Slug-based epithelial-mesenchymal transition gene signature is associated with prolonged time to recurrence in glioblastoma

Background
We previously identified a precise stage-associated gene expression signature of coordinately expressed genes, including the transcription factor Slug (SNAI2) and other epithelial mesenchymal transition (EMT) markers, present in samples from publicly available gene expression datasets in multiple cancer types. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT like process of mesenchymal transition to varying degrees. 

Findings
Here we show that this signature in glioblastoma multiforme (GBM) is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3x10^-7^). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. 

Conclusions 
Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients

Theory of Spin polarized Tunneling in Superconducting Sr2RuO4

A theory of tunneling conductance in ferromagnetic metal/insulator/triplet - supercondcutor junctions is presented for unitary and non-unitary spin triplet pairing states which are promising candidates for the superconducting paring symmetry of Sr2RuO4. As the magnitude of the exchange interaction in the ferromagnetic metal is increased, the conductance for the unitary pairing state below the energy gap is reduced in contrast to the case for the non-unitary pairing state

Generation of transformable spheroplasts from mycelia, macroconidia, microconidia and germinating ascospores of Neurospora crassa

For Neurospora to be generally useful in molecular studies it would be desirable to be able to prepare transformable spheroplasts from mycelia and any of the three types of spores produced by this organism. Transformable spheroplasts are currently prepared from germinating macroconidia by digestion with Novozym 234 in the presence of 1.0 M sorbitol (Vollmer and Yanofsky 1986. PNAS 83:4869-4873). This method is efficient, but requires a 3-5 hr germination step. Elimination of the germination step would be a technical advance. In addition, the standard method is usable only with strains that form large numbers of macroconidia. Thus, interesting mutants that are incapable of forming macro- conidia cannot be used as recipients in cloning experiments. A procedure for generating spheroplasts from mycelia of N. crassa has been reported (Buxton and Radford 1984. MGG 196:339-344). While large numbers of spheroplasts are released by this procedure, the frequency of transformation is low, and we have experienced difficulty obtaining repeatable results. Since we want to clone genes implicated in the macroconidiation process, we devised a procedure that improves the efficiency of transformation of mycelial spheroplasts. As an alternative approach, we developed an transformation protocol for microconidia. Since aconidial mutations can be introduced into a microcycle microconidiating background such as mcm (Maheshwari 1991. Exp. Mycol. 15:346-350), transformation of microconidia represents a viable option for the cloning of conidiation genes. A procedure for generating competent spheroplasts from germinating ascospores also was developed and provides an additional strategy for cloning conidiation genes

Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.

The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen1. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response2-7. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models6-11. Here, we examined B6.Sst1S congenic mice that carry the 'susceptible' allele of the Sst1 locus that results in exacerbated Mtb disease12-14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections6,7,15-18. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1S mice. Our results illustrate the value of the B6.Sst1S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo

Role of the AT2 receptor in modulating the angiotensin II contractile response of the uterine artery at mid-gestation

Introduction: During human pregnancy, circulating concentrations of components of the renin—angiotensin system increase, but pressor refractoriness to angiotensin II (Ang-II) is observed. Given the importance of the Ang-II pressor response in deciding susceptibility to preeclampsia and of the Ang-II system for controlling uterine vasoreactivity, we sought to address the effects of pregnancy on the reactivity of the isolated uterine artery (UA) in mice. Materials and methods : Blood pressure was measured throughout pregnancy in awake C57BL/6J mice. UA segments were isolated from three groups of animals (non-pregnant, mid [day 12—13] and late [day 18—19] gestation) and studied by wire myography. Results: UA diameters, KCl-mediated responses, and acetylcholine-dependent vasorelaxation were greater at mid and late gestation than in non-pregnant animals. Ang-II responses were also greater during pregnancy, with an increased contraction in response to AT2 receptor blockade at mid-gestation. AT1 receptor blockade abolished the Ang-II response in all groups. Conclusions: Study findings are consistent with the possibility that AT2 receptor-mediated vasodilatation plays a role in modulating Ang-II contractile responses in pregnancy

Role of the AT2 receptor in modulating the angiotensin II contractile response of the uterine artery at mid-gestation

Introduction: During human pregnancy, circulating concentrations of components of the renin—angiotensin system increase, but pressor refractoriness to angiotensin II (Ang-II) is observed. Given the importance of the Ang-II pressor response in deciding susceptibility to preeclampsia and of the Ang-II system for controlling uterine vasoreactivity, we sought to address the effects of pregnancy on the reactivity of the isolated uterine artery (UA) in mice. Materials and methods : Blood pressure was measured throughout pregnancy in awake C57BL/6J mice. UA segments were isolated from three groups of animals (non-pregnant, mid [day 12—13] and late [day 18—19] gestation) and studied by wire myography. Results: UA diameters, KCl-mediated responses, and acetylcholine-dependent vasorelaxation were greater at mid and late gestation than in non-pregnant animals. Ang-II responses were also greater during pregnancy, with an increased contraction in response to AT2 receptor blockade at mid-gestation. AT1 receptor blockade abolished the Ang-II response in all groups. Conclusions: Study findings are consistent with the possibility that AT2 receptor-mediated vasodilatation plays a role in modulating Ang-II contractile responses in pregnancy

A Challenging Case of Hepatoblastoma Concomitant with Autosomal Recessive Polycystic Kidney Disease and Caroli Syndrome—Review of the Literature

We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function

A Protocol Guide for the N. crassa Yeast Artificial Chromosome Library

A yeast artificial chromosome (YAC) library of Neurospora crassa strain 74-OR23-1A has been constructed. This library has been used to clone 750 kb of contiguous DNA sequences from the centromere region of linkage group VII (M. Centola and J. Carbon. 1994. Mol. Cell. Biol. 14:1510-1519). The purpose of this article is explicitly to outline procedures that have been developed for library screening and chromosome walking

VEGF(164)-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF(164) increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF(164)-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF(164)-deficient (VEGF(120/188)) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF(+/+)) controls. In contrast, administration of a VEGFk-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF(164) selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined

Theory of magnetotunneling spectroscopy in spin triplet p-wave superconductors

We study the influence of a magnetic field $H$ on the zero-bias conductance peak (ZBCP) due to zero-energy Andreev bound state (ZES) in normal metal / unconventional superconductor. For p-wave junctions, ZBCP does not split into two by $H$ even for sufficiently low transparent junctions, where ZBCP clearly splits for d-wave. This unique property originates from the fact that for p-wave superconductors, perpendicularly injected quasiparticle form ZES, which contribute most dominantly on the tunneling conductance. In addition, we show that for $p_{x}$+i$p_{y}$-wave superconductor junctions, the height of ZBCP is sensitive to $H$ due to the formation of broken time reversal symmetry state. We propose that tunneling spectroscopy in the presence of magnetic field, $i.e.$, $magnetotunneling$, is an promising method to determine the pairing symmetry of unconventional superconductors.Comment: 4 pages, 6 figures, using jpsj2.cl