LKB1 and AMPK and the cancer-metabolism link - ten years after

The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it. In September 2003, our groups published a joint paper [1] in Journal of Biology (now BMC Biology) that identified the long-sought and elusive upstream kinase acting on AMP-activated protein kinase (AMPK) as a complex containing LKB1, a known tumor suppressor. Similar findings were reported at about the same time by David Carling and Marian Carlson [2] and by Reuben Shaw and Lew Cantley [3]; at the time of writing these three papers have received between them a total of over 2,000 citations. These findings provided a direct link between a protein kinase, AMPK, which at the time was mainly associated with regulation of metabolism, and another protein kinase, LKB1, which was known from genetic studies to be a tumor suppressor. While the idea that cancer is in part a metabolic disorder (first suggested by Warburg in the 1920s [4]) is well recognized today [5], this was not the case in 2003, and our paper perhaps contributed towards its renaissance. The aim of this short review is to recall how we made the original finding, and to discuss some of the directions that these findings have taken the field in the ensuing ten years

Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia

Abstract Background A relationship between corneal arcus and atherosclerosis has long been suspected but is controversial. The homozygous familial hypercholesterolemia patients in this study present a unique opportunity to assess this issue. They have both advanced atherosclerosis and corneal arcus. Methods This is a cross-sectional study of 17 patients homozygous for familial hypercholesterolemia presenting to the Clinical Center of the National Institutes of Health. Plasma lipoproteins, circumferential extent of arcus, thoracic aorta and coronary calcific atherosclerosis score, and Achilles tendon width were measured at the National Institutes of Health. Results Patients with corneal arcus had higher scores for calcific atherosclerosis (mean 2865 compared to 412), cholesterol-year score (mean 11830 mg-yr/dl compared to 5707 mg-yr/dl), and Achilles tendon width (mean 2.54 cm compared to 1.41 cm) than those without. Corneal arcus and Achilles tendon width were strongly correlated and predictive of each other. Although corneal arcus was correlated with calcific atherosclerosis (r = 0.67; p = 0.004), it was not as highly correlated as was the Achilles tendon width (r = 0.855; p Conclusion Corneal arcus reflects widespread tissue lipid deposition and is correlated with both calcific atherosclerosis and xanthomatosis in these patients. Patients with more severe arcus tend to have more severe calcific atherosclerosis. Corneal arcus is not as good an indicator of calcific atherosclerosis as Achilles tendon thickness, but its presence suggests increased atherosclerosis in these hypercholesterolemic patients.</p

AKT1 Loss Correlates with Episomal HPV16 in Vulval Intraepithelial Neoplasia

Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma–HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers. Mucosal HPV types can increase AKT phosphorylation and activity whereas cutaneous HPV types down-regulate AKT1 expression, probably to weaken the cornified envelope to promote viral release. We assessed the presence of mucosal and cutaneous HPV in vulval malignancy and its relationship to AKT1 expression in order to establish the corresponding HPV and AKT1 profile of normal vulval skin, vulval intraepithelial neoplasia (VIN) and vulval squamous cell carcinoma (vSCC). We show that HPV16 is the principle HPV type present in VIN, there were few detectable beta types present and AKT1 loss was not associated with the presence of these cutaneous HPV. We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis. AKT1 loss in our VIN cohort correlated with presence of high copy number, episomal HPV16. Maintained AKT1 expression correlated with low copy number, an increased frequency of integration and increased HPV16E7 expression, a finding we replicated in another untyped cohort of vSCC. Since expression of E7 reflects tumour progression, these findings suggest that AKT1 loss associated with episomal HPV16 may have positive prognostic implications in vulval malignancy

Interactions between Predation and Resources Shape Zooplankton Population Dynamics

Identifying the relative importance of predation and resources in population dynamics has a long tradition in ecology, while interactions between them have been studied less intensively. In order to disentangle the effects of predation by juvenile fish, algal resource availability and their interactive effects on zooplankton population dynamics, we conducted an enclosure experiment where zooplankton were exposed to a gradient of predation of roach (Rutilus rutilus) at different algal concentrations. We show that zooplankton populations collapse under high predation pressure irrespective of resource availability, confirming that juvenile fish are able to severely reduce zooplankton prey when occurring in high densities. At lower predation pressure, however, the effect of predation depended on algal resource availability since high algal resource supply buffered against predation. Hence, we suggest that interactions between mass-hatching of fish, and the strong fluctuations in algal resources in spring have the potential to regulate zooplankton population dynamics. In a broader perspective, increasing spring temperatures due to global warming will most likely affect the timing of these processes and have consequences for the spring and summer zooplankton dynamics

COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), a global--clinical evaluations, serum biomarkers, genetic studies and neuroimaging--prospective, multicenter, non-interventional, long-term study on Parkinson's disease progressio

Background: Parkinson?s disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers. Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study protocol of COPPADIS-2015 (COhort of Patients with PArkinson?s DIsease in Spain, 2015), an integral PD project based on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3) Biomarkers; 4) Disease progression.Methods/design: Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives. Study population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson?s Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson?s Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson?s disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-?, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022. Funding: Public/Private. Discussion: COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers

AMPK in Pathogens

During host–pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host–pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.CIHR -Canadian Institutes of Health Researc

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac