Mitotic activity of survivin is regulated by acetylation at K129

Survivin is a cancer-associated protein regulated by multiple factors, including acetylation at K129 within its C-terminal alpha-helical tail. Acetylation of survivin is being pursued as a potential prognostic marker in breast cancer. This modification at K129 may cause nuclear accumulation of survivin in interphase cells; however, whether this affects its essential role during mitosis has not been addressed. We posited whether mimicking acetylation of survivin at K129 alters its activity during mitosis. Fluorescence microscopy and time-lapse imaging showed that, mutating this site to an alanine to act as a constitutive acetyl mimetic, K129A, causes defects in chromosome segregation and cytokinesis. As a non-acetylatable version, K129R, also has difficulty during mitotic exit, we conclude that cyclical acetylation and deacetylation is required for fully functional survivin during mitosis

Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer

Background Survivin is a protein that is normally present only in G2 and M-phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed. Methods Using site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities. Results K129E retains its anti-apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin. Conclusion K129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer

On the (anisotropic) uniform metallic ground states of fermions interacting through arbitrary two-body potentials in d dimensions

We demonstrate that the skeleton of the Fermi surface S_{F;s} pertaining to a uniform metallic ground state (corresponding to fermions with spin index s) is determined by the Hartree-Fock contribution to the dynamic self-energy. The Fermi surface S_{F;s} consists of all points which in addition to satisfying the quasi-particle equation in terms of the Hartree-Fock self-energy, fulfill the equation S_{s}(k) = 0, where S_{s}(k) is defined in the main text; the set of k points which satisfy the Hartree-Fock quasi-particle equation but fail to satisfy S_{s}(k) = 0, constitute the pseudo-gap region of the putative Fermi surface of the interacting system. We consider the behaviour of the ground-state momentum-distribution function n_{s}(k) for k in the vicinity of S_{F;s} and show that whereas for the uniform metallic ground states of the conventional Hubbard Hamiltonian n_{s}(k) is greater/less than 0.5 for k approaching S_{F;s} from inside/outside the Fermi sea, for interactions of non-zero range these inequalities can be violated (without thereby contravening the condition of the non-negativity of the possible jump in n_{s}(k) on k crossing S_{F;s} from directly inside to directly outside the Fermi sea). We discuss, in the light of the findings of the present work, the growing experimental evidence with regard to the `frustration' of the kinetic energy of the charge carriers in the normal states of the copper-oxide-based high-temperature superconducting compounds. [Short abstract]Comment: 30 pages, 3 postscript figures. Brought into conformity with the published versio

Raman spectroscopy in head and neck cancer

In recent years there has been much interest in the use of optical diagnostics in cancer detection. Early diagnosis of cancer affords early intervention and greatest chance of cure. Raman spectroscopy is based on the interaction of photons with the target material producing a highly detailed biochemical 'fingerprint' of the sample. It can be appreciated that such a sensitive biochemical detection system could confer diagnostic benefit in a clinical setting. Raman has been used successfully in key health areas such as cardiovascular diseases, and dental care but there is a paucity of literature on Raman spectroscopy in Head and Neck cancer. Following the introduction of health care targets for cancer, and with an ever-aging population the need for rapid cancer detection has never been greater. Raman spectroscopy could confer great patient benefit with early, rapid and accurate diagnosis. This technique is almost labour free without the need for sample preparation. It could reduce the need for whole pathological specimen examination, in theatre it could help to determine margin status, and finally peripheral blood diagnosis may be an achievable target

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma

PurposeHigh-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.MethodsFor PK analysis, 32 patients received peginterferon α-2b 6 μg/(kg week) subcutaneously for 8 weeks (induction) then 3 μg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied.ResultsPeginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision.ConclusionsPeginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity

Is U.S. health care an appropriate system? A strategic perspective from systems science

<p>Abstract</p> <p>Context</p> <p>Systems science provides organizational principles supported by biologic findings that can be applied to any organization; any incongruence indicates an incomplete or an already failing system. U.S. health care is commonly referred to as a system that consumes an ever- increasing percentage of the gross domestic product and delivers seemingly diminishing value.</p> <p>Objective</p> <p>To perform a comparative study of U.S. health care with the principles of systems science and, if feasible, propose solutions.</p> <p>Design</p> <p>General systems theory provides the theoretical foundation for this observational research.</p> <p>Main Outcome Measures</p> <p>A degree of compliance of U.S. health care with systems principles and its space-time functional location within the dynamic systems model.</p> <p>Results of comparative analysis</p> <p>U.S. health care is an incomplete system further threatened by the fact that it functions in the zone of chaos within the dynamic systems model.</p> <p>Conclusion</p> <p>Complying with systems science principles and the congruence of pertinent cycles, U.S. health care would likely dramatically improve its value creation for all of society as well as its resiliency and long-term sustainability.</p> <p>Immediate corrective steps could be taken: Prioritize and incentivize <it>health </it>over <it>care</it>; restore fiscal soundness by combining health and life insurance for the benefit of the insured and the payer; rebalance horizontal/providers and vertical/government hierarchies.</p

Anticonvulsant effects of aerial parts of Passiflora incarnata extract in mice: involvement of benzodiazepine and opioid receptors

<p>Abstract</p> <p>Background</p> <p>Passion flower (<it>Passiflora incarnata</it>) is used in traditional medicine of Europe and South America to treat anxiety, insomnia and seizure. Recently, it has shown antianxiety and sedative effects in human.</p> <p>Methods</p> <p>In this study, anticonvulsant effects of hydro- alcoholic extract of Passiflora, Pasipay, were examined by using pentylentetrazole model (PTZ) on mice. Pasipay, diazepam, and normal saline were injected intraperitoneally at the doses 0.4–0.05 mg/kg, 0.5–1 mg/kg and 10 ml/kg respectively 30 minutes before PTZ (90 mg/kg, i.p). The time taken before the onset of clonic convulsions, the duration of colonic convulsions, and the percentage of seizure and mortality protection were recorded. For investigating the mechanism of Pasipay, flumazenil (2 mg/kg, i.p) and naloxone (5 mg/kg, i.p) were also injected 5 minutes before Pasipay.</p> <p>Results</p> <p>An ED₅₀value of Pasipay in the PTZ model was 0.23 mg/kg (%95 CL: 0.156, 0.342). Pasipay at the dose of 0.4 mg/kg prolonged the onset time of seizure and decreased the duration of seizures compared to saline group (p < 0.001). At the dose of 0.4 mg/kg, seizure and mortality protection percent were 100%. Flumazenil and naloxone could suppress anticonvulsant effects of Pasipay.</p> <p>Conclusion</p> <p>It seems that Pasipay could be useful for treatment absence seizure and these effects may be related to effect of it on GABAergic and opioid systems. More studies are needed in order to investigate its exact mechanism.</p

Changes in immunocompetent cells after interstitial laser thermotherapy of breast cancer

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.BACKGROUND: Local tumour destruction has been shown to give rise to changes in immunocompetent cells. The aim of this study was to describe the effect of interstitial laser thermotherapy (ILT) of breast carcinoma in the tumour and in regional lymph nodes. METHODS: Seventeen women that underwent radical surgical excision after non-radical ILT were studied. ILT was performed at a steady-state temperature of 48°C for 30 min. Surgical excision was performed 12 (6-23) days after ILT. Six patients with breast cancer not treated with ILT before surgery served as controls. Immunohistological reactions were performed on core needle biopsies prior to treatment and on the excised specimens. RESULTS: ILT resulted in more CD8 lymphocytes and CD68 macrophages within the tumour (P < 0.05 and P < 0.01, respectively) and higher counts of CD20 (P < 0.05), CD68 (P < 0.001) and CD83 (P < 0.01) at the tumour border, when compared to pre-treatment values. In the control patients not receiving ILT, CD8 cells increased within the tumour after resection (P < 0.05). With the probable exception of CD25 Foxp3 cells, the presence of cancer in a lymph node influenced the findings in lymph nodes (examined for CD1a, CD25, Foxp3 CD25, CD83 cells). Thus, comparisons between ILT and control patients were restricted to patients without lymph node metastases. In these patients, ILT and resection were followed by a decrease in CD25 Foxp3 lymphocytes (P < 0.05), when compared to surgical resection alone. CONCLUSIONS: ILT induced changes in immunocompetent cells in patients with breast cancer. The stimulation of the immune system is an added feature of ILT in treatment of patients with breast cancer

Brain Potentials Highlight Stronger Implicit Food Memory for Taste than Health and Context Associations

Increasingly consumption of healthy foods is advised to improve population health. Reasons people give for choosing one food over another suggest that non-sensory features like health aspects are appreciated as of lower importance than taste. However, many food choices are made in the absence of the actual perception of a food's sensory properties, and therefore highly rely on previous experiences of similar consumptions stored in memory. In this study we assessed the differential strength of food associations implicitly stored in memory, using an associative priming paradigm. Participants (N = 30) were exposed to a forced-choice picture-categorization task, in which the food or non-food target images were primed with either non-sensory or sensory related words. We observed a smaller N400 amplitude at the parietal electrodes when categorizing food as compared to non-food images. While this effect was enhanced by the presentation of a food-related word prime during food trials, the primes had no effect in the non-food trials. More specifically, we found that sensory associations are stronger implicitly represented in memory as compared to non-sensory associations. Thus, this study highlights the neuronal mechanisms underlying previous observations that sensory associations are important features of food memory, and therefore a primary motive in food choice.</p