Squamous cell carcinoma arising from oral mucosal epithelium remains a lethal and deforming disease due to tumour invasion, oro‐facial destruction, cervical lymph node metastasis and ultimate ...blood‐borne dissemination. Worldwide, 300 000 new cases are seen each year, with a recent and significant rise in incidence affecting particularly the young. To rationalize perspectives on preventive strategies in oral cancer management, this study addresses a number of fundamental questions regarding carcinogenesis: proliferation—what epithelial cell changes precede tumour development? Position—why are certain oral sites so predisposed to cancer? Progression—why do some precursor lesions progress to invasive carcinoma and others do not? Prediction—how can we predict individual patient and/or lesion behaviour to prevent disease progression? By improving our understanding of oral carcinogenesis, can we thereby facilitate more effective primary, secondary and tertiary preventive strategies and ultimately reduce the global burden of oral squamous cell carcinoma (OSCC)?
The Bright Side of Being Blue Andrews, Paul W; Thomson, J. Anderson
Psychological review,
07/2009, Volume:
116, Issue:
3
Journal Article
Peer reviewed
Open access
Depression is the primary emotional condition for which help is sought. Depressed people often report persistent rumination, which involves analysis, and complex social problems in their lives. ...Analysis is often a useful approach for solving complex problems, but it requires slow, sustained processing, so disruption would interfere with problem solving. The analytical rumination hypothesis proposes that depression is an evolved response to complex problems, whose function is to minimize disruption and sustain analysis of those problems by (a) giving the triggering problem prioritized access to processing resources, (b) reducing the desire to engage in distracting activities (anhedonia), and (c) producing psychomotor changes that reduce exposure to distracting stimuli. As processing resources are limited, sustained analysis of the triggering problem reduces the ability to concentrate on other things. The hypothesis is supported by evidence from many levels-genes, neurotransmitters and their receptors, neurophysiology, neuroanatomy, neuroenergetics, pharmacology, cognition, behavior, and efficacy of treatments. In addition, the hypothesis provides explanations for puzzling findings in the depression literature, challenges the belief that serotonin transmission is low in depression, and has implications for treatment.
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Drug discovery, development and registration is an expensive and time-consuming process associated with a high failure rate Pessetto et al. (Mol Cancer Ther 12:1299–1309,
2013
), Woodcock and Woosley ...(Annu Rev Med 59:1–12,
2008
). Drug ‘repurposing’ is the identification of new therapeutic purposes for already approved drugs and is more affordable and achievable than novel drug discovery Pessetto et al. (Mol Cancer Ther 12:1299–1309,
2013
). Auranofin is a drug that is approved for the treatment of rheumatoid arthritis but is being investigated for potential therapeutic application in a number of other diseases including cancer, neurodegenerative disorders, HIV/AIDS, parasitic infections and bacterial infections Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029–2035,
2013
). The main mechanism of action of auranofin is through the inhibition of reduction/oxidation (redox) enzymes that are essential for maintaining intracellular levels of reactive oxygen species. Inhibition of these enzymes leads to cellular oxidative stress and intrinsic apoptosis Pessetto et al. (Mol Cancer Ther 12:1299–1309,
2013
), Fan et al. (Cell Death Dis 5:e1191,
2014
), Fiskus et al. (Cancer Res 74:2520–2532,
2014
), Marzano et al. (Free Radic Biol Med 42:872–881,
2007
). Drugs such as auranofin that have already been approved for human use Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029–2035,
2013
) can be brought into clinical use for other diseases relatively quickly and for a fraction of the cost of new drugs.
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated ...in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.
Although pre-revascularization ischaemia testing is recommended, the interaction between the extent of ischaemia and myocardial scar with performance of revascularization on patient survival is ...unclear.
We identified 13 969 patients who underwent adenosine or exercise stress SPECT myocardial perfusion scintigraphy (MPS). The percent myocardium ischaemic (%I) and fixed (%F) were calculated using 5 point/20-segment MPS scoring. Patients lost to follow-up (2.8%) were excluded leaving 13 555 patients 35% with history (Hx) of known coronary artery disease (CAD), 65% exercise stress, 61% male, age 66 ± 12. Follow-up was performed at 12-18 months for early revascularization and at >7 years for all-cause death (ACD) (mean follow-up 8.7 ± 3.3 years). All-cause death was modelled using Cox proportional hazards modelling adjusting for logistic-based propensity scores, MPS, revascularization, and baseline characteristics. During FU, 3893 ACD (29%, 3.3%/year) and 1226 early revascularizations (9.0%) occurred. After risk-adjustment, a three-way interaction was present between %I, early revascularization, and HxCAD, such that %I identified a survival benefit with early revascularization in patients without prior myocardial infarction (MI), whereas no such benefit was present in patients with prior MI (overall model χ(2)= 3932, P < 0.001; interaction P < 0.021). Further modelling revealed that after excluding patients with scar >10% total myocardium, %I identified a survival benefit in all patients.
In this large observational series with long-term follow-up, patients with significant ischaemia and without extensive scar were likely to realize a survival benefit from early revascularization. In contrast, the survival of patients with minimal ischaemia was superior with medical therapy without early revascularization.
A kilometers‐thick sedimentary sequence in Gale Crater exhibits stratigraphic changes in lithology that are consistent with transitions in aqueous and climatic conditions purported to be global in ...scale. The sequence is divided into two formations, where the Lower formation exhibits a net transition in mineralogy from clay/sulfate to sulfate/oxide assemblages and is separated from the overlying Upper formation by an erosional unconformity. Superposition and crater counts suggest strata in the Lower formation lie along the Noachian‐Hesperian time‐stratigraphic boundary, whereas beds in the Upper formation, which lack signatures indicative of clay minerals or sulfates, are thinner, more regularly spaced, and clearly younger. The observed stratigraphic trends are consistent with the rocks at Gale Crater recording a global transition from a climate favorable to clay mineral formation to one more favorable to forming sulfates and other salts.
The Connectome of a Decision-Making Neural Network Jarrell, Travis A.; Yi Wang; Bloniarz, Adam E. ...
Science (American Association for the Advancement of Science),
07/2012, Volume:
337, Issue:
6093
Journal Article
Peer reviewed
In order to understand the nervous system, it is necessary to know the synaptic connections between the neurons, yet to date, only the wiring diagram of the adult hermaphrodite of the nematode ...Caenorhabditis elegans has been determined. Here, we present the wiring diagram of the posterior nervous system of the C. elegans adult male, reconstructed from serial electron micrograph sections. This region of the male nervous system contains the sexually dimorphic circuits for mating. The synaptic connections, both chemical and gap junctional, form a neural network with four striking features: multiple, parallel, short synaptic pathways directly connecting sensory neurons to end organs; recurrent and reciprocal connectivity among sensory neurons; modular substructure; and interneurons acting in feedforward loops. These features help to explain how the network robustly and rapidly selects and executes the steps of a behavioral program on the basis of the inputs from multiple sensory neurons.
Integrated photonics changes the scaling laws of information and communication systems offering architectural choices that combine photonics with electronics to optimize performance, power, ...footprint, and cost. Application-specific photonic integrated circuits, where particular circuits/chips are designed to optimally perform particular functionalities, require a considerable number of design and fabrication iterations leading to long development times. A different approach inspired by electronic Field Programmable Gate Arrays is the programmable photonic processor, where a common hardware implemented by a two-dimensional photonic waveguide mesh realizes different functionalities through programming. Here, we report the demonstration of such reconfigurable waveguide mesh in silicon. We demonstrate over 20 different functionalities with a simple seven hexagonal cell structure, which can be applied to different fields including communications, chemical and biomedical sensing, signal processing, multiprocessor networks, and quantum information systems. Our work is an important step toward this paradigm.Integrated optical circuits today are typically designed for a few special functionalities and require complex design and development procedures. Here, the authors demonstrate a reconfigurable but simple silicon waveguide mesh with different functionalities.
Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal ...transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.
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