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Drugs & Diseases > Otolaryngology and Facial Plastic Surgery
Cell Biology of Head and Neck Squamous Cell Carcinoma Brief Overview of Molecular Biology and Cancer
Updated: Mar 14, 2019
Author: Chau T Nguyen, MD; Chief Editor: Arlen D Meyers, MD, MBA more...
Cell Biology of Head and Neck Squamous Cell Carcinoma
Sections Cell Biology of Head and Neck Squamous Cell Carcinoma
Brief Overview of Molecular Biology and Cancer
Cancer Model
External Influences and Molecular Mechanisms
Systemic and Local Factors in Cancer
Cellular and Molecular Interactions
Nuclear Factors in Head and Neck Squamous Cell Carcinoma
Gene Therapy and the Newest Frontiers
The discovery of the structure of DNA by Francis Crick and James Watson in the early 1950s ushered in a new era in molecular biologic science. This technologic and biologic revolution continued through the 1960s to today, and the explosion in technology has fueled the current expansion of knowledge into the working of the human cell. As of 2003, 99% of the chemical base pairs that make up human DNA had been sequenced to within 99.99% accuracy. In turn, as a result of research into the abnormal cancer cell, the basic understanding of the cell has greatly improved. Successful translational research has allowed gene therapy trials to proceed.
Work across many laboratories is geared toward elucidating the genetics behind cancer, discovering cellular mechanisms that lead to cancer, and elucidating intracellular and intercellular interactions that allow this progression. [1] Identifying candidate precursors or enabling genes may pave the way for cancer screening, as with the ret proto-oncogene and medullary thyroid carcinoma. One technique that is garnering wide attention in this realm is the DNA array, in which a number of different genes from an individual can be processed to look at certain genotypes. Eventually, new treatments will develop from these efforts.
A few gene therapy trials now target head and neck cancer, which comprises only 4% of all cancers but has a dismal prognosis in advanced stages. [2, 3, 4, 5] Of the estimated 41,000 patients in the United States who develop this cancer each year, 13,000 are believed to die from the disease. In other parts of the world, head and neck cancer is much more prevalent. The male-to-female ratio in head and neck cancer is 2:1.
An image depicting head and neck squamous cell carcinoma in vitro can be seen below.
Head and neck squamous cell carcinoma in vitro (cell culture).
Cancer is characterized by uncontrolled growth and division of a cell with extension beyond the normally limiting basement membrane and through the boundaries of normal cells. This, in turn, creates a clonal population of a single abnormal cell. Because of its mutated aggressive genetics, this cell has a selective growth advantage over its neighbors. Different theorists have argued how this mutation occurs.
Multihit theory
A reasonable model is based on colon cancer development. This is the multihit theory of tumorigenesis, in which a series of multiple triggering events in the genetic and cellular makeup of a cell ultimately cause cancer. Some modeling analyses suggest 5 separate events are required in colon cancer. [6] These events lead the cancer cell to escape normal cell growth and control mechanisms, to avoid system control mechanisms (ie, immunologic surveillance), and to establish a nutrient supply.
The multihit model postulates that several unique genetic mutations combine to cause cancer. However, which mutations are most important, which events must occur, and if a specific order is involved in molecular tumorigenesis is unclear. In colorectal cancer, multiple mutations are present. For example, in the hereditary cancer syndromes familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, mutations have been discovered in the APC gene and DNA mismatch repair genes. Although the exact process has not been elucidated, the sum of these mutations is believed to lead to cancer development in this model.
In head and neck cancer, the histologic progression of severity from hyperplasia, dysplasia, and carcinoma in situ to invasion provides a framework to understand the genetic progression of cancer. Early clonal genetic events in benign hyperplastic lesions show losses at chromosomes 9p21 and 3p. p21 and other tumor suppressor genes' inactivation are therefore most likely involved in the first steps of the cancer model, with later stages possibly involving protooncogene activation and inflammation. One model postulates 6-10 genetic steps in the pathway from premalignant lesion to frank malignancy. Time and cumulative exposure to carcinogens are believed to greatly modify this risk and development.
Among the risk factors for the development of head and neck cancer are alcohol and tobacco abuse, viral infection, and sun exposure. Each of these external factors has been studied in some detail.
Tobacco abuse
Tobacco has been determined to be carcinogenic in animal models. The effects of tobacco are broad and affect the entire mucosa of the upper aerodigestive tract. It may induce changes in a number of different cellular sites within the pharynx and larynx. This ability has led to one particular model of oral cancer development, field cancerization. In this model, not only is the local cancer a threat, but much of the surrounding tissue is also likely to become cancerous. This has necessitated resection with wide margins in the treatment of oral carcinoma. It also explains the high prevalence of second primary tumors in these locations, especially in the esophagus. Many of these second primary tumors, although separate in time and space, can be traced to a common clonal origin, with similar early genetic alterations leading to the pathway of cancer.
Clinical data have shed further light on the mechanisms of tobacco-induced neoplasms. Certain individuals appear to have greater susceptibility to cancer caused by tobacco because of their genotypic makeup. Specifically, whether or not wild-type p53 is present normally or whether it is mutated, missing, or nonfunctional may affect one's risk of cancer. If p53 is mutated, missing, or nonfunctional, risk of cancer from tobacco use may be increased.
Tobacco is known to have various mutagenic effects through the formation of free radicals and epoxides. Investigators have studied the body's response to these effects via detoxifying enzymes. One example, the glutathione S-transferase enzyme, which has numerous polymorphisms, may be related to the development of cancer in certain predisposed individuals. Another molecular scavenger, uridine 5'-diphospho (UDP)-glucuronosyltransferase, may increase risk of larynx cancer 3.7 times if present with low activity.
Tobacco and alcohol synergy
Tobacco and alcohol use have a synergistic effect that increases the rate of cancer causation. This effect is not merely additive but also geometric. The risk of head and neck cancer in persons who smoke and drink is up to 17 times greater than the risk in persons who neither smoke nor drink.
Viral infections have long been known to cause certain cancers and to be strongly linked to others. Well-known examples include human T-cell lymphoma virus (HTLV) in T-cell lymphoma and human immunodeficiency virus (HIV) in Kaposi sarcoma. In the head and neck, Epstein-Barr virus (EBV) has been implicated in the development of nasopharyngeal carcinoma, antibodies to which may help determine the prognosis.
Human papillomavirus (HPV) DNA, RNA, or both have been found in several types of head and neck cancer. HPV has an affinity for epithelial cells. The E6 protein of HPV binds to RB, a tumor suppressor gene, inactivating it with the potential for unchecked cell growth. One study has shown that HPV-16 DNA detected in the lymph nodes of patients affected with HPV-16–positive oropharyngeal cancer indicates metastatic involvement. Patients with tumor-free lymph nodes but with a high viral load value may have developing lymph node metastasis, and this finding may serve as a marker. [7]
HPV types 16 and 18 have been implicated in cervical cancer. Another tumorigenic mechanism is by E6 protein–mediated pathways that lead to p53 degradation. Research has shown HPV DNA in a high proportion of oropharyngeal head and neck cancer. An inverse relation of HPV positivity in these cases with p53 has also been shown. This suggests a causal mechanism for cell proliferation. The link between HPV and other head and neck subsites, however, is unclear.
Sun exposure is causally linked to squamous cell carcinoma of the skin, as well as to melanoma and basal cell carcinoma. Radiation causes DNA damage in the following 3 ways: directly (breaks DNA), indirectly through changes in oxidative enzyme systems (buildup of free radicals damages DNA), and indirectly to DNA repair mechanisms (causes faulty DNA). Similarly, irradiation has been shown to increase the risk for radiation-related sarcomas and thyroid cancer.
Drug and environmental factors
Certain drugs may predispose one to cancer formation. For instance, immunosuppressive regimens may predispose patients to transplant-associated tumors. Other environmental agents associated with head and neck malignancy are the chewing of betel nuts in Asia (oral cancer) and nickel and wood dust exposure (sinus carcinoma).
In addition to outward influences, intrinsic systems are at work in cancer development.
Systemic factors
For a cancer to grow, it must be able to avoid the body's immunologic cancer surveillance system. This system relies on major histocompatibility (MHC) proteins to recognize self from nonself. It depends on the interrelationships between antigen-presenting cells (APCs) and dendritic cells to effector cells, such as lymphocytes and monocytes, and the humoral immune system. Despite intensive research aimed at identifying cancer-specific antigens for use in directed therapy and vaccines, the apparent lack of specific cancer antigens has complicated this effort. In addition, the cancer state causes widespread immune system suppression, affecting dendritic cells and their production of lymphokines and monokines, cell-signaling molecules. In patients with head and neck cancer, the native output of thymic T-cells is less than that in healthy controls.
Certain lymphocytes are known to target tumor cells, with these tumor-infiltrating lymphocytes (TILs) being found in a number of solid tumors. A study by Ngamphaiboon et al indicated that in patients with head and neck squamous cell carcinoma, a high CD8+ TIL score (6 or greater) is associated with significantly longer overall survival. A correlation was also found between the high score and patients with a status of never having smoked, the presence of oral cavity cancer, and presentation with stage M0. [8]
Similarly, a study by Shimizu et al indicated that in patients with oral squamous cell carcinoma, an association exists between a high CD8+ tumor-infiltrating T-cell density in the parenchyma at the tumor's invading edge and improved overall and disease-specific survival. The investigators also reported a correlation between a high stromal density of these T-cells at the tumor's periphery and improved recurrence-free survival. [9]
One current area of work uses TILs to target tumors by sensitizing them to tumor antigens outside the body and then reintroducing them, making TILs home in on the neoplasm. Patients with head and neck cancer who have a high percentage of apoptotic TILs have lower 5-year survival rates.
Other immune modifications include packaging genes with TIL, such as cytokine tumor necrosis factor (TNF), which causes local tumor cell lysis without systemic side effects. Class I MHC markers such as leukocyte antigen human leukocyte antigen (HLA)-B7 likewise could be activated into populations of tumor cells, leading to expression on the tumor cell surface with subsequent rejection and destruction by the immune apparatus.
Local factors
In addition to systemic factors, local factors allow the maintenance of the cancer state. In squamous cell carcinoma of the head and neck, along with most other cancer conditions, the tumor secretes angiogenic growth factors that promote vascular proliferation. This enables the tumor to grow, because nutrient constraints would eventually limit the tumor's volume unless a new source of nutrition were found. This fact has remarkable implications for newer antiangiogenesis drugs that fight cancer.
The latest antineoplastic drugs include this class of antiangiogenesis compounds. Bevacizumab, a monoclonal antibody that targets this phenomenon of angiogenesis, has shown promise in clinical trials of breast, lung, and colorectal cancer treatment, prolonging survival.
Matrix metalloproteinases (MMP) are a family of proteins involved in degrading the extracellular matrix (ECM) framework of cells, including collagen. Attention has been focused on these molecules because of the potential of metastasis in cells that have this ability to invade the basement membrane. In head and neck cancer cell lines, tumor, and primary larynx cancer, levels of MMP were indeed found to be elevated. Part of this elevation may be in relation to epidermal growth factor (EGF).
Overall, the genetics behind carcinoma in the head and neck region are complex [10] ; environmental influences play a significant role. This is in contrast to some other cancers, such as retinoblastoma, which have a simple Mendelian inheritance pattern.
Perhaps the greatest growth in our understanding of cancer is at the cellular level. Methods that elucidate genomic cancer hotspots include evaluation of chromosomal loss of heterozygosity. Besides gene mutations, other mechanisms of loss of function of an allele may have the same effect. For example, a genetic change that affects a homozygous deletion of a tumor suppressor gene may be a sentinel cancer event. Maternal and paternal alleles in normal tissue are compared with the same in tumor tissue, and the areas of loss or gain are identified. This is aided by analysis of microsatellite markers, which are tandem repeats of the genetic code in mostly noncoding areas. By amplifying these flanking areas around genes through the polymerase chain reaction (PCR), specific genes of interest that correspond to the loss or gain are identified. [11, 12] In this fashion, a map of where to search for candidate genes involved in molecular oncogenesis is created.
In the normal noncancer state, the cell cycle is tightly regulated (see the following image); only a few tissue types have cells that are constantly dividing (eg, skin, mucosa). Other cells go into a state of senescence, whereby they no longer grow and divide. In vitro, cells in culture, such as fibroblasts, divide for only a limited number of cycles. Also, as the cells grow and multiply, they respect the boundaries of neighboring cells. In the cancer cell, however, both of these usual mechanisms are lost; this is abundantly clear in culture.
The cell cycle.
Cancer cells may be continually regenerated and, unabated, will grow in a disorganized manner. Once normal cells enter the quiescent phase of cells leaving the mitotic cycle (G0), or cell senescence, they do not reenter the cycle of growth, synthesis of proteins and DNA, and mitotic division. The gate of entry back into the replicative cycle is the domain of oncogenes, which facilitate entry, and tumor suppressor genes, which block the pathway.
Oncogenes
Among the more well-studied oncogenes is the cyclin family. The cyclins are significant in the entry pathway from the G0 state to the presynthetic gap, or phase of cells before DNA synthesis (G1), growth phase and thereby entry into the cell cycle. In the normal state, cyclins respond to growth factors and are otherwise quickly degraded; however, buildup of cyclin D1 protein, a kinase, leads to the phosphorylation of the Rb protein—a tumor suppressor. This inactivation of Rb allows the cell to progress into division mode. [13, 14]
Cyclin D1 has been shown to be amplified in head and neck squamous cell carcinoma. It resides on chromosome 11q13, which is amplified in up to one third of head and neck cancer cases. [15] Interestingly, most of these cases were from the pharynx. This may suggest a complementary mechanism for p53 inactivation along with human papillomavirus (HPV) oncogenic integration in this cancer subsite. [16] A study by Dhingra et al indicated that in head and neck squamous cell carcinoma, an association exists between greater expression of cyclin D1 and higher tumor stage and lymph node metastasis. [17]
Other oncogenes operative in head and neck cancer resemble this model of tyrosine kinase phosphorylation of key molecules that leads to cell division (eg, human epidermal growth factor receptor [EGFR], the STAT3 protein, myc, ERBB2).
Cetuximab, a monoclonal antibody against EGFR, has been approved for use in human head and neck cancer chemotherapy. Its action is to bind EGFR, thereby preventing epidermal growth factor (EGF) from binding to the cell surface and stimulating cell growth. EGFR overexpression is believed to be an early event in carcinogenesis. Its expression is increased with increased severity of premalignant lesions. In larynx cancer, levels of EGFR have been found to correlate with metastasis-free survival and overall survival.
Downstream from EGFR, the signal transducing and activators of transcription (STATs) are phosphorylated and activated by the tyrosine kinase region of EGFR. They then bind to DNA promoters and effect gene transcription. It may have an antiapoptotic role and has also been found to be a likely early event in the progression to head and neck cancer.
Tumor suppressor genes work in much the opposite fashion. In its hypophosphorylated state, Rb binds and inactivates a transcription factor, EF1, which is responsible for entry into the cell cycle. RB resides on chromosome 13q, and, although loss in this region has been found in head and neck cancer, RB gene mutation has been inconsistently identified.
The p53 protein product is perhaps the most widespread cancer mutation, germane to discussion of head and neck cancer as well. It acts slightly upstream of Rb in the cycle, at the G1/synthesis (S) checkpoint. Normally, p53 is upregulated in response to cellular injury and DNA damage, arresting the cell at this checkpoint. [18] Apoptosis may begin if the damage is irrevocable. With mutant p53, however, this important check is lost, and the cell proceeds with DNA synthesis and cycling. p53 is located on chromosome 17p, another area identified as abnormal in human head and neck squamous cell cancer.
Studies that examine the relation of p53 to head and neck cancer have found mutations in 33-59% of tumors. However, clinical correlations of this significance in prognosis have been equivocal. One study has shown an increasing prevalence of p53 mutation with increasing histologic severity in invasive head and neck cancer.
Another well worked-out pathway of tumor suppressors concern the p family of proteins (p16, p14, p21, p27). These molecules prevent the phosphorylation of Rb and, therefore, the cell's continuation in the cycle as well.
p16 has been studied in some detail. It binds to and inactivates the cyclin-dependent kinases CDK4 and CDK6, preventing the phosphorylation of Rb; thus, the cell's continuation through the G1/S growth checkpoint. The method of faulty p16 production appears to be via hypermethylation of its promoter, a form of gene silencing that does not involve sequence mutation. The p16 gene resides on chromosome 9p21, an area previously shown to be marked by allelic imbalance and loss.
In the nucleus of the cell, DNA replication occurs during the synthesis phase (see the image below). In the normal state, this process is highly accurate, with the frequency of an error occurring estimated at 1 in a billion base pairs per cell generation. Nonetheless, however precise, this system has potential for intrinsic mutations with each passage of the cell through the cycle of division.
To combat potential intrinsic mutations, numerous DNA repair enzymes help to ensure the fidelity of the genetic code; however, even these systems are imperfect and may allow genetic change or mutation. The importance of these repair enzymes is clearly evident in the disease xeroderma pigmentosum, in which a defect in these systems allows unchecked DNA damage from ultraviolet light. Persons with this disorder develop squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin, often at a very early age.
Another mechanism to ensure the appropriateness of the cell is apoptosis. As discussed earlier, p53 protein promotes apoptosis in response to DNA damage. A different protein, Bcl-2, blocks this apoptosis and, in so doing, allows the continuation of the cell through the cycle. In essence, Bcl-2—which has been shown to be overexpressed in human squamous cell carcinoma as well as in its namesake, B-cell lymphoma—prolongs cellular survival.
Another enzyme that may do the same but in a different fashion is telomerase. Telomeres are the ends of DNA strands. They are normally not well replicated and thereby shorten with each replication cycle. By doing so, telomeres function as cellular clocks, keeping track of how many times a cell has divided, until it ultimately remains in a quiet state. Telomerase is an enzyme that is able to lengthen these shortened ends and thus prolong the period in which the cell may divide. It is normally found in germ cells and at low levels in regenerating tissues. Research has highlighted this molecule in human cancers, showing it to be present in up to 90% of all cancers, including head and neck cancer.
A study by Liu et al found that survivin, which belongs to the inhibitor of apoptosis protein family, is not only present in higher quantities in oral squamous cell carcinoma but exists in the nucleus of the carcinoma cells. This contrasts with most normal oral tissue cells, where survivin is either absent or exists in the cytoplasm but not the nucleus. Moreover, statistical analysis demonstrated a correlation between nuclear survivin and the carcinoma's TNM stage and differentiation grade. [19]
Nuclear factor kappa B
Nuclear factor kappa B (NFkB), a cytosolic protein, is normally bound to inhibitor factor kappa B (IkB). IkB is degraded in response to inflammatory cytokines. NFkB also has binding sites for cytokines such as interleukin (IL)-1 and then translocates to the nucleus, where it functions as a transcription factor, having either inhibitory or activating function. Possible roles include immune modulation, inflammation, apoptosis, and cell division. Previously, a mouse model has shown NFkB to have a role in malignant transformation. In head and neck cancer cell lines, inhibition of NFkB led to decreased growth. Multiple molecular targets in the signaling pathway of NFkB have also been shown to be altered in neoplastic transformation.
Cyclooxygenase inhibitors
The cellular inflammatory response may thus be an important source for propagation of cancer. Cyclooxygenase (COX)-1 and -2 upregulation leads to increased levels of prostaglandins in head and neck cancer. They may also play a part in decreasing apoptosis and increasing angiogenesis through an increase in vascular endothelial growth factor. Clinical studies are ongoing to see if COX inhibitors may be useful as chemoprevention in head and neck cancer, as it has been found for colon cancer.
A study that looked at a COX-2 inhibitor, celecoxib, in chemoprevention of oral precancerous lesions showed that COX-2 is overexpressed in a number of premalignant and malignant oral lesions. [20] This is linked to inhibition of apoptosis and metastasizing potential. Administration of celecoxib in a mouse model of oral cancer delayed the onset of early lesions and slowed the growth of established oral tumors. The effect was dose dependent.
Retinoid agents
Chemopreventive measures that involve the administration of retinoid agents have also shown promise in in vivo studies and premalignant head and neck lesions. The retinoic acid receptor family comprises nuclear receptors similar to thyroid and steroid hormones. They function as ligand-dependent transcription factors and are involved in cellular growth, as well as in angiogenesis.
It is probable that no one pathway alone is responsible for squamous cell cancer; rather, like the colon cancer model, many pathways converge to cause this cancer. Multiple mitigating and inciting influences also exist. Advanced age, for example, with the accumulation of genetic changes over time and possible immune suppression, adds to the increased risk of head and neck carcinoma.
A study by Kalfert et al suggested that differences in the microRNA (miR) profile influence the pathobiology of head and neck squamous cell carcinoma of the oropharynx and larynx. The investigators found a correlation between oropharyngeal origin of p16-positive squamous cell carcinoma and tumor levels of miR-34a. The study also noted significant differences in the levels of let-7a, miR-200c, and miR-34a levels between oropharyngeal and laryngeal squamous cell carcinomas, while, compared with normal squamous epithelium, the squamous cell carcinomas showed upregulation of miR-21, miR-200c, and miR-34a and down-regulation of miR-375. [21]
Chromosomal imbalance
The genetic changes, aside from the specific mutations discussed, can be grouped into a larger category of genetic change: chromosomal imbalance. Chromosomal imbalance includes chromosomal instability and break points, translocation, amplification and deletion, oncogene activation, and methylation. The complex external milieu of the cell, with cancer promoting angiogenesis, and the body's natural homeostasis, which favors a steady state, are also factors. Ultimately, both environment and genetics underlie cancer development in susceptible individuals.
Targeted gene therapy
The next frontier in research for squamous cell cancer of the head and neck is in the evolution of newer and better treatments. Because so much has been learned about the genetics of cancer, targeted therapies are possible. Gene therapy has gone from theory to practicality in the form of a number of current research trials that target head and neck cancer. [22, 23, 24, 25, 26, 27, 28, 29] This modality makes sense in the head and neck region, because this region is readily accessible for treatment and injection and is easily monitored [30] ; furthermore, the current disease management has much morbidity and potential for disfigurement, as well as continuing poor prognosis in the later stages.
In vitro, antisense DNA technology against the cyclin family of oncogenes has been used with some success. Human trials have included a marginally successful attempt to replace the wild-type p53 protein in tumors. [31] Human trials have also been undertaken using adenovirus without the E1B region, which normally inactivates p53, with the goal of the virus targeting cells with abnormal p53, such as cancer cells. [32] Some subjects' disease partially responded to this treatment. Another approach has been to inject the class I major histocompatability complex (MHC) molecule into tumors to incite a brisk immune response. This, too, has succeeded in only a few cases.
Other technology that derives from our understanding of the molecular basis for human squamous cell carcinoma includes vaccines. In advanced melanoma, vaccines are made using patients' own immune cells that are selected and sensitized to the tumor and then replaced. This technique has proved promising in a number of patients. Use of various chemokines such as interleukin and tumor necrosis factor (TNF) has been attempted with some response but at the expense of often burdensome adverse effects. One other area in which multiple drugs are being developed is monoclonal antibodies. Blocking antibodies against the epidermal growth factor (EGF) receptor have been used, again, with variable effect.
Clearly then, the clinical translational arm of current research is in its nascent stage. As the growth in knowledge of the fundamentals of cell biology continues, understanding of head and neck squamous cell carcinoma, a complex disease, will progress. Future research will focus on deciphering how molecules and molecular events affect staging and prognosis. New tumor markers have yet to be defined. The ultimate goals include the reduction and prevention of head and neck cancer, which is possible with awareness and tobacco cessation programs, and a simple effective treatment that will lead to a favorable prognosis.
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Chau T Nguyen, MD Clinical Assistant Professor, Division of Head and Neck Surgery, University of California, Los Angeles, David Geffen School of Medicine; Director of Otolaryngology-Head and Neck Surgery, Ventura County Medical Center
Chau T Nguyen, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Head and Neck Society, American Medical Association, California Medical Association, Phi Beta Kappa
Coauthor(s)
Tapan A Padhya, MD Professor and Vice Chairman, Director, Division of Head and Neck Oncology, Department of Otolaryngology-Head and Neck Surgery, University of South Florida College of Medicine
Specialty Editor Board
Disclosure: Received salary from Medscape for employment. for: Medscape.
Karen H Calhoun, MD, FACS, FAAOA Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University College of Medicine
Karen H Calhoun, MD, FACS, FAAOA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Head and Neck Society, Association for Research in Otolaryngology, Southern Medical Association, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, American Rhinologic Society, Society of University Otolaryngologists-Head and Neck Surgeons, Texas Medical Association
Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Benoit J Gosselin, MD, FRCSC Associate Professor of Surgery, Dartmouth Medical School; Director, Comprehensive Head and Neck Oncology Program, Norris Cotton Cancer Center; Staff Otolaryngologist, Division of Otolaryngology-Head and Neck Surgery, Dartmouth-Hitchcock Medical Center
Benoit J Gosselin, MD, FRCSC is a member of the following medical societies: American Head and Neck Society, American Academy of Facial Plastic and Reconstructive Surgery, North American Skull Base Society, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Rhinologic Society, Canadian Medical Association, Canadian Society of Otolaryngology-Head & Neck Surgery, College of Physicians and Surgeons of Ontario, New Hampshire Medical Society, Ontario Medical Association
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Can you first right click in your chart->Properties->Change the chart background to another color such as grey. Next draw using the Ruler tool then double click on the Ruler line which will open the Properties window->Select new colors for Text color and Color->Click Apply->Click Set Default then click Ok.
Once finished setting the Default then change your chart background color back to Black.
It resolved the issue. Thanks!


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Meet Your 2020 Canada Judging Period 3 IsaBody Challenge Finalists
These five Canada IsaBody Challenge Finalists have made amazing transformations. Are YOU ready to make a healthy change? Register now for a chance to compete!
By Sarah Shaver|2019-06-18T13:39:10-07:00June 5th, 2019|Tags: IsaBody Challenge, IsaBody Challenge Finalists, IsaBody Finalists, Success Stories, Transformation, Weight Loss|
Here at Isagenix World Headquarters, we are SO excited, because it's time to announce our 2020 Judging Period 1 Canada IsaBody Challenge® Finalists! We absolutely love this Challenge and everything it represents, because it allows [...]
Meet the 2019 Canada IsaBody Challenge Grand Prize Winner!
By IsaFYI|2019-06-18T13:46:09-07:00May 22nd, 2019|Tags: Canada IsaBody Challenge, IsaBody Challenge, IsaBody Grand Prize Winner, Solutions to Transform Lives, Success Stories, Testimonials, Weight Loss|
At 277 pounds, Chera Hariss had lost all her self-confidence. She was at the lowest point in her life physically and mentally — not even her job brought her joy. She wasn't happy with her [...]
Despite Her Doubt, Natacha Found Great Success With Isagenix
By IsaFYI|2019-06-18T13:50:22-07:00May 15th, 2019|Tags: Financial Opportunity, IsaBody Challenge, isagenix recognition, Results You Can't Get Anywhere Else, Success Stories, Weight Loss|
When a friend on Facebook messaged Natacha about Isagenix, she wasn't sure what to think. As a full-time nurse practitioner, she assumed it was just a fad — some poorly designed system loaded with nonsense. [...]
How Eric Is Building a Whole New Life (and Business!)
By IsaFYI|2019-06-19T08:51:23-07:00February 6th, 2019|Tags: Eric Chen, IsaBody Challenge, START 1000, Success Stories|
When Eric finished his last collegiate swim race after a decade of competitive swimming, he had no idea how different life without swimming would be. In four months' time, he gained 25 pounds and felt [...]
By IsaFYI|2019-06-19T08:54:16-07:00January 29th, 2019|Tags: Canada IsaBody, IsaBody Challenge|
At Isagenix, we LOVE the IsaBody Challenge® because it allows us the privilege of watching participants transform their bodies and their lives through each 16-week journey. That's truly amazing! Now, it's time to do one [...]
How Mathieu Lost (And Is Keeping Off) 100 Pounds
By IsaFYI|2019-06-19T09:23:53-07:00October 17th, 2018|Tags: 100 Pound Club, IsaBody Challenge, Isagenix System, Weight Loss|
You wouldn't know it now, but just two years ago, Mathieu was 100 pounds heavier than he is today. "Since I was about 20 years old, I've been the laziest couch potato alive!" he laughed. [...]
Compete to Be the First-Ever GLOBAL IsaBody Grand Prize Winner!(Deadline Approaching!)
By IsaFYI|2019-06-19T15:20:41-07:00August 6th, 2018|Tags: #GlobalCelebration2018, Global Celebration 2018, IsaBody Challenge, IsaBody Grand Prize Winner|
At Global Celebration 2018, we announced that moving forward, we will now crown a GLOBAL IsaBody™ Grand Prize Winner each year at Global Celebration. That's right – when you compete in the IsaBody Challenge, not [...]
Finalist Conquers Lifelong Battle With Failure, Emerges Victorious!
By IsaFYI|2019-06-19T11:06:32-07:00May 1st, 2018|Tags: IsaBody Challenge, Weight Loss|
Have you ever given up on a diet regime because you didn't see results fast enough? That's how Julie's numerous attempts to lose weight inevitably ended. At 288 pounds, Julie was hurting – emotionally and physically – but she was setting herself up for failure before she even started by giving herself permission to quit if she didn't see instant results.
By IsaFYI|2019-06-19T15:20:42-07:00April 9th, 2018|Tags: IsaBody Challenge, IsaBody Challenge Finalists, IsaBody Finalists|
Amber struggled with yo-yo dieting for almost 20 years. After moving to a new city across the country, she was ready to make a change. She and her fiancé made the commitment together to live a happier and healthier life. Soon after, they were introduced to Isagenix. With the IsaBody Challenge® community, she found the support she was looking for. She felt encouraged and inspired in her journey every day, and over the course of three Challenges, she's lost 22 pounds and has put on lean muscle!*
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redpajama_set_name: RedPajamaCommonCrawl


Malmgren, A.J. (1867). Annulata Polychaeta Spetsbergiæ, Grœnlandiæ, Islandiæ et Scandinaviæ. Hactenus Cognita. Ex Officina Frenckelliana, Helsingforslæ. 127 pp. & XIV plates.
McIntosh, William Carmichael [as M'Intosh]. (1901). Notes from the Gatty Marine Laboratory, St. Andrews. — No. XXI. 1. On some points in the life-history of the littoral fishes. 2 On Japanese annelids — Nephthys and Eteone. 3. On Norwegian annelids collected by Canon Norman. 4. On Canadian Phyllodocidae collected by Mr. Whiteaves. 5. On certain Hesionidae from the 'Porcupine' Expedition of 1870. Annals and Magazine of Natural History, Series 7. 8(45): 216-232, plate I.


508 is a show about Worcester. This week, we talk with Nicole Melone and Greg Opperman about the history of Vegworcester and the upcoming 8th annual New England VegFest. (Sunday, April 30, 2017, 11am-5pm, DCU Center, Worcester, Mass.) Also: Crime.


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Minister of Transport and Communications
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Information Society Code to Parliament
Press release 30.01.2014 13.35 fi sv en
The complete reform of legislation applying to electronic communications is making headway. On 30 January 2014, Finland's Government submitted its proposal for Information Society Code to Parliament.
In accordance with the Government Programme, the key provisions that apply to electronic communications have been integrated in the Information Society Code.
After overlapping items were removed and provisions were consolidated the Information Society Code now consists of just over 350 sections, whereas there were previously 490 sections in ten different acts.
The purpose of the Information Society Code is to ensure that electronic communications services are available throughout Finland. The services must be technologically sophisticated, safe, easy-to-use and reasonably priced. Legislation will also be used to create better than ever conditions for competitive business, development of and innovations in communications technology.
Consumer protection will be improved. In cases where consumers order and pay for products and services via their mobile phone, it has been proposed that telecom operators and the companies selling the said products or services would share accountability. This would mean that in addition to the seller or service provider, consumers could turn to their telecommunications operator if the service or product is faulty or the consumer never receives it or is unable to discontinue a service order.
Special attention has been paid to protection of privacy and information security. Provisions applying to protection of privacy and ensuring information security would be extended to cover all operators that convey communication. The provisions would apply to such matters as confidential messages exchanged via social media.
The major changes faced in the media sector have been taken into account in the proposed new operating licence system. The system would be simplified by transferring a significant part of decisions concerning radio and television programming licences to the Finnish Communications Regulatory Authority (FICORA). In future, new frequency bands that will be utilised for mobile communications could be distributed via auction.
Steps will be taken to make monitoring of the pricing used by companies that hold significant market power more effective. FICORA would, for example, be given the right to determine a maximum price for a telecommunication operator's wholesale products when problems with competition arise.
The integrity of communication services will be promoted by creating better conditions for cooperation between the operators and the authorities in controlling disturbances. The most important network control centres and other critical systems should be maintained so as to allow them to be restored to Finland immediately in the event of special circumstances.
In its session, the Government also adopted three resolutions. In its first resolution the government promises to proactively simplify its operating licence procedures within the confines of laws currently in force.
In its second resolution the Government states that it will form a working group, the task of which will be to promote the development of information society so that users of wireless and cable internet connections can have access to audio-visual content in the open web as cost efficiently, extensively and simultaneously as possible.
According to the third resolution, transfer of the so-called Lex Nokia provisions into legislation on working life will continue.
In the course of preparing the Information Society Code the drafting process was brought up-to-date and made more open. An exceptionally large group of stakeholder representatives took part in the process. The monitoring group was made up of 50 members and the seven working groups consisted of 30-70 persons each.
The Information Society Code is scheduled to enter into force on 1 January 2015.
Ms Maaret Suomi, Senior Adviser for Legislative Affairs, tel. +358 295 34 2150
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The Kool-Aid's in the Coffee: An Interview with David Latourell of Intelligentsia Coffee Roaster
Maybe we're feeling jittery right now, but the adjectives we're psyched about currently are as follows: light, soft, round, voluptuous, caramel-scented, citrusy, brambly. Brambly? What does that even mean? We got the chance to find out when David Latourell of Intelligentsia Coffee Roaster shared some words and a pot of just-in ("pre-production") Tanzanian single-origin coffee (meaning that rather than a blend, this coffee came from just one farm) with us this week.
It's not that blends are at all bad, and no denigration meant on David's part, he explains. It's just that "single origin has the capacity to tell an awesome story, and people like to hear awesome stories." David spoke with us about the relationships different cities seem to have with their coffee drinkers and coffee culture, and how those relationships can be improved with the recognition of the stories a coffee can tell.
Talking to David, it's clear his passion lies not only in how coffee is served, but in how it arrives to the roaster. Intelligentsia follows a rigorous process to determine which coffees they sell. They make sure every person along the way is paid for their part and has a "transparency" contract that reveals what everyone else is being paid for their efforts. And because Intelligentsia is willing to pay top dollar for their beans (sometimes as much as 350% above the market value of commodity coffee – the freeze-dried stuff, for instance), it's not just about increasing consciousness on the consumer level, but as David puts it, shifting the mentality of the farmer to produce a real quality bean.
Intelligentsia started out in Chicago 14 years ago, and in a quickly changing industry, they've evolved their model and developed countless new ones to work with over the years. But these stores aren't the cookie cutter model some companies (we're looking at you, Ubiquitous Green Mermaid) have pursued. The passionate staff (and Intelly hand picks some of the most passionate people available – their director of training, Stephen Morrissey, earned the crown of World Barista Champion a couple years back) ensures that each store matches its locale and takes advantage of the denizens there.
About the LA area, and the new Venice Beach location, David had this to divulge: "We're redefining how things should work here on the consumer side. So with the new concept in Venice, it's very open space, very much something where you can wheel the machine around, bring the person in, show the person what you're doing on the machine, talk about different extraction models you can have." This is what David means when he talks about the different stores: "It's not like we're at the base of Grand Central Station. I don't think we would put a store like that in Grand Central Station. I know that it's incredibly busy already, which is awesome. It's in Venice, so it's a laidback culture as well."
The Chicago stores, on the other hand, are more geared toward the 9-to-5 audience. While each of the 3 cafes has their own character, they are "more suited to the business experience." That is to say, while you often find the baristas there conversing with customers about coffee sourcing and the origin of the beans they use, the emphasis lies more on serving the coffee well and efficiently. The Monadnock store is the epitome of this model, and the original store on Broadway, while extremely busy, also has a larger space for sitting and conversation, an area for cuppings in order to inform the public of industry standards, and a variety of brewing methods to choose among.
Though Intelligentsia hasn't opened a café of their own in New York (yet!), there are great spots all over the city where it can be found, all of whom have at their disposal the Training Lab where we chatted (Flavorpill and Intelligentsia are office neighbors, in fact). We've experienced some of the delights of Intelligentsia coffee from Dean and Deluca and Commodities Market, as well as designated coffee shops like Southside and Ost Café. Some people might recognize names like Ninth Street Espresso, without even knowing that their recent proprietary Alphabet City blend was developed with Intelligentsia, who is now their roaster.
Of the coffee scene in general, David asserts that San Francisco definitely led the pack. He says the opening of Peet's in the Bay Area in the '60s stands as a great example of coffee going along with the food culture progression. As for the current movements, he speaks of "a need to bring people's focus back to the way they eat, and why they would want to put something in their body, and what are they doing with that." Chicago, according to David, has also done a good job of moving coffee culture ahead simultaneously with food culture.
What's happening in New York right now is particularly interesting to David because unlike San Francisco or Chicago, the coffee consciousness of New York seriously lags behind the marvelous food culture. This might seem like a criticism, but David points out that it will likely be a boon to New York's coffee culture. The advantage to coming in late, as he sees it, is that "if you come in late you can jump in at the right level." In this way, David believes the New York coffee scene will not only quickly catch up to the existing scenes in San Francisco and Chicago (not to mention the Pacific Northwest) but be able to surpass the current norms faster and create new designs à la Venice Beach for an innovative New York audience.
TIPS When we asked David for tips on what to look for in a coffee or coffee shop, we received a slew of them to share with you.
1. Be informed. David shrewdly pointed out that anyone can produce propaganda, so a picture of a farmer on a wall does not mean any representative from the company knows that farm or where the bean really comes from. The more you know about what you're buying, the more you can guard against the bad stuff. For instance, if you buy beans from El Salvador in January or February, you should be aware that those are last year's beans, because El Salvador's harvest is around that time of year, and it wouldn't be in the stores in time to buy it in those months. Coffee loses some of its vibrancy after ten months, and while it may not be bad, it certainly helps to know more about what you're getting.
2. Pay attention. That leaf shape in your coffee foam? It's called a "rosetta" and it's pretty indicative of the amount of work your barista has put in. It doesn't necessarily mean your barista knows about the origins of the coffee beans she's using, but it does require well-extracted espresso and well-steamed milk, so chances are you've got a quality drink in your hands. David hopes (as do we, after this conversation) that a well-made latte will stimulate more interest on the part of the consumer to understand what it is they're drinking.
3. Look around. You know that container that the beans are in before they're ground? The one you can see into and gaze at the beans lovingly from the other side of the bar? That's called a hopper. David says if it looks dirty or oily, that's bad news and indicative of an apathetic barista, and you should consider another café.
4. Stay fresh. When you're buying beans for home use, check for a "roasted on" date, and definitely buy beans that are no more than a week and a half past roasting date. Freshness makes a huge difference in taste, and the quality of even the best beans drops rapidly after sitting on the shelf for a couple weeks. Similarly, buying whole beans and having a grinder for home use has a significantly positive impact on your morning experience.
5. Converse! Without being too aggressive, because their job is pretty stressful, it doesn't hurt to ask your barista a bit about the coffee they're serving you. David points out that you can't always expect the best answer, but by showing your baristas that the interest is out there, they'll likely seek out the answers for the next time and take more pride in their work as a result of accumulated knowledge and respect.


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Commission responds to Orbán's latest anti-immigration campaign
By Georgi Gotev | EURACTIV.com
Campaign in the Hungarian newspapers against George Soros, Jean-Claude Juncker. [@NatashaBertaud Twitter]
The European Commission reacted strongly on Thursday (28 February) to a new anti-immigration campaign launched by Hungarian Prime Minister Viktor Orbán earlier this week by saying it "distorts the truth", and by refuting most of its points.
Commission spokesperson Mina Andreeva said the college of commissioners had discussed the Hungarian migration campaign at their weekly meeting on Wednesday.
The Hungarian press reported that Orbán had written a "letter" to his compatriots, saying that "Brussels has learned nothing from the terrible terrorist attacks of recent years and wants to bring more immigrants to Europe"
The website Hungary Today quotes from the letter:
Behold the letter Viktor #Orbán has sent to every voter in #Hungary. Photo: https://t.co/o1GHYpvxyX
"Brussels has learnt nothing from past years' terrible terrorist attacks. It wants to bring even more migrants into Europe. #thread pic.twitter.com/v4J3PUQ3dm
— Viktória Serdült (@sviki1980) February 26, 2019
"The bureaucrats are now preparing to encourage immigration with new measures. After the introduction of the migrant visa and the migrant bank card, more money would be given to George Soros' organizations, supporting immigration. They still want to distribute immigrants with obligatory quotas."
The PM continued by saying Hungarians do not want their country to become an "immigrant country":
"We want to protect our security and our Christian culture. That is why we have built a fence and we are protecting our borders. However, the bureaucrats in Brussels do not want to respect our decision. In order to achieve their goals, they want to break the resistance of countries that stand against immigration."
The letter ends with words from a recent information campaign, stating that people have the right to know "what Brussels is up to." According to the letter, there is an information package attached, detailing Brussels' measures.
This is the second time that Orbán writes a "letter" to Hungarians against Brussels. In April 2017 he launched an initiative called "Let's stop Brussels", only days after leaders gathered in Rome to mark the EU's 60th anniversary.
Commission unmoved by Orbán's 'Stop Europe' initiative
Hungary launched an initiative called "Let's stop Brussels" shortly after its prime minister returned from the Rome summit. Asked about it today (4 April), the Commission highlighted the fact that Viktor Orbán had signed the strongly pro-European text only days before.
Andreeva said the Hungarian campaign, titled "You too have the right to know what Brussels is planning" "distorts the truth and seeks to paint a dark picture about a secret plot to drive more migration to Europe".
She added: "We agree that people want to know the truth, and the truth is the following:
We don't want to introduce mandatory resettlement quotas, but the resettlement of refugees from outside the EU was, is and will always remain on a purely voluntary basis.
The Commission doesn't want to waken the member states right to defend their borders, but in fact the EU supports the national border protection.
The Commission has zero plans to introduce humanitarian visas.
The Commission does not work with any organisations that facilitate irregular migration.
The EU aid doesn't encourage migration, but only assists refugees already in Greece. (She added that this is with regard to the so-called per-paid debit cards.)
It is member states that decide voluntarily whether they want or not to allow skilled legal migration when working with African countries.
EU funding is not linked to support or to opposition to migration by member states."
Andreeva said that Commissioners agreed that clear answers were needed with regard to the serious allegations.
European Commission responds to Hungarian government campaign which is distorting the truth and seeks to paint a dark picture of a secret plot to drive more migration to Europe.The truth is that there is no conspiracy https://t.co/zDb6G8dl8z via @EU_Commission #Orban #Hungary
— Alex von Witzleben (@AlexWitzleben) February 28, 2019
Andreeva was asked what the position of Hungarian Commissioner Tibor Navracsics had been during the College discussion. She answered that the Commission always takes consensual decisions.
"I speak in the name of the entire Commission to which Commissioner Navracsics belongs", she said.
However, there has been a precedent of Navracsics taking one position in Brussels and a completely different stand in Hungary.
Thus, Navracsics said he had voted "No" in the October 2016 referendum in Hungary against the Commission-proposed migration quotas, although he did not oppose the proposal at the college level.
Navracsics voted against the Commission, but his EU commitment remains 'unshaken'
The Commission told EURACTIV today (20 October) that Hungarian Commissioner Tibor Navracsics had clarified with Commission President Jean-Claude Juncker that his commitment to the EU remains "unshaken", despite the fact that he voted against the Commission's policies in the Hungarian referendum.
News from capitals
Tibor Navracsics
Viktor Orbán
2 responses to "Commission responds to Orbán's latest anti-immigration campaign"
Johan Stavers says:
blablabla.. the bottom line is that the EU is never going to do anything that will allow Europe to remain European. Because it is ANTI-RACIST.
Obviously this means a commitment to destroying all measures that will make sure that races continue to exist. Race haters have put this into every constitution and therefore all resistance is futile.
Schuman says:
You're a lying racist who may well belong to be put in jail, alongside Mr Orban.


Discuss shaolin longfist, white crane or other styles. Theory, practice and applications. Please stay on topic.
Suggesting the following DVDs to be converted for Android and IOS.
Hi, thanks for these suggestions. Sorry for the delay in replying.
These deeper martial arts topics are not as popular with the larger mainstream audience, and some of the topics are even "niche". The length of these DVDs, coupled with the smaller audience, makes it hard to justify the expense. Some of the shorter DVDs may be converted over time.
I appreciate your feedback and am really glad the video apps are working for you.


Dr. Colin Lee Soon Soo is a gynecologist and fertility specialist at the Alpha Fertility Centre in Selangor, Malaysia. Dr. Lee's interest in preimplantation genetic screening (PGS) and fertility has led to more than 100 scientific publications over the years. The discussion below touches on current challenges for in vitro fertilization (IVF) research and how Dr. Lee's team addresses them.
Thermo Fisher Scientific: As a leader of preimplantation genetic screening research in Malaysia, can you share how you view PGS, and what challenges exist today?
Lee: At the Alpha Fertility Centre, we are working to be at the forefront of preimplantation genetic screening research. We are not a large centre, with about 1,100 fresh cycles run last year. What we are noticing is that many of the people we see choose to have PGS after they receive full counseling regarding the pros and cons of such testing; when people are made aware of what PGS offers, a majority of them choose it. For example, in the last four months, 70% of our participants undergoing egg pickup have opted for PGS. That's very encouraging.
However, increasing interest comes with several challenges. First, there is a lack of awareness around the need for preimplantation genetic screening, not just among patients, but among many doctors as well. For instance, if I told you that among certain age groups, as many as 90% of the eggs are chromosomally abnormal, you may not believe me. It is difficult for anyone to accept that, including doctors. That is a big hurdle to overcome in terms of awareness and education.
A second challenge is ensuring the reliability of results: that when we say the embryo is abnormal, it really is abnormal. We as clinical researchers are developing a better understanding that an abnormal embryo will have a certain degree of mosaicism. We now realize that many of these embryos actually "self-correct", resulting in a normal baby. While the sensitivity and specificity of PGS technology is improving, more work is still being done to help ensure healthy outcomes.
The third challenge I would raise is about cost. As it stands, the technology is still fairly expensive. It is not just the screening process itself that costs money. In my view, preimplantation genetic screening is best implemented in an elective, frozen embryo transfer protocol. That too costs additional money and time for the patient. So awareness and education, refinements in the technology, and cost are three big hurdles that the field still needs to address.
Thermo Fisher: You mentioned the sensitivity and specificity of PGS technology as a challenge. What are the technologies you have used for PGS?
Lee: We started preimplantation genetic screening in 2004, and that time was the era of fluorescence in situ hybridization (FISH) and also the era where most people did their biopsy on day 3 embryos. Of course, we now know the limitations of those two things. We then moved on to microarray comparative genomic hybridization (CGH). In fact, we were the first in Asia and Australia to use microarray CGH with fresh transfer in 2009. We started doing all that when the microarray CGH technology became available, which was also in 2009. Then, three years ago we moved on to next-generation sequencing (NGS) using the Ion Torrent™ system.
Thermo Fisher: What impact has NGS had on your work?
Lee: Before we switched to NGS, we were using microarray CGH, which basically detects aneuploidy copy number variation. Many people who require PGS present with thalassemia. As such, those cases would need another PCR method, typically Sanger sequencing. Another challenge was that initially they would require two biopsies, and we know that has negative effects on the viability of the embryo or blastocyst.
As our understanding grew, we saw the need for increased use of preimplantation genetic diagnosis (PGD). That is one of the main reasons we chose the Ion Torrent system; we can do PGS and PGD using a single biopsy sample on a single platform. We spare the embryo or the blastocyst a double biopsy. It also saves time since these two things are done simultaneously. Further, the entire workflow process is optimized. In fact, we are now starting to do human leukocyte antigen (HLA) typing in addition to PGD and PGS—all on the same biopsy sample.
Thermo Fisher: How did you go about selecting an NGS system? What criteria were important to you?
Lee: First and foremost, I think the reliability of the system is critical. So, we looked at the sensitivity and specificity to be sure that results obtained are accurate. Another key consideration is the cost of setting up the system and not just that, the cost to run a sample. We have to align that to the number of samples that we expect to run.
The complexity of using the system, the complexity of the machine, the complexity of the labor, and the amount of labor that is needed are considerations. Another important benchmark that I looked at before we made a decision is the flexibility of what this system can do: the capability of extending beyond just screening to diagnosis, and as I mentioned earlier, the ability to do HLA typing as well.
One more point is that in addition to copy number variations, we also want a system that can tell us about chromosomal aberration. Evidence is coming out that chromosomal aberrations can also contribute to a failure of either implantation or causing early miscarriages. So, when I consider buying a system, one of the things to consider is whether the system is able to help us in reporting chromosomal aberrations because it is something that we are gaining a better understanding of now, and will continue to research in the years to come.
Thermo Fisher: What do you like about Ion Torrent NGS?
Lee: We have been using Ion Torrent NGS now for about three years. The result are clear. We don't have many ambiguous or questionable results. That is something we like. The scalability of the system is good, and as our experience with the system increases, so does our confidence in the results we obtain. I'm sure that confidence is evident when we discuss results. So, the volume that we expected to run before we bought the Ion Torrent system has been far exceeded.
Flexibility and scalability are important to our lab. Using Ion Torrent NGS, we're able to add PGD onto PGS. Recently, we've been very excited about being able to add HLA typing onto the platform as well, so we can get results for three things at once.
Thermo Fisher: How did you implement NGS?
Lee: We were using microarray CGH and we obviously did not stop doing microarray CGH to switch to NGS completely. What we did was a sensible thing. We actually ran the two systems at the same time, and as we gained confidence in the new system, we slowly phased out the old one. So today, we have completely phased out microarray CGH and we are using NGS exclusively.
Thermo Fisher: What advantages does the Ion ReproSeq™ PGS Kit give you over other methods you've tried?
Lee: We compared two methods in the past. For FISH, of course, we were using only five probes and occasionally more. I don't think there is really a comparison. And, if you look at the microarray CGH, we were very happy with it. I think it served our purpose at that time. But as we now are experiencing higher volume, NGS in fact is a little bit cheaper per sample compared to microarray CGH. And, we have made a very important move in the last two years; NGS helps us optimize cost per sample in the area of elective frozen embryo transfer. Of course, the other main advantage is that we were doing PGS, and now we are doing both PGS and PGD. As our confidence in the technology increases, so too does the number of PGD cases we see. Now that we are on more confident footing, we can tell people if they have this problem, we may be able to help.
Thermo Fisher: What do you think still needs to be done to move our understanding in this field even further forward?
Lee: At this stage, we are able to determine whether an embryo is chromosomally, even genetically normal. Yet, when we transfer that embryo to the womb, we are not able to achieve a 100% pregnancy rate. We are above 80% implantation rate with excellent blastocysts in frozen cycles. That gap needs to be filled with evolving technologies, methodologies, and techniques in the clinic, in the laboratory, and in the transfer room. We hope to narrow that gap as much as it is possible. I suppose we will never reach 100%, but we would certainly want to get very close to that.
Thermo Fisher: What about this work drives you and gives you the greatest satisfaction?
Lee: The bottom line is that we want to see a couple having a positive result, which is the delivery of a healthy child. And in that process, we want to provide a new hope using a new technology, a new form of treatment that can give patients success where previously that wasn't achievable.
Thermo Fisher: How do you think your research will impact future generations?
Lee: One of the things we are doing now is demonstrating the potential use of apronuclear (0PN)- and unipronuclear (1PN)-derived embryos. Based on our findings, we noticed, if the 0PN and 1PN develop into morphologically normal-looking embryos or blastocysts (as defined by decent quality or morphological assessment using an embryo-grading system), these embryos will share similar euploid rates as those derived from 2PN embryos. We have already published data proving it and will continue to demonstrate this with more data. This continuing research will impact the basic practice of IVF around the world as 0PN and 1PN will no longer be thrown away. This will help to expand the opportunities for quite a few people.


text:
Резеда бухарская () — вид травянистых растений рода Резеда семейства Резедовые (Resedaceae).

Впервые вид был описан русским ботаником, флористом Дмитрием Ивановичем Литвиновым.

Естественным образом распространён на территории Центральной Азии, в Туркестане, на Памире и в Афганистане.

Является кормовым растением для гусениц бабочек глауконома.

Примечания

Ссылки

Резедовые

redpajama_set_name: RedPajamaWikipedia


Lachlan Cramsie has been crowned the 2013 Rebel Sport Pro Tour, at Coffs Harbour, Australia, during the 32nd RAW National Bodyboarding Titles.
The Queensland bodyboarder proved that he is currently the best competitive rider in the country, by not only winning the Open Men and Pro Men titles, but claiming the Rebel Sport Pro Tour Championship as well.
Cramsie's clean-up began when he defeated some tough opposition in the Open Men's final, defeating Lewy Finnegan, Pearson Tully and Joey Orme.
"I'm so happy. After finishing runner-up in Kiama I was determined to get a win in Coffs this year", reveals Cramsie.
Cramsie's next hurdle came in the form of Jones Russell. Jones lead the Rebel Pro Tour for the majority of 2013, but Cramsie pegged him back with a win at King of the Box, and a second in South Australia, to lead the rankings into the final event at Coffs Harbour.
In the Pro Women's division, it was a one-on-one battle between Lauren Frost and Jane Keel. Both girls entered the water knowing that who ever came out on top would be crowned the 2013 Rebel Sport Pro Tour Women's champion.
Jane Keel blasted out of the gates with two high scoring waves, including a 7.5 that left Lauren Frost chasing scores for the remainder of the final.
"I knew I had a chance coming up here. But now I've actually won the title... I'm so stoked!", Keel laughed.
In the Pro DK division, Queensland's Shane Griffiths was untouchable and never dropped a heat during the entire tournament, but it was Jimmy Lear who clinched the 2013 title by finishing runner up to Griffiths.
"It's been a year to remember. I got married, had a baby and won the tour. I'm stoked", adds Lear.


text:
Q: GWT JsArray of self, recursive object array I am building a tree structure which an object references itself in like so:
public class ProjectObjectOL extends JavaScriptObject {

    protected ProjectObjectOL() { }

    public final native boolean getStatus()  /*-{ return this.status;  }-*/;
    public final native String getError()  /*-{ return this.error_message;  }-*/;

    public final native JsArray<ProjectObjectOL> getChildren() /*-{ this.children; }-*/;

}

My problem is that I can't seem to get the children of the object.  I've tested it out, and I'm quite sure the JSON structure being passed back consists of an object that contains an array of children of that type which can contain children, etc.
...but when trying to access even the simplest information about the children, the length of the array, it returns 0 every time.  I've tried with no success to figure out what it's doing wrong, all the other data returns fine, but this one piece will NOT retrieve the children.  Here is an example of how I might (directly) access the length for testing:
JSONObject oResults = (JSONObject) JSONParser.parse(response.getText());
                    ProjectListOL testoutputOL = oResults.isObject().getJavaScriptObject().cast();
                    ProjectObjectOL testObject = testoutputOL.getProjectList().get(1);
                    Window.alert(testObject.getChildren().length()+"");

A ProjectListOL contains an array of ProjectObjectOLs.  In the example above I simply grabbed the one I KNOW has children.  I'm using ColdFusion for the backend that returns the JSON object.  Once again, I have output this object multiple times, both in GWT and outside (directly dumping the JSON object from the file) verifying that the object is indeed set up how I expect it to be set up.

A: I missed an obvious mistake:
public final native JsArray<ProjectObjectOL> getChildren() /*-{ this.children; }-*/;

OOPS:
public final native JsArray<ProjectObjectOL> getChildren() /*-{ **return** this.children; }-*/;

redpajama_set_name: RedPajamaStackExchange


text:
Q: Как получить / обработать двойной клик по кнопке? У меня есть форма и на ней GroupBox. У GroupBox Width = 0, при нажатии на button размер GroupBox меняется. Как сделать при двойном нажатии на button Width GroupBox = 0. Посмотрел на Events button там нету OnDblClick.

A: Вместо Button используйте SpeedButton. Плюс другие варианты вместо кнопки: Panel, Label и т.п.

A: вместо button использовать Label все заработало

"показать"
grp1.Height:=200;
grp1.Width:=200;
lbl1.Caption:='Скрыть';

"скрыть"
grp1.Height:=0;
grp1.Width:=0;
lbl1.Caption:='Показать';

A: сделал как slippyk написал тоже все норм всем спасибо за помощь
 begin
          if lbl16.Tag = 0 then
            begin
              grp1.Height:=200;
              grp1.Width:=195;
              lbl16.Caption:='Скрыть';
              lbl16.Tag:= 1;
            end
            else
            begin
              grp1.Height:=200;
              grp1.Width:=0;
              lbl16.Caption:='Показать';
              lbl16.Tag:= 0;
          end;
        end;


text:
Apple Executive Analysis
Paper type: Process Analysis Essay
Direction: Business
Subject: Management
Subtopics: Apple Inc.
Words: 1600 Pages: 6 5 min. Cite this
In week 8 of AMBA 640, we will be analyzing the Apple case located in chapter one of Management Information Systems: Business Driven MIS Inc from an information systems management perspective. Our analysis will look at some of the common tools used to analyze competitive intelligence such as Porter's Five Forces Model, the three generic strategies for choosing a business focus and the value chain analysis. We will also discuss why and how data, information, business intelligence and knowledge are important to Apple.
This analysis will also include how Apple identified areas where it achieved a competitive advantage using management information systems and why competitive advantages are temporary. ? Introduction Apple was launched April 1, 1976 by Steve Jobs, Ronald Wayne and Steve Wozniak and is considered to be one of the most innovative technologies companies in the world. The company is responsible for products and services such as the Macintosh desktop and laptop computers, iTunes, iPod, iPhone, iTouch, iPad, Apple TV, and iCloud.
Apple also develops its own software to run on its computers, its philosophy "has always been to create products that consumers find easy to use and marry innovative technology to work productivity and personal entertainment" (Mallin & Finkle, p. 49, 2011). This accomplished company faces constant challenges from a competitive market to a technology lifecycle that is continuously being shortened and thus must make key decisions on which products to build or discontinue in order maintaining its competitive edge. This analysis will look at several analytical tools that can be used to evaluate Apple's competitive intelligence.
The tools are; The Five Forces Model, the three generic strategies, value chain analysis, SWOT analysis. This analysis will also look into evidence of Apple's usage of business intelligence, enterprise resource planning (ERP), customer relationship management (CRM), data mining and, intelligent systems. ? The Five Forces Model The five forces model, developed by Michael Porter of Harvard Business School in 1979, provides methods in which corporations can evaluate their competition and determine strategy. The model looks at the strength of five competitive forces and, when combined, determines long-term profitability and competition.
Baltzan (2011) lists the five competitive forces as buyer power, supplier power, threat of substitute products or services, threat of new entrants and, rivalry among existing competitors. Buyer Power Buyer power is important because buyers can force lower prices, demand better quality product or services and play competitors against each other (http://www. referenceforbusiness. com/management). Buyer power can be measured by the number of buyers for the product, their sensitivity to price, the size of the order, difference between competitors and, the availability of alternative products.
However in the case of Apples' introduction of the iPod in October of 2001, buyer power was not a strong force because the limited amount of digital players available to the market that contained a proprietary digital media service specifically designed for the player. Apple is a forward thinking company and recognized very early that people will be listening to more music through their computers rather than purchasing compact discs. This forward thinking resulted in the introduction of iTunes, a media player program, before the iPod in January of 2001 (www.
wikipedia. org). Supplier Power Baltzan defines supplier power as "the suppliers' ability to influence the prices they charge for supplies (including materials, labor, and services. Factors used to appraise supplier power include number of suppliers, size of suppliers, uniqueness of services, and availability of substitute products" (Baltzan, 2012, p. 17). Apple uses suppliers for key components from Japan, Korea, and U. S. and completes the assembly by a Taiwanese manufacturer in China (Linden, Kraemer & Dedrick, 2009).
Due to their market share in smart phone users, Apple is in better position to negotiate the prices it will pay for these components. Threats of Substitute Products or Services Substitute products or services are a result of competition and can limit the profitability in that industry. Threat level is considered high when there are multiple alternatives for the product or service. The threat level for Apple is high due to the numerous options that consumers have to choose from. Amazon and Android both offer buyers the ability to download digital content, i. e.
books, music, movies, and etcetera through its online store. Samsung, Sony, Motorola and Microsoft sell various products (tablets, mp3 players, cellular phones) that directly compete for the same consumers as Apple. Threat of New Entrants The threat of new entrants into an industry is largely dependent on the barriers to entry. Baltzan defines an entry barrier as "a feature of a product or service that customers have come to expect and entering competitors must offer the same for survival (Baltzan, 2012, p. 17)". Porter identified six barriers (http://www. referenceforbusiness.
com/management/Or-Pr/Porter-s-5-Forces-Model. html): •Economies of scale, or decline in unit costs of the product, which force the entrant to enter on a large scale and risk a strong reaction from firms already in the industry, or accepting a disadvantage of costs if entering on a small scale. • Product differentiation, or brand identification and customer loyalty. • Capital requirements for entry; the investment of large capital, after all, presents a significant risk. • Switching costs, or the cost the buyer has to absorb to switch from one supplier to another.
• Access to distribution channels. New entrants have to establish their distribution in a market with established distribution channels to secure a space for their product. • Cost disadvantages independent of scale, whereby established companies already have product technology, access to raw materials, favorable sites, advantages in the form of government subsidies, and experience. Apple charges a premium on the products that are available to consumers however, based on the barriers listed above, this price premium does not equate to a high threat level of new entrants to Apple.
When the iPad 2 was launched in March 2011, it was estimated that 500,000 units were sold on the first day of availability. There have been many tablet competitors that came to market that year and Apple still retained almost 73% of the market share (Olenick, 2011). Rivalry among Existing Competitors Rivalry among existing competitors is considered to be high when there is strong competition in the same market. The life cycle in the technology sector is short and there are new products that come out every year. Apple stays ahead of the competition by developing products that exceed the needs of their consumers.
The business strategy has kept them leaders in their sector for the past decade. Customer Developed Applications and the Five Forces Model Through its customer developed applications, better known as the App Store, Apple has addressed the three of the five forces of Porter's model. As of March 2012, there is approximately 585,000 available applications in the App Store with more than 25 billion downloads. In comparison Google Play, which offers applications for the Android operating system, has 15 billion downloads and a total of 500,000 applications.
According to an article dated December 2011 in the NY Times online, there are more phones being sold with the Android operating system than Apple's iPhone. Android offers its operating system for free and a host of manufacturers such as Samsung, HTC, Motorola, LG, and Sony Ericsson are currently using it. Apple has fought these threats with lawsuits. Apple and Samsung have engaged in 21 different lawsuits in at least 10 different countries. Apple sued Samsung in the U. S. claiming patent violations and unlawfully copying design and feel of its iPhone and iPad.
In turn Samsung has sued Apple in South Korea, Japan and, Germany for wireless patent violations. Apple has won temporary injunctions forbidding the sale of the Galaxy 10. 1 tab in Germany and Australia (O'Rourke, 2011). Porter generic strategies are ways to gain a competitive advantage. They can be broken down into broad cost leadership, broad differentiation and focused strategy. Broad strategies are designed to reach a large market and focused are designed to reach a smaller group through cost or differentiation. Apple's generic strategy suggests a broad differentiation strategy.
This strategy involves making your products or services distinctive and more appealing (Baltzan, 2012). The targeted consumer of is not price sensitive to the products or services of this generic strategy. To be successful in the differential strategy, the company needs to have good R&D and innovation, the ability to deliver high-quality products or services and a successful sales and marketing team that knows how to reach its market and effectively communicate the benefits of product or services over the competitors. Value Chain Analysis
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Value chain analysis is a tool that companies can use to identify competitive advantage. Competitive advantage is the trait or traits of a product or service that a buyer would place a greater value on over similar items from a competitor. The analysis can be broken down into three steps. The first step is activity analysis. This involves identifying the actions needed to deliver the product or service to the market. The second step is value analysis. At this step you must think about what needs to be done to add value for your buyer and the last step is evaluate and planning.
The third step requires you to evaluate whether or not the changes are worth it and then plan for action. Apple greatest strength in the value chain is its innovation. Apple products are ascetically appealing to the eye and their integration of service across all product lines helps them maintain a dominant market share. SWOT Analysis SWOT analysis is an excellent tool to use to identify strengths, weaknesses, opportunities and threats (www. mindtools. com). There are several questions that you should be able to answer when using this tool. • What advantages does your company have (strength)?
This Process Analysis Essay on "Apple Executive Analysis" was written and submitted by your fellow student. You are free to use it for research and reference purposes in order to write your own paper; however, you must cite it accordingly.
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Kudos to this new Adventure:) keep posting Desparado dear!
hello thr kaalicharan…. well it would be tough time for you now as i too have entered the arena.
Great Calvy…I have held the Canine many times and everytime I do this She comes to me with more Enthusiasm & love.