Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Are women residency supervisors obligated to nurture?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73923/1/j.1365-2929.2006.02635.x.pd

A Fungal Metabolite Asperparaline A Strongly and Selectively Blocks Insect Nicotinic Acetylcholine Receptors: The First Report on the Mode of Action

Asperparalines produced by Aspergillus japonicus JV-23 induce paralysis in silkworm (Bombyx mori) larvae, but the target underlying insect toxicity remains unknown. In the present study, we have investigated the actions of asperparaline A on ligand-gated ion channels expressed in cultured larval brain neurons of the silkworm using patch-clamp electrophysiology. Bath-application of asperparaline A (10 µM) had no effect on the membrane current, but when delivered for 1 min prior to co-application with 10 µM acetylcholine (ACh), it blocked completely the ACh-induced current that was sensitive to mecamylamine, a nicotinic acetylcholine receptor (nAChR)-selective antaogonist. In contrast, 10 µM asperparaline A was ineffective on the γ-aminobutyric acid- and L-glutamate-induced responses of the Bombyx larval neurons. The fungal alkaloid showed no-use dependency in blocking the ACh-induced response with distinct affinity for the peak and slowly-desensitizing current amplitudes of the response to 10 µM ACh in terms of IC50 values of 20.2 and 39.6 nM, respectively. Asperparaline A (100 nM) reduced the maximum neuron response to ACh with a minimal shift in EC50, suggesting that the alkaloid is non-competitive with ACh. In contrast to showing marked blocking action on the insect nAChRs, it exhibited only a weak blocking action on chicken α3β4, α4β2 and α7 nAChRs expressed in Xenopus laevis oocytes, suggesting a high selectivity for insect over certain vertebrate nAChRs

Clinical Features and Long-Term Follow-Up of Quasi-Moyamoya Disease in Children.

Background: Inherited or acquired disorders and conditions may present in conjunction with moyamoya disease. This condition is known as quasi-moyamoya disease. Methods: A retrospective review of 69 moyamoya disease patients treated for the past 20 years identified 7 patients with quasi-moyamoya disease and 5 of them were pediatric patients. Results: The mean age at initial diagnosis was 6.4 years (range 5-9). Associated disorders were: craniosynostosis, dwarfism with coarctation of aorta, Proteus syndrome, and cranial irradiation for brain tumor. Their clinical type included cerebral ischemia in 3 patients, cerebral bleeding with ischemia in 1 and epilepsy in 1. The 3 patients with cerebral ischemia underwent bypass surgery and their ischemia was improved. One patient died of brain tumor recurrence and the activities of daily living in the remaining patients were affected by mental retardation. Conclusions: The clinical course and radiological finding of quasi-moyamoya disease are diverse because of associated disorders, distinguishing definite moyamoya disease

Solving discrete logarithms on a 170-bit MNT curve by pairing reduction

Pairing based cryptography is in a dangerous position following the breakthroughs on discrete logarithms computations in finite fields of small characteristic. Remaining instances are built over finite fields of large characteristic and their security relies on the fact that the embedding field of the underlying curve is relatively large. How large is debatable. The aim of our work is to sustain the claim that the combination of degree 3 embedding and too small finite fields obviously does not provide enough security. As a computational example, we solve the DLP on a 170-bit MNT curve, by exploiting the pairing embedding to a 508-bit, degree-3 extension of the base field.Comment: to appear in the Lecture Notes in Computer Science (LNCS

Immunolocalization of dually phosphorylated MAPKs in dividing root meristem cells of Vicia faba, Pisum sativum, Lupinus luteus and Lycopersicon esculentum

Key message In plants, phosphorylated MAPKs display constitutive nuclear localization; however, not all studied plant species show co-localization of activated MAPKs to mitotic microtubules. Abstract The mitogen-activated protein kinase (MAPK) signaling pathway is involved not only in the cellular response to biotic and abiotic stress but also in the regulation of cell cycle and plant development. The role of MAPKs in the formation of a mitotic spindle has been widely studied and the MAPK signaling pathway was found to be indispensable for the unperturbed course of cell division. Here we show cellular localization of activated MAPKs (dually phosphorylated at their TXY motifs) in both interphase and mitotic root meristem cells of Lupinus luteus, Pisum sativum, Vicia faba (Fabaceae) and Lycopersicon esculentum (Solanaceae). Nuclear localization of activated MAPKs has been found in all species. Colocalization of these kinases to mitotic microtubules was most evident in L. esculentum, while only about 50 % of mitotic cells in the root meristems of P. sativum and V. faba displayed activated MAPKs localized to microtubules during mitosis. Unexpectedly, no evident immunofluorescence signals at spindle microtubules and phragmoplast were noted in L. luteus. Considering immunocytochemical analyses and studies on the impact of FR180204 (an inhibitor of animal ERK1/2) on mitotic cells, we hypothesize that MAPKs may not play prominent role in the regulation of microtubule dynamics in all plant species

Mucoepidermoid carcinoma of the lung: a case report

Mucoepidermoid carcinoma of the lung (MEC) is a tumor of low malignant potential of bronchial gland origin. MEC and adenoid cystic carcinoma are both considered to be salivary gland-type neoplasms. MECs are comparatively rare with an incidence of all lung cancers. We recently encountered a case of this type of lung cancer. A 60-year-old man was found to have an abnormal shadow in the left lower lung field on a regular check-up for lung cancer at his company. Chest radiography and CT revealed a mass shadow measuring 30 mm in diameter in the left lower lung field. Bronchoscopy revealed a protuberant tumor in the S9 bronchus, leading to a diagnosis of low-grade MEC by transbronchial lung biopsy. He underwent left lower lobe resection and mediastinal lymph node dissection using VATS. Tumor cells had a scattering of mucus-producing epithelial components in papillary growth of stratified squamous epithelia with anisokaryosis and minimal pleomorphism, indicating a diagnosis of MEC. Because the postoperative course was good and the tumor was low-grade, no adjuvant treatment was administered. The patient has had no signs of tumor recurrence for 9 months, to date, since resection of the tumo

Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents

Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3, also disrupts the p53/Mdm2 interaction. All of the 11 UKF-NB-3 sub-lines adapted to RITA that we established retained functional wild-type p53 although RITA induced a substantial p53 response. Moreover, all RITA-adapted cell lines remained sensitive to nutlin-3, whereas only five out of 10 nutlin-3-adapted cell lines retained their sensitivity to RITA. In addition, repeated adaptation of the RITA-adapted sub-line UKF-NB-3rRITA10 μM to nutlin-3 resulted in p53 mutations. The RITA-adapted UKF-NB-3 sub-lines displayed no or less pronounced resistance to vincristine, cisplatin, and irradiation than nutlin-3-adapted UKF-NB-3 sub-lines. Furthermore, adaptation to RITA was associated with fewer changes at the expression level of antiapoptotic factors than observed with adaptation to nutlin-3. Transcriptomic analyses indicated the RITA-adapted sub-lines to be more similar at the gene expression level to the parental UKF-NB-3 cells than nutlin-3-adapted UKF-NB-3 sub-lines, which correlates with the observed chemotherapy and irradiation sensitivity phenotypes. In conclusion, RITA-adapted cells retain functional p53, remain sensitive to nutlin-3, and display a less pronounced resistance phenotype than nutlin-3-adapted cells

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Wilson Lines and a Canonical Basis of SU(4) Heterotic Standard Models

The spontaneous breaking of SU(4) heterotic standard models by Z_3 x Z_3 Wilson lines to the MSSM with three right-handed neutrino supermultiplets and gauge group SU(3)_C x SU(2)_L x U(1) x U(1) is explored. The two-dimensional subspace of the Spin(10) Lie algebra that commutes with su(3)_C + su(2)_L is analyzed. It is shown that there is a unique basis for which the initial soft supersymmetry breaking parameters are uncorrelated and for which the U(1) x U(1) field strengths have no kinetic mixing at any scale. If the Wilson lines "turn on" at different scales, there is an intermediate regime with either a left-right or a Pati-Salam type model. We compute their spectra directly from string theory, and adjust the associated mass parameter so that all gauge parameters exactly unify. A detailed analysis of the running gauge couplings and soft gaugino masses is presented.Comment: 59 pages, 9 figure