Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis

SummaryDespite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC

Positive Signature-Tagged Mutagenesis in Pseudomonas aeruginosa: Tracking Patho-Adaptive Mutations Promoting Airways Chronic Infection

The opportunistic pathogen Pseudomonas aeruginosa can establish life-long chronic infections in the airways of cystic fibrosis (CF) patients. Persistent lifestyle is established with P. aeruginosa patho-adaptive variants, which are clonal with the initially-acquired strains. Several reports indicated that P. aeruginosa adapts by loss-of-function mutations which enhance fitness in CF airways and sustain its clonal expansion during chronic infection. To validate this model of P. aeruginosa adaptation to CF airways and to identify novel genes involved in this microevolution, we designed a novel approach of positive-selection screening by PCR-based signature-tagged mutagenesis (Pos-STM) in a murine model of chronic airways infection. A systematic positive-selection scheme using sequential rounds of in vivo screenings for bacterial maintenance, as opposed to elimination, generated a list of genes whose inactivation increased the colonization and persistence in chronic airways infection. The phenotypes associated to these Pos-STM mutations reflect alterations in diverse aspects of P. aeruginosa biology which include lack of swimming and twitching motility, lack of production of the virulence factors such as pyocyanin, biofilm formation, and metabolic functions. In addition, Pos-STM mutants showed altered invasion and stimulation of immune response when tested in human respiratory epithelial cells, indicating that P. aeruginosa is prone to revise the interaction with its host during persistent lifestyle. Finally, sequence analysis of Pos-STM genes in longitudinally P. aeruginosa isolates from CF patients identified signs of patho-adaptive mutations within the genome. This novel Pos-STM approach identified bacterial functions that can have important clinical implications for the persistent lifestyle and disease progression of the airway chronic infection

Diagnosis of peripheral pulmonary carcinoid tumor using endobronchial ultrasound

A 51-year-old woman with severe asthma underwent bronchoscopy and endobronchial ultrasound (EBUS) for investigation of a 15-mm peripheral lung nodule. Histology demonstrated a typical carcinoid tumor. Pulmonary location is the second commonest site for carcinoid tumors. Diagnosis of peripheral carcinoid tumor of the lung is difficult due to its small size, poor accuracy of cytologic diagnosis, and low sensitivity of positron emission tomography in detecting it. EBUS has a high diagnostic yield and a low complication rate in the evaluation of small solitary pulmonary nodules. The ultrasound appearance of carcinoid tumors is identical to that of lung carcinomas. Prompt diagnosis of carcinoid tumor is desirable as regional lymph node metastasis is seen in 10% of patients and is associated with a reduced 5-year survival. We feel that, where possible, all patients presenting with solitary pulmonary nodules should be investigated initially using EBUS due to its high diagnostic rate and the very low incidence of adverse events

New practice, good practice The role of reflection in adult literacies tutor training

Includes bibliographical referencesSIGLEAvailable from British Library Document Supply Centre- DSC:7736. 665(24) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Temporal trends in stroke incidence in South Asian, Chinese and white patients: A population based analysis.

BACKGROUND:Little is known about potential ethnic differences in stroke incidence. We compared incidence and time trends of ischemic stroke and primary intracerebral hemorrhage in South Asian, Chinese and white persons in a population-based study. METHODS:Population based census and administrative data analysis in the provinces of Ontario and British Columbia, Canada using validated ICD 9/ICD 10 coding for acute ischemic and hemorrhagic stroke (1997-2010). RESULTS:There were 3290 South Asians, 4444 Chinese and 160944 white patients with acute ischemic stroke and 535 South Asian, 1376 Chinese and 21842 white patients with intracerebral hemorrhage. South Asians were younger than whites at onset of stroke (70 vs. 74 years for ischemic and 67 vs. 71 years for hemorrhagic stroke). Age and sex adjusted ischemic stroke incidence in 2010 was 43% lower in Chinese and 63% lower in South Asian than in White patients. Age and sex adjusted intracerebral hemorrhage incidence was 18% higher in Chinese patients, and 66% lower in South Asian relative to white patients. Stroke incidence declined in all ethnic groups (relative reduction 69% in South Asians, 25% in Chinese, and 34% in white patients for ischemic stroke and for intracerebral hemorrhage, 79% for South Asians, 51% for Chinese and 30% in white patients). CONCLUSION:Although stroke rates declined across all ethnic groups, these rates differed significantly by ethnicity. Further study is needed to understand mechanisms underlying the higher ischemic stroke incidence in white patients and intracerebral hemorrhage in Chinese patients

Risk factors, quality of care and prognosis in South Asian, East Asian and White patients with stroke

Background: Stroke has emerged as a significant and escalating health problem for Asian populations. We compared risk factors, quality of care and risk of death or recurrent stroke in South Asian, East Asian and White patients with acute ischemic and hemorrhagic stroke. Methods Retrospective analysis was performed on consecutive patients with ischemic stroke or intracerebral hemorrhage admitted to 12 stroke centers in Ontario, Canada (July 2003-March 2008) and included in the Registry of the Canadian Stroke Network database. The database was linked to population-based administrative databases to determine one-year risk of death or recurrent stroke. Results The study included 253 South Asian, 513 East Asian and 8231 White patients. East Asian patients were more likely to present with intracerebral hemorrhage (30%) compared to South Asian (17%) or White patients (15%) (p2 hours for more than two thirds of patients in all ethnic groups. Processes of stroke care, including thrombolysis, diagnostic imaging, antithrombotic medications, and rehabilitation services were similar among ethnic groups. Risk of death or recurrent stroke at one year after ischemic stroke was similar for patients who were White (27.6%), East Asian (24.7%, aHR 0.97, 95% CI 0.78-1.21 vs. White), or South Asian (21.9%, aHR 0.91, 95% CI 0.67-1.24 vs. White). Although risk of death or recurrent stroke at one year after intracerebral hemorrhage was higher in East Asian (35.5%) and White patients (47.9%) compared to South Asian patients (30.2%) (p=0.002), these differences disappeared after adjustment for age, sex, stroke severity and comorbid conditions (aHR 0.89 [0.67-1.19] for East Asian vs White and 0.99 [0.54-1.81] for South Asian vs. White). Conclusion After stratification by stroke type, stroke care and outcomes are similar across ethnic groups in Ontario. Enhanced health promotion is needed to reduce delays to hospital for all ethnic groups.Medicine, Department ofMedicine, Faculty ofNon UBCReviewedFacult

Risk factors, quality of care and prognosis in South Asian, East Asian and White patients with stroke

Abstract Background Stroke has emerged as a significant and escalating health problem for Asian populations. We compared risk factors, quality of care and risk of death or recurrent stroke in South Asian, East Asian and White patients with acute ischemic and hemorrhagic stroke. Methods Retrospective analysis was performed on consecutive patients with ischemic stroke or intracerebral hemorrhage admitted to 12 stroke centers in Ontario, Canada (July 2003-March 2008) and included in the Registry of the Canadian Stroke Network database. The database was linked to population-based administrative databases to determine one-year risk of death or recurrent stroke. Results The study included 253 South Asian, 513 East Asian and 8231 White patients. East Asian patients were more likely to present with intracerebral hemorrhage (30%) compared to South Asian (17%) or White patients (15%) (p2 hours for more than two thirds of patients in all ethnic groups. Processes of stroke care, including thrombolysis, diagnostic imaging, antithrombotic medications, and rehabilitation services were similar among ethnic groups. Risk of death or recurrent stroke at one year after ischemic stroke was similar for patients who were White (27.6%), East Asian (24.7%, aHR 0.97, 95% CI 0.78-1.21 vs. White), or South Asian (21.9%, aHR 0.91, 95% CI 0.67-1.24 vs. White). Although risk of death or recurrent stroke at one year after intracerebral hemorrhage was higher in East Asian (35.5%) and White patients (47.9%) compared to South Asian patients (30.2%) (p=0.002), these differences disappeared after adjustment for age, sex, stroke severity and comorbid conditions (aHR 0.89 [0.67-1.19] for East Asian vs White and 0.99 [0.54-1.81] for South Asian vs. White). Conclusion After stratification by stroke type, stroke care and outcomes are similar across ethnic groups in Ontario. Enhanced health promotion is needed to reduce delays to hospital for all ethnic groups

Baseline characteristics by ethnicity.

<p>Baseline characteristics by ethnicity.</p

Age and sex standardized incidence of ischemic stroke per 100,000 persons by ethnic group, 1998 to 2010.

<p>Age and sex standardized incidence of ischemic stroke per 100,000 persons by ethnic group, 1998 to 2010.</p