Atlas of Science

Tag: head

  • Oncogenic role of CircPVT1 in head and neck squamous cell carcinoma

    Oncogenic role of CircPVT1 in head and neck squamous cell carcinoma

    Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that have recently shown to behave as gene regulators in eukaryotic cells, extending our previous knowledge regarding the diversity and complexity of the transcriptome. Nowadays, circRNAs have become an important research subject, attracting interest from different areas including the field of cancer research. CircRNAs can regulate alternative splicing, sequester RNA-binding proteins and ribonucleoprotein complexes. They can be translated and bind in trans to other RNA sequences. CircRNAs can also act as microRNA (miRNA) sponge, binding the miRNAs and consequently repressing their function. The miRNA sponge activity seems to be one of the most favourite mechanisms in cancer.

    Fig. 1. A. circPVT1 expression analysis in tumoral samples matched with their normal counterparts.
    B. circPVT1 expression analysis in mut-p53 compared to wild-type samples. (T, tumoral; N, normal; wt, wild type; mut, p53 mutation; meanNorm, mean Normalizers) [modified from Verduci L, et al. Genome Biol. (2017)]
    In our work, we explored the role of circPVT1 in the oncogenic context of Head and Neck Squamous Cell Carcinoma (HNSCC). HNSCC is the sixth leading cancer by incidence worldwide and the eighth most common cause of cancer death.

    We started with a bioinformatics-based approach using the HNSCC cancer data set provided by The Cancer Genome Atlas (TCGA). We found that circPVT1 was up-regulated in tumors with TP53 mutations compared to non-tumoral samples. TP53 gene missense mutations produce full-length mutant p53 proteins, which are abundantly present in cancer cells, and frequently gain oncogenic activities. We recently showed that mutant p53 protein is able to interact with the transcriptional co-factor YAP (Yes-Associated Protein) that in turn enhances the expression of the pro-proliferative genes regulated by mutant-p53. We found circPVT1 up-regulated in tumors carrying mut-p53 proteins in comparison to non-tumoral samples also using a molecular approach where we determined the circPVT1 expression by real time PCR using our home collection of HNSCC samples (Fig. 1). Notably, we found that high circPVT1 levels associated with poorer overall survival of HNSCC patients.

    Mechanistically, we document a molecular scenario in which the circPVT1 expression is transcriptionally enhanced by the mut-p53/YAP/TEAD complex and by circPVT1 itself through YAP binding (Fig. 2). YAP acts as an effector of the Hippo pathway in cancer and its biological function is mainly mediated by the TEAD transcription factors. We founds that circPVT1 behaved like an oncogene modulating the expression of the tumor suppressor miR-497-5p, a microRNA associated with mutant p53, and the expression of genes involved in cell proliferation such as aurka, mki67 and bub1.

    Fig. 2. Schematic model of the oncogenic role of circPVT1 in tumor cells [modified from Verduci L, et al. Genome Biol. (2017)].
    Based on their high stability, high abundance in body fluids and high conservation among the species, circRNAs are promising biomarkers and potential therapeutic targets. Our study describes the oncogenic function of circPVT1 and it might hold the potential to design new diagnostic and therapeutic strategies in HNSCC.

    Lorena Verduci, Giovanni Blandino
    Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy

    Publication

    The oncogenic role of circPVT1 in head and neck squamous cell carcinoma is mediated through the mutant p53/YAP/TEAD transcription-competent complex.
    Verduci L, Ferraiuolo M, Sacconi A, Ganci F, Vitale J, Colombo T, Paci P, Strano S, Macino G, Rajewsky N, Blandino G
    Genome Biol. 2017 Dec 20

  • Head in the trough

    Head in the trough

    A healthy and alert clinician is safer and more effective. It has long been known that doctors and surgeons work long and demanding hours with changing shifts, in an environment where the stakes are high. The risk of patient death from medical error is at around 1 per day in the U.K. and this does not account for medical injury from error.

    We reviewed the dangers of missing meals and not having enough fluid. The aviation industry and military provide copious information about the dangers of missing meals and underhydration. However, there is little research relating to medical environments, in spite of this being an area where we would hope and expect those working in it to be as safe and efficient as possible. Our own (unpublished) surveys have shown that only 25% of clinicians eat breakfast and 50% leave the house for work having not even had a drink. This deficit is not then compensated whilst at work for a number of habitual, cultural and practical reasons.

    There is a “stiff upper lip” and “get on with it” culture in medicine and a perception of weakness or inadequacy for wanting to have regular meals and fluid. In spite of the advice that medics give their patients regarding food and drink, medics do not often enough abide by their own advice or knowledge, either willingly or due to work demand circumstances.

    Work establishments do little to support a culture of self-care in these areas; clinicians are not encouraged to take breaks by senior staff or management and accessibility to food and drink is often poor at the time of need.

    Whilst there is an emerging trend that recognises the importance of Human Factors for clinicians and their patients, it is clear that we are a long way from providing the right cultural and practical work environments for clinicians, necessary for them to be optimally healthy and efficient.

    When researching the effects upon performance, mood, illness, safety and effectiveness, it is not surprising that all these areas suffer when someone isn’t properly “fed and watered”. What was surprising however is the degree to which they are affected and how quickly the deleterious effects can emerge.

    Water comprises over 60% of body mass, being the most abundant component of the body. Only a 2% bodyweight reduction in water leads to headaches, impatience, sleepiness and apathy. The body’s core temperature is raised by up to 0.2C for each 1% of bodyweight water loss. Individual fluid intake varies greatly and is linked to activity and bodyweight. Environmental effects like temperature also alter requirements.

    Missing meals and hunger have been shown to lead to poor communication, bad decision making, worse short-term memory and reduced cognitive function. Moreover, missing meals has been proven to be an ineffective approach to weight loss, as people tend to over eat later and gain more weight.

    Breakfast is a particularly important meal and missing it is linked with reduced learning ability and memory.

    The effect of adequate hydration and nutrition on performance in healthcare staff is rarely discussed or publicised. Health Trusts should be promoting and facilitating their staff to drink and eat regularly and providing adequate provision for this. With regular breaks introduced as part of the new junior doctor’s contract, surely it is time for all healthcare professionals to recognise the importance of looking after themselves at work and recognise that adequate hydration and dietary intake is essential.

    D. Parry 1, R. Oeppen 2, P. Brennan 3
    1King’s College London, Hodgkin Building, London, SE1 1UH, United Kingdom
    2University Hospital Southampton, Southanpton, SO16 6YD, United Kingdom
    3Queen Alexandra Hospital, Portsmouth, PO6 3LY, United Kingdom

    Publication

    Impact of hydration and nutrition on personal performance in the clinical workplace.
    Parry D, Oeppen RS, Gass H, Brennan PA
    Br J Oral Maxillofac Surg. 2017 Dec

  • Combining radiation with a PI3K/MTOR inhibitor

    Combining radiation with a PI3K/MTOR inhibitor

    Patients with HPV-negative head and neck cancer (HNSCC) carry a poor prognosis despite optimal treatment with chemoradiation, with a 5 year survival of less than 50%. The future for this disease must lie in further escalation of therapy which represents a difficult task given the fact that the current standard treatment of radiation and cisplatin already approaches the limit of tolerance. The emergence of a wide array of molecularly targeted agents over the last decade with the unique capacity of modulating cancer-specific cellular signaling and response to chemoradiation has garnered significant enthusiasm in the radiation oncology community based on the potential of these compounds to serve as radiation sensitizers. The Cancer Genome Atlas (TCGA) has uncovered a series of genes with common mutations in a large cohort of HNSCC patient samples. From these studies, common actionable mutations are present in HNSCC. One of these is PI3KCA which is a component of the PI3K/AKT/MTOR/PTEN signaling pathway involved in regulation of cell survival, growth, proliferation, metabolism and motility and an attractive drug target in cancer. The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (MTOR) signaling pathways have been found to have an important role in the pathogenesis of HNSCC  and there is evidence PI3K/MTOR antagonists are active against head and neck cancer cells. In this study we investigated whether a molecular targeted agent (PF-04691502) active against two components of the PI3K/AKT/MTOR survival pathway could enhance the effect of radiation treatment in two mouse xenograft models (UT-SCC-14 and UT-SCC-15) of HNSCC.

    Fig. 1. The effect of PF-04691502 on tumor growth, in combination with radiation, in UT-SCC-14 (A) and UT-SCC-15 (B) xenografts. The data were normalized to the individual tumor volumes at the start of treatment.

    The key findings from the study was that the drug was effective at inhibiting the growth of both cell lines in vitro but had no effect on growth of the cell lines as tumor models. The drug resulted in increased radiosensitivity of the UT-SCC-14 cells but not the Ut-SCC-15 cell line. This was mirrored in vivo where the drug was very effective when combined with radiation in UT-SCC-14 (Fig. 1A) but this added effect was not seen in UT-SCC-15 (Fig. 1B). Interestingly, the drug alone was able to inhibit levels of phosphorylated proteins in PI3K/AKT/MTOR pathway in both tumor models but when combined with radiation, the inhibition was reduced in the UT-SCC-15 tumors. This highlights the complexity of combining radiation with pathway inhibiting drugs as radiation is known to cause an upregulation of these pathways as a cell survival mechanism. In addition we studied the mutation status of some key genes and observed that UT-SCC-15 harbors substantially more variants in PI3K/AKT/MTOR-associated genes as well as mutations in in HRAS and KRAS and has a higher mutational burden than UT-SCC-14.

    The data in this study showed that although one HNSCC xenograft model showed significant radiosensitization resulting from the combination with PF-04691502 another xenograft did not. The resistant model was a later-stage cancer and may have become resistant to the targeted therapy due to the more complex molecular dependencies that had developed which led to the activation of other survival pathways. It is clear that not every group of head and neck cancer patients will respond the same to therapy. Much research is still required to understand the contribution of mutations and deregulated pathways in HNSCC and to determine the effects of inhibitors that target molecules in these pathways. In some HNSCCs, a single targeted agent may be sufficient but others may require treatments that target several survival pathways.

    George Wilson
    Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, USA

     

    Publication

    Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.
    Tonlaar N, Galoforo S, Thibodeau BJ, Ahmed S, Wilson TG, Yumpo Cardenas P, Marples B, Wilson GD
    Radiother Oncol. 2017 Sep

  • Hospital readmission after head and neck microvascular reconstruction

    Unplanned readmissions are associated with decreased healthcare quality and increased costs. This nationwide study examines causes for unplanned readmission among head and neck cancer patients undergoing immediate microsurgical reconstruction.

    Patients undergoing head and neck tumor resection with microsurgical reconstruction were identified in the 2011-2014 National Surgical Quality Improvement Program database. Clinical characteristics and complications were compared among patients who did and did not undergo unplanned readmission. Univariate and multivariate logistic regression analyses were performed.

    Database search revealed 1,063 patients, 94 (8.8%) of whom had unplanned readmissions. Readmitted patients had significantly higher ASA scores (14.9% vs.7.3% ASA class 4 patients; P = 0.03) and significantly higher rates of disseminated cancer (14.9% vs.7.1%; P = 0.01), laryngopharyngectomy (17.0% vs.6.9%; P = 0.0005), deep wound infection (22.3% vs.2.4%; P < 0.0001), wound dehiscence (19.1% vs.3.3%; P < 0.0001), and blood transfusion within 72 h of surgery (44.7% vs.32.6%; P = 0.02). Multivariate logistic regression revealed deep wound infection (OR = 8.65, P < 0.0001) and wound dehiscence (OR = 3.69, P = 0.0004) to be independent predictors of unplanned readmission.

    Deep wound infection and wound dehiscence were independent predictors of unplanned readmission among head and neck cancer patients undergoing immediate microsurgical reconstruction. Institutions should focus efforts on improving wound surveillance, outpatient strategies for wound care, and optimization of discharge planning for this complex patient population.

    Ravi K Garg 1, Aaron M Wieland 2, Gregory K Hartig 2, Samuel O Poore 1
    1Division of Plastic and Reconstructive Surgery, Department of Surgery,
    University of Wisconsin, Madison, Wisconsin, USA
    2Division of Otolaryngology-Head and Neck Surgery, Department of Surgery,
    University of Wisconsin, Madison, Wisconsin, USA

     

    Publication

    Risk factors for unplanned readmission following head and neck microvascular reconstruction: Results from the National Surgical Quality Improvement Program, 2011-2014.
    Garg RK, Wieland AM, Hartig GK, Poore SO
    Microsurgery. 2016 Sep 23

  • Why is radiation treatment more effective for cancers caused by HPV?

    Why is radiation treatment more effective for cancers caused by HPV?

    Human papilloma virus (HPV) is the most common sexually transmitted infection in the United States and can lead to cancers in the affected organ such as the cervix. In the last 15 years, the rise in prevalence of HPV has also been linked to cancers of the throat, in particular a region called the oropharynx which includes the tonsils and the base of tongue. Cancers in this area are often caused by alcohol and tobacco use but the recent epidemic of HPV has lead to a surge in cases of virally induced tumors of the oropharynx which if not treated appropriately can spread to lymph nodes or other organs in the body. HPV-related oropharynx cancer afflicts over 25,000 people each year.

    Three mechanisms that account for HPV radiosensitivity: DNA repair effects, enhanced immune response and increased oxygen levels.

    Fortunately, HPV-related oropharynx cancers respond extraordinarily well to radiation treatment, which is often given with chemotherapy to enhance its effect. The majority of HPV-related oropharynx cancers can be eliminated, effectively cured, with such treatment- a result that is much more difficult to achieve with cancers caused by tobacco and alcohol. There is something about HPV-related cancers that causes them to respond dramatically to radiation treatment, but the reason for this is not well understood. If we can identify the key to these tumor’s “radiosensitivity”, we may be able to tailor and personalize cancer treatment for these patients to a better degree and apply the lessons learned to more difficult to treat and deadly cancers. Some think that it may be because HPV-related tumors have higher levels of oxygen, which is an essential part of the chemical and physical reactions caused by radiation that lead to killing of cancer cells. It may also be that when HPV tumors are exposed to radiation, the immune system is somehow spurred into action to fight the virus-related cancer. In fact, cancers caused by other viruses, including the Epstein-Barr virus, also shrink rapidly when treated with radiation.

    However, we believe the central reason underlying why HPV induced tumors are so sensitive to radiation treatment lies in a process called DNA repair, which is critical to the cell’s ability to survive and divide. Radiation works to kill cancer cells primarily by causing damage to DNA in the cancer cell. While normal cells have developed processes over the course of evolution to repair certain amounts of such damage and continue to survive in the face of injury, cancer cells often have mutations or abnormalities that prevent them from repairing their DNA effectively- an Achilles heel that can be exploited with radiation treatment. We believe that HPV, in the process of infecting cells in the throat and transforming them into cancer cells, also prevents them from being able to reliably repair damage caused to DNA, including that caused by therapeutic radiation and chemotherapy. In this complicated interaction with the cell, the HPV virus hijacks the cell’s intrinsic DNA repair machinery for its own survival and as a result deprives the cell of necessary defenses to fend off lethal injury such as that caused by radiation. Components of DNA repair pathways are increasingly being recognized as targets for cancer therapies that are generating significant excitement. We envision that a better understanding of the intricacies of how DNA repair mechanisms are interrupted by HPV will lead to more effective cancer treatments for many patients.

    Jonathan E. Leeman, Nadeem Riaz, Nancy Lee
    Department of Radiation Oncology,
    Memorial Sloan Kettering Cancer Center, New York, NY, USA

     

    Publication

    Biological Features of Human Papillomavirus-related Head and Neck Cancers Contributing to Improved Response.
    Cleary C, Leeman JE, Higginson DS, Katabi N, Sherman E, Morris L, McBride S, Lee N, Riaz N
    Clin Oncol (R Coll Radiol). 2016 Jul

  • The real life of crab louse

    The real life of crab louse

    Pubic louse, also known as “crab” louse due to its form, is smaller than the head louse. It can lead to an infestation of the pubis (generally sexually transmitted), and sometimes of the eyelashes, or the body hair with severe itch. As its size is less than 2 mm, it is not easy to see these black dots between the hair.

    Fig. 1. A. Pubic louse. B. Pubic louse grasping hair.

    New medical devices, as dermoscopy (epiluminescence microscopy, 5 megapixels, magnification 250 x), permits to watch the louse (pictures) , including its inner body; its characteristics are: smaller than the head and body lice, round form, thick back pair of legs and large claws, grasping 2 hairs (one from each side of its body). Contrarily, head louse catch generally 1 hair.

    This so named “crab” louse, is closely related to the gorilla’s louse we could caught more than 3 million years ago, probably using the animal sleeping’s sites. Both belong to the same genus, phtirius (phtirus pubis and phtirus gorilla), when head and body lice are designated as pediculus (pediculus capitis and pediculus corporis).

    But the “crab-gorilla” louse colonization is perhaps not achieved. Indeed, the popularity of pubic hair removal could put this louse endangered. For this reason, it has no choice, disappear or evolve,  changing its usual home (the pubis), and colonizing other parts of the body, as the head.

    François Desruelles
    Private office, 20 avenue Malaussena, Nice, France
    Archet 2 hospital, Nice, France

     

    Publication

    A lousy diagnosis.
    Desruelles F.
    N Engl J Med. 2015 Dec