread 2 and 4, and Thread 2 triggered Thread 3 on every B-scan acquired and processed, respectively, as indicated by the dashed arrows. A circular memory buffer and two semaphores (flags to prevent simultaneous reading and writing to the same memory address) were used between Thread 1 and 2 to regulate data flow from the motherboard to the GPU. The solid arrows show the data flow through each hardware or processing kernel. In Thread 2, a MZI clock for A-scan recalibration was pre-stored on the GPU memory, whereas the average A-scan intensity of a B-scan could be updated on the fly to remove the DC noise. A Hanning window and zero padding were applied to each A-scan followed by fast Fourier transform (FFT). Either structural or averaged structural plus speckle variance OCT images were calculated and finally displayed by Thread 3. Any data that resided on the GPU memory could be continuously copied back to the host memory and transferred to the SSD for storage. The recalibrated (DC component removed) data were saved for post processing and 3D visualization purposes.
Bulk tissue motion (BTM), such as cardio-respiratory motion, cannot be avoided during in vivo imaging, and this results in a lower vascular contrast in the SV images. A subpixel image registration algorithm [16] was adopted and implemented on the GPU using custom CUDA kernels and built-in CUDA libraries. The aim was to reduce the adverse effects of the BTM by digital realignment of the structural images prior to the SV calculation. The algorithm assumes 2D rigid translation between two images, and first obtains an initial estimate of whole pixel shifts using a traditional 2× upsampled FFT cross correlation technique. Subpixel shifts are then calculated using a single-step discrete Fourier transform (DFT) algorithm, where an upsampled cross correlation (by a user-defined upsampling factor, κ) is computed in 1.5 × 1.5 pixel neighborhood about the initial estimate. The use of DFT greatly reduces the memory and computational requirement when compared to traditional FFT approach.
We have previously demonstrated SV in a low BTM scenario by imaging mouse dorsal skinfold window chamber, where small capillaries could be detected with relatively slow image speed of 36kHz by optimizing the SV parameters (i.e. gate length, n, or the number of frames used to calculate the SV, and frame rate, F) [6]. In this study, the viability of the fast imaging system (108kHz) was evaluated in a high BTM scenario by in vivo imaging of non-stabilized human fingernail root on a healthy volunteer. B-mode scanning and real-time display of averaged structural OCT and SV image were examined first. Each B-scan consisted of 512 A-lines spanning over 2mm. Each A-scan had 2096 and ~364 samples before and after recalibration, respectively, which was zero padded to 1024 prior to the FFT. Subpixel image registration was performed on the top center region (256 × 256) of the structural image with an upsampling factor of 100. For calculating SV in a high BTM case, a small gate length of either 2 or 4 and a fast frame rate are desired to obtain a high SV signal-to-noise ratio (SNR) [6]. While the A-line density fixed the frame rate at 216fps, the software allowed for a real-time update of the gate length between 2 to 16. A gate length of 4 was chosen to reconstruct the averaged structural OCT and SV images, as shown in Fig. 3 , at an effectively display rate of 54fps. The galvanometer sweepback is seen on the right of each image. Layers of tissue morphology could be delineated easily in the structural image, whereas microvasculature appears as high contrast regions in the SV images. Figure 3(a) (Media 1) and 3(b) (Media 2) compare the SV image quality with and without subpixel image registration realignment, clearly showing less bulk tissue signal and higher vascular contrast in the realigned image.
With the same B-mode imaging parameters as above, the software performance was analyzed using the CUDA's built-in visual compute profiler 4.2, which provided detailed timing statistics of each kernel executed on the GPU as shown in Fig. 4 . The longest possible processing path was considered by including all data transfers to and from the GPU, subpixel image registration, and SV calculation on the nth frame. The GPU times were the average of 100 kernel calls, and the total processing time per SV image was ~3.02ms. This processing speed can theoretically support a 169kHz SS-OCT system at 2096 samples per A-scan. The most time-consuming step was the image registration algorithm, which took 1.6ms to complete. Compared with a CPU implementation reported by Guizar-Sicairos et al. [16] which employed the same algorithm (image size of 256 × 256, and an upsampling factor κ = 25), our GPU implementation with κ = 100 is two orders of magnitude faster. SV calculation and data transfer to the GPU took 388μs and 372μs, respectively, making these tasks the second and third most time-consuming step. The GPU time for the SV calculation is independent of the number of frames used. This is because the mean structural OCT and the sum of squares are calculated as each frame is being acquired, and on the nth frame the same number of arithmetic operations are performed to produce the SV image. It is worthwhile to note that the structural image calculation only took 195μs, and for normal structural OCT imaging, where image registration is not essential, the processing time becomes ~1.23ms, which can theoretically support a 416kHz system. Approximately 30MB of GPU memory was allocated to process each B-scan of 2.15MB in size. Such low memory requirement allows for this parallelized implantation through standard, commercially available GPUs. Finally, each recalibrated B-scan contained ~745kB of data and took on average 573μs to transfer to the solid state drive. This data transfer is relatively time-consuming and will require its own dedicated thread to hide this latency for larger data sizes.
To test the 3D SV imaging capability the real-time data saving function, 10,000 B-scans (512 A-lines in each B-scan) of recalibrated data covering a 2mm-by-2mm region were saved for post-processing. Data transfer did not degrade the software performance, which provided the shortest time delay between adjacent frames, and hence the higher SV SNR. In our previous study [6], a 50% decrease in variance signal was observed when the frame step size was the same as the beam spot size. Here, the large number of frames corresponded to a 0.2µm step size, which was 65× smaller than the beam spot size of 13µm.
In post-processing, the same steps were followed as in real-time processing. Figure 5(a) shows an en face 2D SV projection image in which the high contrast regions closely resemble capillary loops commonly observed in nailfold capillaroscopy [17]. The projection image is a summation over 860μm starting from 310μm below the tissue surface. Motion artifacts due to heartbeat and breathing can be seen as periodic horizontal striations (indicated by the white arrows) resulted from an increase of the noise floor of the entire SV image and adjacent frames. Figure 5(b) shows the projection image after the structural images are realignment using the image registration algorithm, which improved the image quality via the removal of the periodic striation noise.
In using image registration to realign the structural data, it was assumed that the motion was non-deformable and had no rotational components. It was further assumed that out-of-plane motion was limited due to our relatively high imaging speed and because there is no available method to account for this type motion. The cross correlation algorithm revealed subpixel and pixel size movements in the lateral and axial direction, respectively, in all adjacent B-scans. This corresponded to a <10-20 micron shift between frames. Our imaging speed of 216fps was sufficient in capturing this motion smoothly and the resultant change in the speckle pattern, allowing the image registration algorithm to improve the image quality. In an application where motion in 3D space is equally likely, the requirement for faster image speed becomes ever more stringent for clinical applications.
SV and related methods have assisted functional magnetic resonance imaging in measuring functional hyperemia and cerebral blood flow in rat models [18,19]. This combination helps to identify pathological changes in stroke, Alzheimer's, and brain injuries, but traditionally long processing times limit SV to preclinical studies. The ability to image microvasculature in real-time would allow SV to move beyond stroke research and perhaps guide interventional procedures for stroke patients as changes in microvasculature during and prior to treatment highlight progression of the effects of stroke. Another potential application of a high-frame rate SV SS-OCT system includes the intra-operative evaluation of damaged vasculature after spinal cord injury.
In addition, microvasculature in the retina and the choroid have been mapped by SV for the study of retinal diseases, specifically diabetic retinopathy and AMD [20,21]. One treatment for AMD is the use of anti-vascular endothelial growth factor (VEGF) drugs, which reduces VEGF responsible for stimulating growth in new blood vessels [22]. In this case, the ability of real-time SV imaging could be used to help guide intra-vitreal injections of anti-VEGF drugs and subsequently monitor changes in the microvasculature.
Finally, microvasculature imaging is also important for the identification and treatment of various types of cancer. Tumor growth often results in increased blood flow to cancerous regions and thus certain treatment methods focus on the disruption of the tumor microvasculature [23]. Whereas previous imaging of microvasculature only provided before and after information of the treatment, functional imaging with SV has the potential to show changes during treatments such as photodynamic therapy [24].
In summary, a real-time high speed SV SS-OCT imaging system using an NVIDIA GPU was demonstrated. An A-scan rate of 108kHz was fully utilized, allowing structural images (512 × 512 pixels) to be acquired, processed, and displayed at 216 fps, and SV images at 56 fps, which demonstrated excellent flow sensitivity capable of distinguishing microcirculation from the non-stabilized bulk tissue in a human fingernail fold. In addition, subpixel image registration algorithm digitally reduced the BTM and significantly improved the SV image quality. Whereas SV has been limited in the past by processing times to preclinical studies, real-time SV opens new potential applications include guiding interventional procedures for stroke, SCI, AMD, and oncology. In these cases, microvascular changes can be monitored without the implementation of gating or post-processing. Our custom-built software has been designed to be versatile, such that it can work for both non-linear and linear swept source laser systems. On-going research includes combining our software with higher resolution and faster OCT systems to achieve real-time 3D microvasculature display that may be packaged with existing interstitial or catheter technology to provide real-time in vivo microvasculature rendering of deeply situated organs.
The authors acknowledge funding support from the National Sciences and Engineering Research Council of Canada, Early Research Award Ontario, and Mitacs. In addition, we would like to thank Mr. Muneeb Khalid, President. Alazar Technology Inc., for the continuing technical support.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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12 November 2007,
Price realised CHF 43,000
Ulysse Nardin. An unusual and large 18K pink gold self-winding dual time wristwatch with sweep centre seconds, date, countdown indicator and musical alarm
Signed Ulysse Nardin, Sonata, No. 252, Ref. 666-88, circa 2005
Cal. UN-66 nickel-finished lever movement, 109 jewels, alarm on one gong, the silvered dial with applied luminous dagger numerals on outer recessed ring, skeletonized luminous blued steel hands, sweep centre seconds, large double date window, three subsidiary engine-turned dials indicating alarm countdown combined with am and pm display, alarm and second time zone, aperture for alarm on/off indication, visible alarm's centrifugal governor under a blued steel bridge, in large water-resistant-type circular case with raised bezel, fluted downturned lugs, the back secured by six screws, the alarm wound and set through the crown, patented mechanism to adjust the hour hand backwards/forwards by pushing buttons to 4 and 8 o'clock, alarm activated/deactivated by a push button at 9 o'clock, 18K pink gold Ulysse Nardin deployant clasp, case, dial and movement signed
42 mm. diam.
New York +1 212 636 2000
London +44 (0)20 7839 9060
Hong Kong +852 2760 1766
Shanghai +86 21 6355 1766
Accompanied by Ulysse Nardin Certificate dated 27.03.2005, booklet, instruction manual in Japanese, original fitted wooden presentation box and outer packaging.
The Sonata, a unique and amazing multifunctional mechanical instrument, is an in-house development, inspired by Dr. Ludwig Oechslin, constructed by Pierre Gygax and Lucas Humair.
The engineers and technicians of Ulysse Nardin spent nearly seven years on the development of this patented self-winding in-house calibre. It combines the novel alarm setting with a countdown indicator and the dual time system with the instant time zone adjustor conceived by Dr. Oechslin and featured in many Ulysse Nardin watches.
This patented dual time function permits time zone adjustments forward and backward by simply pressing the pushers plus (+) or minus (-) to change the position of the hour hand. The original home time (reference time) stays displayed while the date, the alarm and countdown adjust automatically when a time zone adjustment is made.
The melodic chiming of the alarm is based on a novel 24 hours mechanism which allows setting the alarm 23 hours ahead, for 7.35 pm the same day or 7.35 am the next day.
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text:
Friday, September 07, 2007
The more hectic our work schedules, the more we miss our carefree student lives. Especially on Teacher's Day, memories of classroom capers and idling away time with friends come rushing back to all of us. Amit Sareen aka Kshitij of "Doli Saja Ke Rakhna" recalls some memorable moments from his school and college days.
Like all schoolboys, Amit too was smitten by a teacher. "I used to like my English teacher as she had a very dynamic style of speaking and she also used to dress up very nicely. At that age, she was like a goddess for all of us. And we boys used to eagerly await her lectures. We even used to take the trouble of turning up neatly dressed for her lectures. When our term got over, we used to miss her a lot," Amit says.
By the time he reached college, Amit had become a full-fledged prankster, bunking classes and ridiculing teachers. "I would not like to name this teacher in college, but he was a very simple and polite man. I was the prank master of the class, and almost all my classmates were good friends. A bunch of us used to mark our attendance and then slowly sneak out of the class while the teacher used to write notes on the board. I thought he was unaware of this. But after about nine lectures, he called me and said 'Beta, I know these attendances are fake but I just want you to study hard and achieve something in your life'. I was extremely guilt-ridden and from then on, I never missed his lectures," recalls the actor.
On the occasion of Teacher's Day, that just passed by, Amit has a message for all his fans. "Whatever you achieve is because of your Guruji. Hence, at least on Teacher's Day, get in touch with them, tell them that you are doing well in life and make them feel proud of you."
For one, Amit's teachers would surely be very proud of him today. The actor had earlier played the character of Sahil in "Kyunki Saas Bhi Kabhi Bahu Thi". And now, there are bigger and better things coming his way. "I quit "Kyunki" long time ago, but there is a big project about which it is too early to talk now. I will let you all know in the coming days," he signs off.


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Skip to: Features – Charity – Lodging – Maps & Course Deets – Pricing – Volunteer – Event Schedule – Event Information
Congratulations 2017 Finishers…
And yup… you can look forward to your next brag tag too!
Designed to attach nicely to your finisher's medal and available ONLY to alumni.
Get ready for some fun in the sun and a great mid-season test of your training as we bring our 5th Annual Dog Days 1M, 5K, 10K & Half Marathon! Centrally located between Denver & Boulder just a mile off US 36 at Westminster's award-winning City Park, along with its Endless Series sidekick in December… Fa La La, the beauty of our breathtaking Flatirons as a backdrop will inspire you every step of these 1M, 5K, 10K & Half Marathon courses along Big Dry Creek Trail… well known as a Colorado favorite!
|♦ RRCA Certified Race Director- Organization you can count on!
With 50+ events under the belt of our director and a staff with more than 15 years experience, your event will run smoothly. (Ha! No pun intended.)
|♦ Early AND Race Day Packet Pick-Up- For those who like to prep in advance!
Sure, picking up early gets you another chance to win a prize, but no worries if you wait until race day… we make it quick & easy.
|♦ Tech Shirts- No cotton allowed!
Super comfy, moisture wicking & gender specific.
|♦ Finisher Medals- Custom molded & distance specific, even for the 5K!
Then a little something special for our 1 Milers too.
|♦ Alumni Brag Tags- For all 2x, 3x, 4x & 5x Finishers!
Our little way of saying 'Thanks for making Summer Breeze a tradition!'
|♦ Even More SWAG- Icy towels… yours to keep!
Dripping with ice water and ready to cool your core temp at the finish line.
|♦ Souvenir Race Bibs- With pull tags for your convenience!
Yet another keepsake to remember your day, plus your meal & prize tickets are right there at your finger tips.
|♦ FREE Race Pics- Unlimited downloads are on us!
Professional photographers at the finish line AND on course… enjoy!
|♦ Gear Check- No trips back to the car for our athletes… no sir-ee!
Leave it with us… we'll keep an eye on it for you.
|♦ Porta-Poos-A-Plenty- 3 Units for 500 people? What, are you crazy?
Ever had to run without using a restroom because the lines were too long? Us too… ouch! We provide more than TRIPLE the facilities as other events.
|♦ Accurately Measured Courses- Race the distance you trained for!
Not a little more and not a little less… we measure each course no fewer than 3 times before race day and mark them so they're crystal clear.
|♦ Medical Support- Nothing is more important than your safety!
Here's hopin' those guys are really bored, but just in case… you'll find our med crew both at the start / finish AND on course. Plus, each and every volunteer you pass knows who to call for help.
|♦ Tons of Aid Stations- No need to carry any extra weight!
Not only will both water & electrolytes be handed to you at the finish line, but course aid stations are an average of just 1 mile apart.
|♦ Disposable Timing Chips- No hassle at the finish line!
And no fees if you forget to return your timing chip either… we don't need it back.
|♦ Electronic Results- No more endless sheets of data to sort through!
All results scroll on easy to read computer screens in the expo area during the event and are posted online by the end of the day.
|♦ Text Results & Placements- Individually sent to all who opt in!
Just provide your mobile number with your entry, then text the keyword ALLOUT to 550055 from that mobile device. Yup… it's that easy!
|♦ Post-Race Meal- Breakfast tacos, fruit, bagels, chocolate milk & OTTER POPS for all!
Yup, even if you're dead last… we're not going anywhere until we cheer you in.
|♦ 3 Deep Awards- Overall AND Divisions!
Events small enough to stay friendly and personal give you a better chance of landing on the podium! (1 Mile awards will be given to the top 3 in each gender only, for the time being.)
|♦ Prizes Galore- If you're registered, you're entered… easy peasy! Just bring us your ticket at the start of your award ceremony and you're in! (Psst… in most cases, everyone who sticks around for the giveaway goes home with a prize!)
|As a part of our first-of-its-kind race that doesn't end, (yes, it goes on and on my friend), run the same distance at back-to-back events to measure your progress on identical Endless Series courses. Prizes may be awarded to those who beat their previous time! Click here for more information.
|With about a gazillion reasons why you might not be able to join us on race day, we know you still want to race with your friends & family. Well, we've got your back! Space will be extremely limited, so get in early if you want to race from afar for any reason. Click here for more information.
Benefitting Charity
Dedicated in Support of Colorado Canine Rescue!
Rescuing 'next-in-line' dogs of all breeds from overcrowded shelters, Dog Days is presented in support of
the Colorado Canine Rescue. Run entirely by volunteers, and with no central location… only
foster homes, please consider a generous donation when you register!
Walking distance from the race start / finish, enjoy a relaxing night's sleep at The Westin Westminster!
With their spacious guest rooms, spectacular views, complimentary WiFi and signature
Heavenly® Beds, you'll be all set to go All-Out on race day!
Reserve your room by July 8th to get our very special rate of just $119!
Call 888.627.8448 to tell them you qualify for our Dog Days 2017 Room Block or click below to reserve online.
Maps & Course Deets
|Site Map
|Printable PDF
Westminster City Park
Just NW of 104th & Sheridan Blvd
Please be sure to scroll to 'Event Information' for parking deets and please plan to utilize approved lots only.
|1M Course (30% Asphalt / 70% Concrete)
|Interactive Map
|Printable PDF
|1 Mile athletes will leave the lot at City Park heading southwest on Big Dry Creek Trail. As an out-and-back course, athletes will run exactly .5 miles to the turnaround then return the way they came.
|Male Record: Dylan Taylor- 6:25 Female Record: Zora Lockman- 13:15 Course Average: 15:37
|5K Course (13% Asphalt / 87% Concrete)
|Interactive Map
|Printable PDF
|5K athletes will leave the lot at City Park heading southwest on Big Dry Creek Trail. As an out-and-back course, athletes will run approximately 1.5 miles to the turnaround then return the way they came.
|Male Record: Nick Kadlec- 15:51 (5:07) Female Record: Katie Beringer- 20:39 (6:39) Event Average: 36:05 (11:38)
|10K Course (6% Asphalt / 83% Concrete / 11% Soft Surface)
|Interactive Map
|Printable PDF
|10K athletes will leave the lot at City Park heading southwest on Big Dry Creek Trail. As a double out-and-back course, athletes will run approximately 1.5 miles to the 1st turnaround then return the way they came, passing City Park to run another 1.5 miles to the 2nd turnaround, before returning directly to the finish line.
|Male Record: Julian Wheating- 34:20 (5:33) Female Record: Sarah Bay- 40:19 (6:31) Event Average: 1:06:11 (10:41)
|Half Marathon Course (3% Asphalt / 48% Concrete / 49% Soft Surface)
|Interactive Map
|Printable PDF
|Half marathon athletes will leave the lot at City Park heading southwest on Big Dry Creek Trail. As a double out-and-back course, athletes will run approximately 1.5 miles to the 1st turnaround then return the way they came, passing City Park to run another 5 miles to the 2nd turnaround before returning directly to the finish line.
|Male Record: Cory Logsdon- 1:17:35 (5:56) Female Record: Jeanni Seymour- 1:23:33 (6:23) Event Average: 2:12:32 (10:07)
|Aid Station Deets
|Early: Thru 5/22
|Advance: Thru 7/8
|*Late: Thru 7/19
|$25 / $20 (no swag)
|$30 / $25 (no swag)
|$35 / $30 (no swag)
|$40 / $35 (no swag)
|$45 / $40 (no swag)
|$50 / $45 (no swag)
|$65 / $60 (no swag)
|$70 / $65 (no swag)
Too many race shirts to wear 'em all? Not a fan of goodies in a bag? That's cool… just enter this discount code when you register and bam… $5 saved! (Don't worry, you'll still be sportin' that finish line bling with a burrito filled belly when you download all those free race pics!)
Discount Code: NOSWAG
IMPORTANT: Your decision to forego your race SWAG and register at the reduced rate is final. The moment you provide payment information & click to process your entry, changing your mind to add a shirt and goodie bag later will not be an option under any circumstances.
*Because goodies must be ordered far enough in advance to have them printed & shipped, late and walk-up entrants will receive SWAG on a first come, first-served basis. If the shirt size you prefer is unavailable when you register, please select your next best size to be sure you get one, then stop by the packet pick-up area after you race to see if a swap is possible.
Without YOU, these events simply wouldn't be possible!
From prep to packet pick-up, and from marshals to meal service, there are a variety of ways you can help. Sure… when you volunteer, you can look forward to that warm & fuzzy feeling that comes by giving back, but with All-Out, there's WAY more to it than that. There's no experience necessary, but space is limited so please let us know you're available right away! Athletes: We know endurance sports can take a big chunk out of your pocketbook and we've got your back. Check out our 'Earn a Free Entry' program! Groups: Tired of those bake sales & car washes? We are happy to be a part of your fundraising efforts! (Donations begin with just 10 volunteers and you need not be an official nonprofit.) Students: Earn those credits in the most fun way possible!
Event Schedule
|Monday, 5/22
|Early Pricing Ends
|Saturday, 7/8
|Advance Pricing Ends
|Wednesday, 7/19
|Late pricing Ends & Online Registration Closes
|Thursday, 7/20
|4:00 – 7:00p
|Early Packet Pick-Up & Walk-Up Registration- Photo ID Required
Road Runner Sports: 10436 Town Center Dr, Westminster Click here for directions.
(Don't wait until race morning to pick up your packet! Why? Prizes, prizes, prizes! In most cases, our phenomenal sponsors contribute SO many that some or all who pick up early will go home with a little something extra. Oh, and winning at packet pick-up will not reduce your chances of winning again on race day.)
|Saturday, 7/22
|Volunteer Check-In
|Race Day Packet Pick-Up & Walk-Up Registration- Photo ID Required
|Half Marathon Walk-Up Registration Closes
|Half Marathon Start
|5 & 10K Walk-Up Registration Closes
|10K Start
|1M Walk-Up Registration Closes
|5K Start
|1M Start
|1M Awards & Prize Drawing
|5K Awards & Prize Drawing
|10K Awards & Prize Drawing
|Half Marathon Awards & Prize Drawing
General Information
Directions – Westminster's City Park is located just northwest of 104th Ave & Sheridan Blvd. From US36, you'd go east on 104th Ave just under half a mile to the park entrance on the north side of the street. Once inside the park, turn east & follow the main roads around to the venue. Click here for a map or to get directions.
Parking (Updated 7/19) – We've received a last minute request from the City of Westminster to change the parking plan just a smidge. No worries… there will still be plenty of space, just please follow the signs on race morning to avoid any headaches. Athletes & spectators will be allowed to park in the lots indicated as 'A' & 'B' only, leaving other lots available for park maintenance, fitness center patrons and the softball tournaments scheduled for the same morning.
Towels – It's gonna be HOT! As great as the ice water dripping from your finish line towel will feel, please DO NOT return to the finish aid tent to re-dip your towel once it starts to dry. (Think about that for a minute… ewww!)
The above information is only that which is unique to this event.
Please click here to review other general but important details and AMP Company Policies.


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Reviews - Westwood5
Torrs Park ,, Ilfracombe, EX34 8AZ
Customer Reviews
Our reviews are from genuine LateRooms.com customers. We verify that the customer has stayed before leaving a review.
100% would recommend it to a friend
Customer service
Food quality
Room quality
Excellent Hotel
We were met by a very pleasant lady/owner who upgraded our room with out us asking due to a cancelation.
The quality of this room was fantastic. The mattress was second to none. We had a brilliant 2 nights sleep. The shower was very modern and again very good. Normally there is always something to moan about in any hotel but for once this was very good
Read More Less
Post retirement break
Excellent experience from arrival to departure.
Helen could not have been more welcoming. Breakfast excellent local produce. Felt looked after from booking restaurants and taxis to local knowledge. Would not hesitate to go again.
Read More Less
Birthday surprise
I booked this guest house as a surprise for my wife's birthday.
We were meeting some friends there although my wife was unaware of this. The owner is a lovely lady, called Helen, and she was there to greet us on our arrival. She was very helpful and obliging, and went out of her way to make our stay as pleasant as she possibly could. The room was absolutely wonderful (room 1), beautifully decorated, with a large en suite and the bed was very comfortable. Breakfast was to a very high standard with plenty of choice. I would highly recommend this guest house to anyone staying in Ilfracombe.
Read More Less
Cosy stay
Nice owner, good location and cosy place to stay.
Could do with room being updated (bathroom/shower). Owner recommended fantastic local pubs and restaurants.
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Well deserved 6/6 - not just clean, professional, lovely room, excellent food - but most important of all friendly service and made to feel right at home.
Well done on such a lovely Bed and Breakfast
Read More Less
Excellent customer service, great food and breathtaking views of the town.
What a great place with a real welcome you need after a long journey.
Breakfast was superb, wish evening meals were available. Only issue was the steep drive and parking in the drive although plenty of room on the road. Night lights would be great. Definitely can recommend to anyone.
Read More Less
Top Notch
Westwood is lovely in all aspects.
Breakfast is great, room is great and our host, Helen, couldn't be more helpful. Ilfracombe has eateries for all tastes and budgets and there's good local walks. The driveway is a bit steep but you could park on the street.
Read More Less
Outstanding B&B - will never stay anywhere else in Ilfracombe
Westwood is a beautiful late Victorian house with large rooms, high ceilings, big windows, and superb views.
It has been beautifully updated and modishly decorated by the proprietor. We stayed in the big room on the second floor, which has recently had a large and beautiful bathroom added. The step beyond that takes this B&B into the level of luxury accommodation is the detail - top quality bedlinen, superbly comfortable beds, exquisitely selected antique furniture (stuff from the 1960s is now antique!) and such pleasing details as real coffee and a mini-caffetiere in the room, delicious hand-baked biscuits, fluffy bathrobes, good quality bath and shower gel. The breakfast was truly wonderful, and included the most delicious pork sausage I have ever tasted, sourced from the local butcher in the High Street. Helen is a wonderfully warm and friendly host, with excellent local knowledge. I have stayed in a number of other B&Bs and hotels in Ilfracombe and this is simply the best - I will never stay anywhere else and if it's full I will wait till they have room free.
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Highly recommended!
We enjoyed our brief stay.
The owner was welcoming and professional. We had a beautiful and quiet room with amazing view. There was also a large breakfast served in the morning. Ticks all the boxes!
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Superb hotel, very welcoming and overall a lovely stay, couple of niggly bits...
The hotel was absolutely near perfect.
We stopped for 2 nights and thoroughly enjoyed our visit. We was well greeted and warmly welcomed in. The room itself was large, along with great facilities. Decent sized TV for when we got back in the evening to watch in bed. Kingsize soft bed. Couple of chairs so you can sit by the window and take a lovely view of the town. Also optional blankets for those warmer evenings. Just a couple of minor issues we have to be honest about though. The breakfast on morning 1 (2nd morning wasn't an issue), had 2 what looked like dog hairs that I had to seperate from my food. The bathroom needs mats near shower on the floor. Also perhaps a small fan for the rooms just so don't have to have both windows open in the heat. And a pre-warning for a very steep drive, would suggest any cars that are lower than most to park on street. Very minor points though and would insist people to stop at this hotel as it was lust to say the least. Happy customer here!
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Response from hotel
Thank you for taking the time to right a review for Westwood. I'm delighted that you enjoyed your stay.Im sorry that you didn't bring the points you mention to my attention while you were here. We pride ourselves on our hygiene in the kitchen and can only apologies for a stray hair if it came from this direction. I would have immediately offered you an alternative breakfast. I've noted your other comments and whilst we don't offer fans in the rooms and can't alter our driveway, I will take up the missing mat with housekeeping as all bathrooms should have bath mats.
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Horst Piepenburg preliminary insolvency administrator of SolarWorld affiliated companies
Παρασκευή, 19.05.2017 10:43
• Quickly familiarizing with the current situation of the company
• Maintaining business operations smoothly
• Safeguarding wages and salaries for the coming three months
Today, the local court of Bonn, Germany, as the competent court of insolvency, appointed the renowned restructuring expert Horst Piepenburg of the Piepenburg-Gerling law firm as preliminary insolvency administrator of SolarWorld AG and its affiliated companies SolarWorld Industries Sachsen GmbH, SolarWorld Industries Thüringen GmbH, SolarWorld Industries Deutschland GmbH and SolarWorld Innovations GmbH.
On May 11, 2017, the Management Board of Germany's biggest solar manufacturer filed for insolvency proceedings due to over-indebtedness. The management of the affiliated companies mentioned above filed for insolvency proceedings on May 12, 2017.
"Together with my team, I will quickly familiarize myself with the current situation of the company," Mr. Piepenburg said. The preliminary administrator has already contacted the managing directors of the affiliated companies as well as the employee representatives and has informed employees about the current status of the proceedings at a staff meeting in Bonn.
Furthermore, the preliminary administrator will arrange to safeguard wages and salaries for May, June and July 2017 through pre-financing through an insolvency allowance. According to Mr. Piepenburg, it is now of major importance to maintain business operations as smoothly as possible.
Dr.-Ing. E. h. Frank Asbeck, CEO of SolarWorld AG, said, "We will provide thorough and prompt assistance to the preliminary insolvency administrator."
The SolarWorld group has about 3,000 employees worldwide, about 250 of which work in the group headquarters in Bonn. The revenue of the solar power technology group totaled over € 800 million in 2016.
At the site in Freiberg, Saxony, SolarWorld employs about 1,260 people and 33 trainees. In Arnstadt, Thuringia, there are 735 employees and seven trainees.
About SolarWorld
SolarWorld manufactures and sells high-tech solar power solutions and, in doing so, contributes to a cleaner energy supply worldwide. The group, headquartered in Bonn, Germany, operates facilities in Freiberg, Germany; Arnstadt, Germany; and Hillsboro, Oregon, USA, as well as in a joint venture with Qatar Solar Technologies. From raw material silicon to solar wafers, cells and modules, SolarWorld manages all stages of production ‒ including research and development in its own company, SolarWorld Innovations.
Through an international distribution network with locations in Europe, USA, Singapore, Japan, South Africa and Qatar, SolarWorld supplies customers all over the world. SolarWorld was founded in 1998 and has been publicly traded on the stock market since 1999. More information at www.solarworld.com
About Piepenburg-Gerling law firm
The law firm was founded in 2001. As an insolvency or bankruptcy administrator, attorney Horst Piepenburg has supervised and supported about 2,000 mandates in the past 30 years. Furthermore, he was active as self-administrative manager at, for example, Babcock Borsig or the mail service PIN.
Between 1999 and 2013, Piepenburg was chairman of the Insolvency Law and Financial Restructuring Working Group at the German Lawyers' Association. For many years, he has been a member of the Gravenbruch Circle, the association of Germany's leading insolvency administrators and restructuring experts.
thomas SCHULZ, tsc.komm
Phone: +49 (0) 171 86 86 482
Email: email@example.com
Contact for product media:
Tiffany Künster
SolarWorld AG
Martin-Luther-King-Str. 24
53175 Bonn
Phone: +49 (0) 228 55920 314
Email: email@example.com


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Flaky Face
How to prevent: To keep skin from flaking, avoid products that contain alcohol, which is drying. Instead, use a gentle cleanser and switch to a richer moisturizer, such as Neutrogena Norwegian Formula Moisturizing Cream ($10.50 at drugstores). "I especially use it after skiing," Felderman says.
How to treat: Continue to wash with a mild cleanser, such as Cetaphil. Moisturize several times a day. At night apply a heavy-duty lotion, such as Lac-Hydrin Five Moisturizing Lotion.
When to see a professional: If skin sheds excessively, a light chemical peel can remove the dead top layer of skin in one office visit. If flaky areas are itchy and irritated, you may have an allergy. A dermatologist can prescribe the appropriate cream.


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Arts, Literature, Education, Language CoursesFollow
Build your vocabulary with Merriam-Webster's Word of the Day! Each day a Merriam-Webster editor offers insight into a fascinating new word -- explaining its meaning, current use, and little-known details about its origin.
December 15th, 2014
Episode 46 of 923 episodes
Merriam-Webster's Word of the Day for December 15, 2014 is: incommensurable \in-kuh-MEN-suh-ruh-bul\ adjective : not commensurable; broadly : lacking a basis of comparison in respect to a quality normally subject to comparison Examples: The two theories are incommensurable, making any attempt at comparison across disciplines ridiculous. "Camus' own predicament as an Algerian of European descent sympathetic to both sides of the Algerian War led him to recognize a collision of incommensurable truths and embrace classical moderation." Steven G. Kellman, The Texas Observer, December 2013 Did you know? Commensurable means "having a common measure" or "corresponding in size, extent, amount, or degree." Its antonym incommensurable generally refers to things that are unlike and incompatible, sharing no common ground (as in the "incommensurable theories" of the first example sentence), or to things that are very disproportionate, often to the point of defying comparison ("incommensurable crimes"). Both words entered English in the 1500s and were originally used (as they still can be) for numbers that have or don't have a common divisor. They came to English by way of Middle French and Late Latin, ultimately deriving from the Latin noun mensura, meaning "measure." Mensura is also an ancestor of commensurate (meaning "coextensive" or "proportionate") and incommensurate ("disproportionate" or "insufficient"), which overlap in meaning with commensurable and incommensurable but are not exact synonyms.
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Welcome to the Brain Training Podcast, the daily audio workout for your head. In this podcast we have two games for you, each with three rounds which get progressively harder. To enjoy the full experience, relax, and avoid distractions whilst you listen.


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After standing on the side of a highway in France for a touch longer than she fancied, Mira from WanderjahrJill came up with a new way to get a ride:
That is right, not even a little leg show or burly old me hiding in the bushes was going to get these French drivers to stop, but Mira dancing, and the both of us laughing and having a good time, was just the ticket to warming a Frenchman's heart in winter.
So Mira took off her hobo hat and stoic glare and cut a rug right on the side of the highway. And it worked. Withing minutes we had four different offers to take us in the opposite direction than we were traveling. A few minutes later we landed a ride in a sleek sports car going straight to the city that we after.
This may seem odd, but who would want to pick up a couple of grumpy old hitchhikers? My travel advice: if you want a ride, make the drivers laugh. People pick up hitchhikers not just out of the kindness of their hearts, but also because they want a story, some one to talk to, an adventure, to laugh, or because they are just bored. To make yourself seem like a humorous chap while thumbing it is a sure way to hitchhike across the planet with assurance . . . and laughs.
The Dancing Hitchhiker Video is below:
Notice how she stopped dancing for the truck drivers . . . Wanderjahr Jill did not want to advertise anything other than her dancing ability. haha.
Wade from Vagabond Journey.com
Anduze, France
December 23, 2007


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Originally posted on 60 Max Power O | Last updated 12/21/12
The Viking faithful knows it; Christian Ponder knows it, as well as Alex Smith of the San Francisco 49ers. The elephant in the room has just moved a little, just a little. However, far down the road it may seem, Smith is a good addition to a football team that needs a quarterback who can manage a game, but go outside the box. Ponder is still young in his second year, but if your looking for a quarterback with an upside bursting out of the box, it's Smith. Don't buy Jim Harbaugh saved him, Smith was an overall number one pick in the 2005 draft, he has the talent, but just needs a good quarterback driven Head Coach. If Ponder leads the Vikings to the playoffs then the pressure would be off for the time, but if management feels they could bring in a quarterback that could bring more to the table, like an Smith type, it could spell trouble. Ponder's recent public love affair gone marriage with ESPN sideline reporter Samantha Steele only fueled speculation that Ponder had left his game in his pants, ESPN's Kevin Seifert wrote: ""In evaluating Ponder after the season, we won't give him the out of blaming it on his love life. And if he plays well Sunday and takes the Vikings to the playoffs, I hope no one stoops to the idea that getting married cleared his head. So where does that leave us?" So where does that leave us? It leaves the Vikings fans with a running back that is carrying the team in Adrian Peterson in epic proportions, but next year the Vikings may not be so lucky to have another historic season from Peterson. Will they wait to see, or will they be proactive in the off-season?
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- HubPages»
- Entertainment and Media»
- Television & TV Shows»
- TV Shows
Classic Television Memories: Get Smart! 1965-1970
Ah, come in. I'm just doing a little control tweaking. Welcome to this installment of my Classic Television Memories hub. For the newbies, we take a trip back in time to revisit classic TV shows from the decade of the 1960's. The reason I chose this decade is because I consider this era the most important in television history, and some of the greatest shows came from this time period. On a personal level, these television shows provided me with hours of fine entertainment as well as fond childhood memories. Now, having said that, let's strap in and as in the words of the immortal Jackie Gleason, And awaaaaay we go!
Get Smart Opening
The Cold War provided the world with more than threats of annihilation, but have provided the world of entertainment with a plethora of spy-themed TV shows and movies. Beginning with the James Bond flick To Russia With Love (1962), spy and secret agent entertainment took off and running, and ran through the era of the 1960's. Television shows like I Spy, Man From U.N.C.L.E, and its spin-off, Girl From U.N.C.L.E, Code Name: Blue Light, Mission:Impossible, as well as British imports The Avengers, Danger Man (Secret Agent in the U.S.), The Prisioner, The Champions, and others ruled the airwaves.
Most of these shows were serious in nature, but the show we're focusing on in our trip, played the Cold War theme strickly for laughs. The show is Get Smart! Starring Don Adams, Barbara Feldon, and Ed Platt. Adams was also the voice of the cartoon character Tennessee Tuxedo (1963-1966), for us classic cartoon buffs.
We'll get to Smart in a moment, but first, a word from our sponsor.
Welcome back. The series was the brainchild of zany comedian, writer, director, producer Mel Brooks (The Producers, Young Frankenstein), and Buck Henry. The show was a send up of the Man From U.N.C.L.E. series with Robert Vaughn, and David McCallum (1964-1968).
Get Smart premiered on NBC on September 18, 1965. The series follows the further adventures or mis-adventures of bumbling secret agent Maxwell Smart, Agent 86 (Adams), and his more seasoned partner Agent 99 (Feldon). The duo are employed by CONTROL, a secret government counter-intelligence agency based in Washington, D.C. Smart's and 99's missions is supervised by the often frustrated leader of CONTROL known simply as Chief (Platt).
CONTROL'S nemesis on the series is KAOS, an organization of evil whose chief objective is - you guessed it, world domination. Many famous guest stars have played KAOS agents, but the chief of the organization is Conrad Seigfried played by comedian Bernie Kopell, later of The Love Boat.
In his fight against evil, Smart employs many secret weapons ala James Bond. His car has the famous ejector seat and weapons. Most notable of his gadgets are the Shoe Phone, and my personal favorite, the Cone Of Silence.
Cone Of Silence
Chief is always reluctant to assign Smart to missions because of his ineptness. However, the job gets completed in spite of his bungling.
Smart and 99 (real name unknown), find time while saving the world to fall in love and eventually get married and have children by Season Five.
Get Smart ran on NBC from 1965-1969, and moved to CBS for the last season 1969-1970.
The last episode of the original series aired on May 15, 1970. Since then the show has enjoyed syndication success and revivals, including a theatrical film starring Steve Carell.
Gone But Not Forgotten
Don Adams (Maxwell Smart, Agent 86) April 13, 1923 - September 25, 2005
Ed Platt (Chief) February 14, 1916 - March 19, 1974
Closing Sequence
Well that's it for this hub. See you for the next trip. Same time, Same channel.
I loved Get Smart. Did you know Gary Clarke, (the former Steve Hill on The Virginian) wrote some of these episodes? I got to meet Gary at the Memphis Film Festival this year. He's a really fun loving guy still yet today.
Yes, I loved this TV series and Maxwell Smart, 86, was my favorite television character.


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Connecting Families to Senior Living
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Talk to a local Advisor about this community
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1025 Bell Ave
Facility License: 0013777
Caretypes Provided: Assisted Living, Alzheimer's Memory Care
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*Prices quoted are monthly rental charges and are provided by the communities themselves. Actual prices may differ due to one-time fees, timing and care services required. Speak with your Senior Living Advisor to learn more.
Our apologies. Pricing is currently unavailable for this particular community.
Open your heart to a homelike atmosphere when taking up residence at The Waterford at Hartford. Our Assisted Living and Memory Care community in Hartford, WI enriches the lives of residents by providing an environment that is physically, mentally, spiritually and emotionally stimulating. Spacious one- and two-bedroom apartment homes in Assisted Living feature kitchenettes and large bathrooms with safety features including hand rails and walk-in showers. Our Memory Care common area boasts an abundance of gardening opportunities in addition to an outdoor patio where residents can get out and enjoy sunny weather. Small pets are welcome in our well-appointed community with an activity room where residents can challenge their friends, neighbors and loved ones to card and board games. Our caring and professional staff provides a helping hand for residents who may appreciate assistance with activities of daily living. You can be assured that our Hartford Assisted Living and Memory Care community provides the quality care that will allow residents to remain as self-reliant as possible while living in a supportive environment where 24-hour staffing is available. Caregivers offer medication reminders and housekeeping and laundry services so residents can say goodbye to the worries of living alone and hello to a relaxed lifestyle in the city near Pike Lake. Scheduled courtesy transportation can take our residents to some of the premier shopping, dining and entertainment in and around the area. Since 1990, Capital Senior Living has grown to become one of the largest senior living providers in the United States. With a goal of offering affordable housing and an enriched lifestyle to thousands of seniors, our dedicated team of professionals succeeds in providing quality care in each of our unique communities.
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Grace Miller
Vice President of Product
As Vice President of Product, Grace is responsible for managing the technology roadmap and turning vision into execution. She works with stakeholders across all facets of the company to ensure that the technology is meeting client needs as well as making internal teams more efficient and scalable. She is passionately dedicated to solving problems through the innovative use of technology.
"There's a natural high that comes from building something you know is amazing. I count myself very fortunate to be working with such an incredibly talented development team."
Prior to joining Scorpion, Grace spent almost 9 years helping to build ReachLocal from a startup into an international, publicly-traded company. She held many roles during that time, the most recent being the Vice President of Product Management and Integration.
Grace holds a BA in English from the University of North Texas and lives in Valencia with her husband and two young daughters. When she isn't working, she enjoys exercising outdoors, wine tasting, and excellent Mexican food.


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The BLACK & DECKER BDPA15N Wide/Fan Paint Sprayer Nozzle is great for painting wide patterns and large surfaces. This nozzle works with the BDPS Series paint sprayers (BDPS400, BDPS600 & BDPS200). Designed with Spray Pattern Indication for easy spray pattern set up.
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- Click here to learn more about paint sprayers


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Simplicity 8652; ©1978; Cathy Hardwick - Misses' Pullover Two-Piece Dress in Two Lengths - Sized for stretch knits only: Top-stitched top has long raglan sleeves and self drawstring through casing. Regular length skirt V. 1 and long length skirt V. 2 have elastic waistline casing and side pockets.
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- Twilight's Fancy
- Out of the Ashes Collectibles
- Vintage-A-Go-Go Sz 8
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Texas Cottage Law
Decorating By heavenscent Updated 10 Aug 2011 , 1:39pm by TexasSugar
OK so stupid question I know. However I was trying to read about this and just saw where it looked more liked sales for jams canning etc. Can we bake and sell cakes out of the home starting September 1st. Thanks
Yes we can!!!!
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In a somewhat surprising move a couple of years ago, the Tigers elected to not hold their annual Fall Instructional League, a roughly one-month long endeavor down at Tigertown in Lakeland.
The reasons given were multiple, including that after a six-month grind, players weren't ready for another month of baseball, and that efforts redirected elsewhere at player development could be more effective. Minicamps were held during the winter months instead, and some more experienced players got in work in various winter leagues, especially in Latin America.
That changed this year, when the Tigers elected to bring back the Fall Ball club. That decision was driven largely by new leadership atop the baseball organization, including general manager Al Avila and Brad Ausmus. According to Littlefield, "We spoke with Al and Brad, and they both felt that there were some players, especially some of the younger guys, that could use some extra work."
When expanding on which players they were focusing on, Littlefield continued to specify, "those guys, that missed time because of injury, or were recent draftees and could use some more work, or just younger guys in A-ball, we felt we had an opportunity to hold the session and it'd be beneficial to them – focus more on their fundamental and provide them more reps."
The Tigers however aren't shifting back to the old way entirely, as they'll still hold a minicamp. The camp this time around however will instead be held when big leaguers report for spring training, lasting for a few weeks between big leaguers reporting and the minor leaguers reporting for camp.
This minicamp will be focused as well, according to Littlefield. "The minicamp in spring will be focused one some more of our top prospects, and will allow for some specific and focused instruction for those prospects that would benefit from the additional work."
Finally, the topic of the Arizona Fall League was broached – currently, the Tigers have pegged seven players to attend the AFL, including JaCoby Jones, who is currently with the big league club as part of the expanded roster. Littlefield said as of now that group in its entirety is still slated to head to Arizona in October to compete among the MLB's best young talent.
As Littlefield appropriately caveated though, "In our business, things are always subject to change, but as of now, those guys that we selected to head to Arizona next month are all going to be going there."
Those seven players are right-handers Artie Lewicki, Adam Ravenelle, Jeff Thompson and Spencer Turnbull, catcher Grayson Greiner, outfielder Christin Stewart and utility man JaCoby Jones.
So based on direction from the club's GM and manager the organization is bringing back Fall Ball while keeping their minicamp concept introduced a couple of years ago, with more targeted efforts for development in each endeavor.