Refractory lympho-epithelial carcinoma of the nasopharynx: a case report illustrating a protracted clinical course

Nasopharyngeal carcinoma is an uncommon cancer in North America. Its clinical course is typified by locally advanced disease at diagnosis and has a high propensity for both regional and distant spread. It is, therefore, typically treated with a combination of radiation and chemotherapy. This report describes our 10-year clinical and radiological findings in a 48-year-old Vietnamese male patient with locally-advanced T4N1M0 lympho-epithelial carcinoma of the nasopharynx. Despite a long remission period after his initial course of aggressive chemoradiation, his tumor recurred locally after 4 years. Thereafter, throughout a period of over 10 years, he has been treated with multiple courses of re-irradiation and three different trials of chemotherapy. He was ultimately provided with over 30 months of progression-free tumor control with the epidermal growth factor receptor (EGFR)-inhibitor cetuximab. This case illustrates the commonly protracted course of this disease and its responsiveness to multiple treatment modalities

Cross-over study of novice intubators performing endotracheal intubation in an upright versus supine position

There are a number of potential physical advantages to performing orotracheal intubation in an upright position. The objective of this study was to measure the success of intubation of a simulated patient in an upright versus supine position by novice intubators after brief training. This was a cross-over design study in which learners (medical students, physician assistant students, and paramedic students) intubated mannequins in both a supine (head of the bed at 0°) and upright (head of bed elevated at 45°) position. The primary outcome of interest was successful intubation of the trachea. Secondary outcomes included log time to intubation, Cormack–Lehane view obtained, Percent of Glottic Opening score, provider assessment of difficulty, and overall provider satisfaction with the position. There were a total of 126 participants: 34 medical students, 84 physician assistant students, and 8 paramedic students. Successful tracheal intubation was achieved in 114 supine attempts (90.5 %) and 123 upright attempts (97.6 %; P = 0.283). Upright positioning was associated with significantly faster log time to intubation, higher likelihood of achieving Grade I Cormack–Lehane view, higher Percent of Glottic Opening score, lower perceived difficulty, and higher provider satisfaction. A subset of 74 participants had no previous intubation training or experience. For these providers, there was a non-significant trend toward improved intubation success with upright positioning vs supine positioning (98.6 % vs. 87.8 %, P = 0.283). For all secondary outcomes in this group, upright positioning significantly outperformed supine positioning

Feasibility of upright patient positioning and intubation success rates at two academic emergency departments

Objectives Endotracheal intubation is most commonly taught and performed in the supine position. Recent literature suggests that elevating the patient's head to a more upright position may decrease peri-intubation complications. However, there is little data on the feasibility of upright intubation in the emergency department. The goal of this study was to measure the success rate of emergency medicine residents performing intubation in supine and non-supine, including upright positions. Methods This was a prospective observational study. Residents performing intubation recorded the angle of the head of the bed. The number of attempts required for successful intubation was recorded by faculty and espiratory therapists. The primary outcome of first past success was calculated with respect to three groups: 0–10° (supine), 11–44° (inclined), and ≥ 45° (upright); first past success was also analyzed in 5 degree angle increments. Results A total of 231 intubations performed by 58 residents were analyzed. First pass success was 65.8% for the supine group, 77.9% for the inclined group, and 85.6% for the upright group (p = 0.024). For every 5 degree increase in angle, there was increased likelihood of first pass success (AOR = 1.11; 95% CI = 1.01–1.22, p = 0.043). Conclusions In our study emergency medicine residents had a high rate of success intubating in the upright position. While this does not demonstrate causation, it correlates with recent literature challenging the traditional supine approach to intubation and indicates that further investigation into optimal positioning during emergency department intubations is warranted

MARCKS phosphorylation is modulated by a peptide mimetic of MARCKS effector domain leading to increased radiation sensitivity in lung cancer cell lines

Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hyperactivation is a known mechanism of tumorigenesis. The phosphorylation status of the plasma membrane-associated protein myristoylated alanine rich C-kinase substrate (MARCKS) effector domain (ED) was previously established as being important in the sensitivity of lung cancer to radiation. Specifically, when MARCKS ED was in a non-phosphorylated state, lung cancer cells were more susceptible to ionizing radiation and experienced prolonged double-strand DNA breaks. Additional studies demonstrated that the phosphorylation status of MARCKS ED is important for gene expression and in vivo tumor growth. The present study used a peptide mimetic of MARCKS ED as a therapeutic intervention to modulate MARCKS phosphorylation. Culturing A549, H1792 and H1975 lung cancer cell lines with the MARCKS ED peptide led to reduced levels of phosphorylated MARCKS and phosphorylated Akt serine/threonine kinase 1. Further investigation demonstrated that the peptide therapy was able to reduce lung cancer cell proliferation and increase radiation sensitivity. In addition, the MARCKS peptide therapy was able to prolong double-strand DNA breaks following ionizing radiation exposure. The results of the present study demonstrate that a peptide mimetic of MARCKS ED is able to modulate MARCKS phosphorylation, leading to an increase in sensitivity to radiation. Keywords: lung cancer, myristoylated alanine rich C-kinase substrate, radiation sensitivity, effector domain, peptide mimeti

Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology

Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or “xenolines”)

Targeting the effector domain of the myristoylated alanine rich C-kinase substrate enhances lung cancer radiation sensitivity

Lung cancer is the leading cause of cancer related deaths. Common molecular drivers of lung cancer are mutations in receptor tyrosine kinases (RTKs) leading to activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pro-growth, pro-survival signaling pathways. Myristoylated alanine rich C-kinase substrate (MARCKS) is a protein that has the ability to mitigate this signaling cascade by sequestering the target of PI3K, phosphatidylinositol (4,5)-bisphosphate (PIP2). As such, MARCKS has been implicated as a tumor suppressor, though there is some evidence that MARCKS may be tumor promoting in certain cancer types. Since the MARCKS function depends on its phosphorylation status, which impacts its subcellular location, MARCKS role in cancer may depend highly on the signaling context. Currently, the importance of MARCKS in lung cancer biology is limited. Thus, we investigated MARCKS in both clinical specimens and cell culture models. Immunohistochemistry scoring of MARCKS protein expression in a diverse lung tumor tissue array revealed that the majority of squamous cell carcinomas stained positive for MARCKS while other histologies, such as adenocarcinomas, had lower levels. To study the importance of MARCKS in lung cancer biology, we used inducible overexpression of wild-type (WT) and non-phosphorylatable (NP)-MARCKS in A549 lung cancer cells that had a low level of endogenous MARCKS. We found that NP-MARCKS expression, but not WT-MARCKS, enhanced the radiosensitivity of A549 cells in part by inhibiting DNA repair as evidenced by prolonged radiation-induced DNA double strand breaks. We confirmed the importance of MARCKS phosphorylation status by treating several lung cancer cell lines with a peptide mimetic of the phosphorylation domain, the effector domain (ED), which effectively attenuated cell growth as measured by cell index. Thus, the MARCKS ED appears to be an important target for lung cancer therapeutic development

MARCKS regulates growth and radiation sensitivity and is a novel prognostic factor for glioma

Purpose This study assessed whether Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) can regulate glioblastoma (GBM) growth, radiation sensitivity and clinical outcome. Experimental Design MARCKS protein levels were analyzed in five GBM explant cell lines and eight patient-derived xenograft tumors by immunoblot, and these levels were correlated to proliferation rates and intracranial growth rates, respectively. Manipulation of MARCKS protein levels was assessed by lentiviral-mediated shRNA knockdown in the U251 cell line and MARCKS over-expression in the U87 cell line. The effect of manipulation of MARCKS on proliferation, radiation sensitivity and senescence was assessed. MARCKS gene expression was correlated with survival outcomes in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) Database and The Cancer Genome Atlas (TCGA). Results MARCKS protein expression was inversely correlated with GBM proliferation and intracranial xenograft growth rates. Genetic silencing of MARCKS promoted GBM proliferation and radiation resistance, while MARCKS overexpression greatly reduced GBM growth potential and induced senescence. We found MARCKS gene expression to be directly correlated with survival in both the REMBRANDT and TCGA databases. Specifically, patients with high MARCKS expressing tumors of the Proneural molecular subtype had significantly increased survival rates. This effect was most pronounced in tumors with unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoters, a traditionally poor prognostic factor. Conclusions MARCKS levels impact GBM growth and radiation sensitivity. High MARCKS expressing GBM tumors are associated with improved survival, particularly with unmethylated MGMT promoters. These findings suggest the use of MARCKS as a novel target and biomarker for prognosis in the Proneural subtype of GBM

The crossroads of evidence-based medicine and health policy: implications for urology

As healthcare spending in the United States continues to rise at an unsustainable rate, recent policy decisions introduced at the national level will rely on precepts of evidence-based medicine to promote the determination, dissemination, and delivery of “best practices” or quality care while simultaneously reducing cost. We discuss the influence of evidence-based medicine on policy and, in turn, the impact of policy on the developing clinical evidence base with an eye to the potential effects of these relationships on the practice and provision of urologic care

Implementation of U.K. Earth system models for CMIP6

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere-land-ocean-sea ice model HadGEM3-GC3.1 and the Earth system model UKESM1 which adds a carbon-nitrogen cycle and atmospheric chemistry to HadGEM3-GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions.We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3-GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation.We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility