More than two thirds of Earth's surface is covered by water.
If Earth's primordial water was boiled off from the intense heat during planetary cooling, where did Earth's abundant water originate?
The origin of Earth's water remains a mystery.
Recent analysis of the composition of water sampled on comet 67P suggest Earth's water might not have come from cometary collisions (Life from Comet Collisions).
Scientists suggest that one key to solving the mystery of Earth's abundant water is found in the D/H ratio or the flavor of water. The D/H ratio is the proportion of Deuterium (symbol D) to Hydrogen (symbol H). The ratio of these two hydrogen isotopes might provide clues to the origin of Earth's water.
Deuterium is a form of hydrogen (i.e., hydrogen isotope) that has an additional neutron not present in common hydrogen. There are about 6,420 hydrogen atoms for every deuterium atom found in the world's oceans.
Deuterium can replace hydrogen in water molecules. The properties of D2O differ from H2O (common water). D2O is called heavy water because it's 10.6% denser than H2O. D2O is also more viscous than H2O.
The current opinion that science and poetry are opposed is a delusion. On the contrary science opens up realms of poetry where to the unscientific all is a blank. Those engaged in scientific researches constantly show us that they realize not less vividly, but more vividly, than others, the poetry of their subjects.
Analysis of the composition of water sampled on comet 67P, along with previous D/H analysis of other comets show a range of ratios generally containing higher amounts of deuterium than Earth.
Of the 11 comets for which measurements have been made, it is only the Jupiter-family Comet 103P/Hartley 2 that was found to match the composition of Earth's water.
The D/H ratio of water sampled on comet 67P is three times greater than that of Earth's oceans.
Scientists are are turning their attention to asteroids. Meteorites from asteroids in the Asteroid Belt have a closer match to the D/H ratio of water on Earth. Meteorites have a much lower water content than comets. However multiple serious of meteorite bombardments could have produced Earth's oceans.
Water does not resist. Water flows. When you plunge your hand into it, all you feel is a caress. Water is not a solid wall, it will not stop you. But water always goes where it wants to go, and nothing in the end can stand against it. Water is patient. Dripping water wears away a stone.
A Comet's Tale, shared on Google Plus by Brian Koberlein, 11 Dec 2014.
Origin of Water on Earth, Wikipedia.
Rosetta Fuels Debate on Origin of Earth's Oceans, European Space Agency, 10 December 2014.


text:
Q: Получить значение из stdClass Object находящегося в массиве? stdClass Object
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                (
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                        (
                            [ID] => 44926100
                            [MAC] => 12310515551D
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A: Решение которое сработало.
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redpajama_set_name: RedPajamaStackExchange


text:
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Hot Topic| Volume 68, P145-154, July 01, 2018
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Glioblastoma quo vadis: Will migration and invasiveness reemerge as therapeutic targets?
Florence Lefranc
Corresponding author at: Service de Neurochirurgie – Hôpital Erasme- Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium.
Department of Neurosurgery, Hôpital Erasme; Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
Emilie Le Rhun
University of Lille, U-1192, F-59000 Lille, France
Inserm, U-1192, F-59000 Lille, France
CHU Lille, General and Stereotaxic Neurosurgery Service, F-59000 Lille, France
Robert Kiss
FRS-FNRS, Brussels, Belgium
Michael Weller
Department of Neurology, University Hospital & University of Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland
Open AccessPublished:June 26, 2018DOI:https://doi.org/10.1016/j.ctrv.2018.06.017
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The purpose of the current review is to highlight, on one hand, the fact that the migratory pattern of glioma cells is the major obstacle to combat them with chemotherapy, and on the other one, the new treatment strategies to overcome this obstacle.
This review surveys several membrane and extracellular molecules involved in glioma cell migration, invasiveness and resistance to apoptosis.
This review focuses on signaling pathways implicated in the positive regulation of glioblastoma cell migration, including glutamate and ion channel networks, microtubes and membrane-derived extracellular vesicles (EV) containing microRNAs. Glioma cells release glutamate to the extracellular matrix, inducing neuronal cell death, which may facilitate glioma growth and invasion. Glioma cell migration and invasion are further facilitated through ion channels and transporters that modify cellular volume. Microtubes and EV promote connections and communication among glioma cells and with the microenvironment and are associated with progression and resistance to therapy. Potential therapies linked to these pathways for glioblastoma are being developed.
Our view is evolving from an intracellular view of the complex intracellular signaling pathways to one of orchestral machinery, including connections between heterogeneous tumoral and nontumoral cells and with the microenvironment through channels, microtubes, and extracellular miRNA, generating different signals at different times. All of these elements give rise to a new perspective for the treatment of glioblastoma.
Gliomas, including the most common variant, glioblastoma, are the most common primary malignant brain tumors, with an annual incidence of 5.26 cases per 100,000 population or 17,000 new diagnoses per year [
Ostrom Q.T.
Gittleman H.
Liao P.
CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014.
Neuro-Oncol. 2017; 19: 1-88
]. Glioblastoma remains one of the most lethal forms of cancer. The high spatial and temporal glioblastoma heterogeneity due to functionally diverse cell types, chaotic leaky vasculature and tumor cell infiltration contributes to poor prognosis in patients [
Reardon D.A.
Wen P.Y.
Glioma in 2014: unravelling tumour heterogeneity-implications for therapy.
Nat Rev Clin Oncol. 2015; 12: 69-70
]. The current understanding of the biology and genetics of glioblastoma has greatly improved in the past two decades. Two major multi-institutional programs, the Glioma Molecular Diagnostic Initiative and The Cancer Genome Atlas (TCGA), have pursued comprehensive genomic characterization of a large number of clinical glioma samples using a variety of technologies to measure gene expression, chromosomal copy number alterations, somatic and germline mutations, DNA methylation, microRNA, and proteomic changes. These data will facilitate the discovery of therapeutic and diagnostic targets and pathway candidates, validation of research and clinical observations and generation of unanticipated hypotheses that can advance the molecular understanding of this lethal cancer [
Riddick G.
Fine H.A.
Integration and analysis of genome-scale data from gliomas.
Nat Rev Neurol. 2011; 7: 439-450
]. Sturm et al. identified six epigenetic glioblastoma subgroups displaying characteristic global DNA methylation patterns, harboring distinct hotspot mutations, DNA copy-number alterations, and transcriptomic patterns [
Sturm D.
Witt H.
Hovestadt V.
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.
Cancer Cell. 2012; 22: 425-437
]. Brenann et al. provided a comprehensive and in-depth overview of the genetic, epigenetic and transcriptional profiles associated with glioblastoma [
Brennan C.W.
Verhaak R.G.
McKenna A.
TCGA Research Network. The somatic genomic landscape of glioblastoma.
Cell. 2013; 155: 462-477
]. The new WHO 2016 classification, therefore, is not only based on the histological features of the tumor but also includes isocitrate dehydrogenase (IDH) mutation and chromosomal arms 1p and 19q codeletion status to classify diffuse gliomas of adulthood [
Louis D.N.
Perry A.
Reifenberger G.
The 2016 world health organization classification of tumors of the central nervous system: a summary.
Acta Neuropathol. 2016; 131: 803-820
]. However, each individual glioblastoma should be considered as an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states. It is becoming clear that glioblastoma is a composite of multiple cell populations in the same tumor, and this heterogeneity makes the design of effective treatment modalities challenging [
Patel A.P.
Tirosh I.
Trombetta J.J.
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.
Science. 2014; 344: 1396-1401
Sottoriva A.
Spiteri I.
Piccirillo S.G.
Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.
Proc Natl Acad Sci U S A. 2013; 110: 4009-4014
Diffuse glioma genesis
In the context of gliomagenesis, glial cells were once considered the only dividing cells in the postnatal brain, making these cells the only brain cells susceptible to transformation [
Sanai N.
Alvarez-Buylla A.
Berger M.S.
Neural stem cells and the origin of gliomas.
Holland E.C.
Progenitor cells and glioma formation.
Curr Opin Neurol. 2001; 14: 683-688
]. It is now known that both multipotent and self-renewing neural stem cells and self-renewing glial progenitor cells produce astrocytes and oligodendrocytes in limited regions of the adult brain including the subventricular zone, the subgranular zone of the dentate gyrus and possibly other minor stem-cell niches throughout the brain [
Gould E.
How widespread is adult neurogenesis in mammals?.
Nature Rev Neurosci. 2007; 8: 481-488
Nunes M.C.
Roy N.S.
Keyoung H.M.
Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain.
Nature Med. 2003; 9: 439-447
Canoll P.
Goldman J.E.
The interface between glial progenitors and gliomas.
]. These stem cell and progenitor elements, in addition to differentiating into adult glia, are now thought to constitute a substrate for neoplastic transformation, termed glioma initiating cells or glioma stem cells (GSCs), a small population of self-renewal, therapy-resistant and slow-dividing malignant cells inside the main tumor bulk. Calabrese et al. found that a significant proportion of vessel-associated Nestin + tumor cells are proliferating and that these cells are distributed throughout tumors, from all regions of the cerebrum and cerebellum [
Calabrese C.
Poppleton H.
Kocak M.
A perivascular niche for brain tumor stem cells.
Cancer Cell. 2007; 11: 69-82
]. In the early 70 s, Pierce proposed that tumors arise from carcinogenic events occurring in stem cells of a particular tissue that cause a defect in the control of normal stem cell function, including self-renewal and differentiation [
Pierce G.B.
Neoplasms, differentiations and mutations.
Am J Pathol. 1974; 77: 103-118
]. In the adult brain, neural stem cells commonly possess features associated with gliomas, including a robust proliferative potential, high motility, diverse progeny, associations with blood vessels and white-matter tracts and an immature gene expression profile characterized by expression of nestin, epidermal growth factor receptor (EGFR), Notch and PTEN, telomerase activity, and Hedgehog and Wnt pathway activities [
Jackson E.L.
Garcia-Verdugo J.M.
Gil-Perotin S.
PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling.
Neuron. 2006; 51: 187-199
Tramontin A.D.
Quiñones-Hinojosa A.
Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.
Merkle F.T.
García-Verdugo J.M.
Radial glia give rise to adult neural stem cells in the subventricular zone.
Proc Natl Acad Sci U S A. 2004; 101: 17528-17532
Westphal M.
Lamszus K.
The neurobiology of gliomas: from cell biology to the development of therapeutic approaches.
Nat Rev Neurosci. 2011; 12: 495-508
GSCs expresse nestin (an intermediate filament protein) and CD133 (also known as prominin 1, a transmembrane glycoprotein), factors associated with neural stem cells, although some GSCs are CD133-negative [
Chen R.
Nishimura M.C.
Bumbaca S.M.
A hierarchy of self-renewing tumor-initiating cell types in glioblastoma.
]. Although CD133 expression seems to be related to stemness, it might only indicate an intermediate, adaptive state of a cell rather than a stable phenotype [
Griguer C.E.
Oliva C.R.
Gobin E.
CD133 is a marker of bioenergetic stress in human glioma.
PLoS One. 2008; 3: e3655
]. A tumor is therefore a caricature of normal tissue and appears to be undifferentiated because of the preponderance of undifferentiated proliferating stem cells in relationship to the number of cells that have differentiated and are post-mitotic.
Stem and progenitor cells in the central nervous system may be particularly at risk for malignant transformation since they constitutively activate the cellular machinery necessary for tumor initiation, progression or both (including growth factor receptor EGFR, PI3K, Akt, mTOR, Ras, mitogen-activated protein kinase (MAPK) members). Thus, neural stem cells may represent the path of least resistance in tumorigenesis since these cells already have the ability to bypass apoptosis and senescence. As a result, neural stem cells may require less than the estimated four to seven mutations needed to induce malignant change in a differentiated cell [
Scadden D.T.
The stem-cell niche as an entity of action.
]. In gliomas, as in several solid tumors outside the central nervous system, only a small fraction of the total population of cancer cells are clonogenic cancerous neural stem cells. However, this resistant population is considered the primary cause of glioblastoma invasion and responsible for the maintenance of a minimal residual disease, which commonly leads to post-therapeutic recurrence [
Singh S.K.
Hawkins C.
Clarke I.D.
Identification of human brain tumour initiating cells.
]. Evidence from human gliomas and rodent glioma models indicate that the glioma vascular niche supports glioma stem cell maintenance and nurtures tumor growth by offering nutrients necessary for unlimited glioma stem cell proliferation [
Sharma A.
Shiras A.
Cancer stem cell-vascular endothelial cell interactions in glioblastoma.
Biochem Biophys Res Commun. 2016; 473: 688-692
]. Several embryonic signaling pathways, such as Notch, Hedgehog and Wnt/b-catenin, have been reported to help maintain the GSC pool and thus provide potentials target for treating glioblastoma [
Thomas A.A.
DeAngelis L.M.
Emerging therapies for glioblastoma.
JAMA Neurol. 2014; 71: 1437-1444
]. Paw et al. [
Paw I.
Carpenter R.C.
Watabe K.
Mechanisms regulating glioma invasion.
Cancer Lett. 2015; 362: 1-7
] and Lee et al. [
Lee Y.
Lee J.K.
Ahn S.H.
WNT signaling in glioblastoma and therapeutic opportunities.
Lab Invest. 2016; 96: 137-150
] recently provided an overview of the specific signaling pathways that regulate glioblastoma stem cell maintenance and migration.
On the basis of their histological appearance, gliomas have been traditionally classified as astrocytic, oligodendroglial or ependymal tumors and assigned WHO grades I-IV, which indicate different degrees of malignancy. Diffusely infiltrating gliomas in adults are now separated into three overarching tumor groups with distinct natural histories, responses to treatment and outcomes: IDH-mutant, 1p/19q co-deleted tumors with mostly oligodendroglial morphology that are associated with the best prognosis; IDH-mutant, 1p/19q non-co-deleted tumors with mostly astrocytic histology that are associated with intermediate outcome; and IDH wild-type, mostly higher WHO grade (III or IV) tumors that are associated with poor prognosis [
Weller M.
Wick W.
Aldape K.
Glioma.
Nat Rev Dis Primers. 2015; 1: 15017
The current standard treatment for glioblastoma includes surgical resection, followed by radiotherapy plus concomitant temozolomide (TMZ) followed by six cycles of maintenance TMZ [
van den Bent M.
Tonn J.C.
European Association for Neuro-Oncology (EANO) Task Force on Gliomas. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.
Lancet Oncol. 2017; 18: e315-e329
Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: p. 459–66.
]. These treatments allow a median overall survival in the range of 16 months in clinical trial patient populations, but are never curative. Indeed, less than 10% of the 77,000 patients diagnosed each year with glioblastoma in the USA and Europe will survive more than 5 years. This dismal prognosis reflects the high rate of tumor recurrence approaching 100% which is linked to the profoundly infiltrative nature of this tumor, rendering curative surgical resection elusive, and its relative resistance not only to the conventional treatments of genotoxic radiotherapy and chemotherapy, but also more recently to targeted therapies. Antiangiogenic therapies have dominated the clinical trial landscape of glioblastoma. However, it has now become clear that this approach is hopeless, at least with a view to prolonging overall survival. Indeed, while anti-angiogenic treatment targeting VEGF exerts anti-edema effects in glioblastoma which may translate into clinical benefit in subgroups of patients, no clinical trial has demonstrated a survival benefit afforded by anti-angiogenic agents.
Glioblastoma migration: What is new?
In a previous review we highlighted the complex dynamic processes governing glioma cell migration in general and in glioblastoma in particular [
Lefranc F.
Brotchi J.
Kiss R.
Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis.
]. This dynamic process includes, among others, (i) cell adhesion to numerous components of a modified (when compared to normal parenchyma) extracellular matrix (ECM); (ii) cell motility, which involves the reorganization of the actin cytoskeleton, primarily through modifications in the field of integrin network–ECM component interactions; and (iii) invasion, which involves the degradation of matrix proteins by tumor-secreted proteolytic enzymes, primarily serine proteases, cathepsins and metalloproteinases (MMPs). Admittedly, no effective treatments for human glioma patients have evolved from these avenues of research.
In the present review, we analyzed the recent literature on new promising therapies to combat glioblastoma with a focus on two pathognomonic features of glioblastoma biology, i.e., glioblastoma cell migration and invasion through the brain parenchyma and, associated with that, the apparent intrinsic resistance of migrating glioblastoma cells to pro-apoptotic stimuli, including cytotoxic chemotherapy and radiotherapy.
We focused in the current review on glutamate, ion channels, tumor microtubules and several signaling pathways. While there is a myriad of signaling pathways that influence the migratory behavior of malignant astrocytes [
], we decided to restrain ourselves on the "glutamate pathway" because we are convinced that impairing this malignant astrocyte-migration avenue of invasion within the brain parenchyma would actually contribute therapeutic benefits to the patients. We detail below why we believe in this avenue to combat malignant gliomas.
Interaction of glutamate, glutamate transporters and glutamate receptors
The release of the neurotransmitter glutamate from glioma cells has been well studied in vitro and in vivo as well as in glioblastoma patient populations [
Ye Z.C.
Sontheimer H.
Glioma cells release excitotoxic concentrations of glutamate.
Lyons S.A.
Chung W.J.
Weaver A.K.
Autocrine glutamate signaling promotes glioma cell invasion.
Robert S.M.
Buckingham S.C.
Campbell S.L.
SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.
Sci Transl Med. 2015; 7: 289ra86
]. The Na+-independent, Cl--dependent, cystine/glutamate exchanger system (SXC) is the only transporter identified in glioma cells that has the ability to release large amounts of glutamate [
]. Glutamate released from malignant glioma cells into the extracellular space has been linked to seizure induction, and at higher concentration, glutamate is thought to induce neuronal cell death, mediated mainly by prolonged activation of N-methyl-D-aspartate (NMDA) receptors, but also via α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors resulting in Ca2+ influx and Ca2+-mediated cell death (Fig. 1) [
Lin J.H.
Arcuino G.
Glutamate release promotes growth of malignant gliomas.
Nat Med. 2001; 7: 1010-1015
Rothstein J.D.
Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange.
J Neurosci. 1999; 19: 10767-10777
Nelson G.M.
Inhibition of cystine uptake disrupts the growth of primary brain tumors.
J Neurosci. 2005; 25: 7101-7110
]. In the healthy brain, excitatory amino acid transporters (EAAT), located on astrocytes (EAAT1 and-2) and neurons (EAAT2), are responsible for the majority of glutamate uptake, and astrocytes can rapidly reduce toxic concentrations of extracellular glutamate. Glioma cells lack EAAT-mediated glutamate transport which contributes to the elevated peritumoral levels observed in glioma patients and in animal models of glioma [
Glutamate transporters in the biology of malignant gliomas.
Cell Mol Life Sci. 2014; 71: 1839-1854
]. Moreover, Robert and Sontheimer hypothesized that glioma cells alter peritumoral astrocyte EAAT function, preventing the re-establishment of glutamate homeostasis, as typically occurs in the healthy brain [
]. Investigations effectively discovered that glioma cells lack EAAT2-mediated glutamate transport [
De Groot J.F.
Liu T.J.
Fuller G.
The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo.
]. These findings were corroborated by microarray analyses of human glioma biopsies demonstrating the absence of EAAT2 expression in patient glioma tissue [
Fig. 1The glutamatergic system in glioblastoma. Glial tumor cells release glutamate by means of the Na+-independent, Cl--dependent, cystine/glutamate exchanger system (SXC) transporter. Glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and, at a higher concentration, neuronal cell death, which is mediated by prolonged activation of neuronal N-methyl-D-aspartate (NMDA) receptors, resulting in Ca2+ influx and Ca2+-mediated cell death. This neuronal cell death may facilitate tumor growth. Glutamate also stimulates growth, migration and invasion of glial tumor cells through activation of Ca2+-permeable glutamate AMPA receptors on glioma cells in a paracrine and autocrine manner.
Download (PPT)
By contrast, glioma cells express NMDA, a-amino-3-hydroxy-5-methyl-4-isoxaole propionic acid (AMPA) and metabotropic (mGlu) receptors [
Ishiuchi S.
Tsuzuki K.
Yoshida Y.
Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells.
Nat Med. 2002; 8: 971-978
]. However, van Vuurden et al. showed that on protein level, AMPA-type glutamate receptor subunits are variably expressed in glioblastoma and are overall down-regulated as compared to the normal brain tissue [
van Vuurden D.G.
Yazdani M.
Bosma I.
Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment.
]. These authors further reported that down-regulation of AMPA receptor expression and mislocalization of these receptors enables the cells to survive in a high glutamate environment without undergoing excitotoxic cell death themselves [
Glutamate stimulates the growth, migration and invasion of neuroglial tumor cells through activation of Ca2+-permeable glutamate AMPA receptors on glioma cells in a paracrine and autocrine manner (Fig. 1). AMPA receptor expression correlates with an increase in surface expression of β1 integrin, a molecule implicated in glioma invasion, and AMPA receptor stimulation increases glioma cell de-adhesion from surrounding cells. Glial AMPA receptors activate focal adhesion kinase (FAK) which influences cytoskeletal rearrangement and focal adhesion contact formation [
Piao Y.
Lu L.
de Groot J.
AMPA receptors promote perivascular glioma invasion via beta1 integrin-dependent adhesion to the extracellular matrix.
Neuro Oncol. 2009; 11: 260-273
Additionally, in response to reactive oxygen species (ROS), glioma cells upregulate SXC activity to provide intracellular cysteine for enhanced glutathione (GSH) synthesis, an important intracellular antioxidant that promotes cell survival [
Ogunrinu-Babarinde T.
Holt K.T.
Role of glutamate transporters in redox homeostasis of the brain.
Neurochem Int. 2014; 73: 181-191
]. Increased GSH neutralizes ROS, preventing cell destruction triggered by hypoxia; inhibits apoptosis signaling, protecting cells from degradation; and via ROS antagonism, may play an important role in the development of resistance to radiotherapy and chemotherapy [
Moellering D.R.
Gillespie G.Y.
Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production.
Roles of ion channels, transporters and exchangers
Increasing evidence suggests that cellular migration and invasion in cancer cells in general and glioma cells in particular results from shape and volume changes facilitated by ion channels and transporters [
Schwab A.
Fabian A.
Hanley P.J.
Role of ion channels and transporters in cell migration.
Physiol Rev. 2012; 92: 1865-1913
Cuddapah V.A.
Ion channels and transporters [corrected] in cancer. 2. Ion channels and the control of cancer cell migration.
Am J Physiol Cell Physiol. 2011; 301: C541-C549
Robel S.
Watkins S.
A neurocentric perspective on glioma invasion.
Pardo L.A.
Stühmer W.
The roles of K(+) channels in cancer.
Nat Rev Cancer. 2014; 14: 39-48
]. Glioma cells principally use voltage-gated chloride and potassium channels as well as the KCa family of Ca2+-activated potassium channels ([
] for a review of this topic) (Fig. 2).
Fig. 2Glioma cell volume and shape regulation: involvement of ion channels. Cell migration and glioblastoma cell migration in particular is characterized by the polarized cellular and molecular processes that promote the protrusion of the leading edge (local volume increase) and retraction of the trailing edge (local volume reduction). A net outflow of ions and water at the cell trailing edge and a net inflow of ions and water at the cell leading edge underlie these localized hydrodynamic changes. Ion channels and transporters display polarized subcellular distribution. At the trailing edge, calcium entry through calcium-permeable channels can activate calcium-activated potassium channels (KCa) to promote potassium efflux. The opening of chloride (KCl) and potassium channels (Kv) further enhances the outflow of ions Cl- and K+, followed by obligatory water efflux through aquaporins. At the leading edge, an assortment of inward ion channels, such as the Na+/K+ ATPase and the Na+-K+-Cl- cotransporters (NKCC1) together with aquaporins, regulate ion and water influx. This ion and water influx drives local cell volume increase in the protruding lamellipodium for leading edge extension.
Among ion transporters, potassium channels show the highest variability and the most frequently altered pattern of expression in many tumor types [
Hervé J.C.
Membrane channels and transporters in cancers.
BBA. 2015; 1848: 2473-2476
]. Cell cycle, proliferation, migration, invasion, angiogenesis and apoptosis are all processes that can be modified by the expression of potassium channels [
Comes N.
Serrano-Albarrás A.
Capera J.
Involvement of potassium channels in the progression of cancer to a more malignant phenotype.
]. Potassium channels have been implicated in every step of adhesion and migration [
]. Interactions of potassium channels with crucial contributors to cell adhesion, such as FAK and cortactin, an actin-interacting protein implicated in the cytoskeletal architecture and often amplified in several types of cancer, have been reported (Fig. 2) [
Herrmann S.
Ninkovic M.
Kohl T.
Cortactin controls surface expression of the voltage-gated potassium channel K(V)10.1.
J Biol Chem. 2012; 287: 44151-44163
]. Potassium channels also associate with the main contributors to cell adhesion signaling, integrins. The most important understood mechanisms by which particular potassium channels contribute to cancer initiation and progression have recently been reviewed [
]. Here we focus on the literature on potassium channels involved in glioma progression and migration, e.g. Kv1.3 and Kv1.5 [
Preussat K.
Beetz C.
Schrey M.
Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas.
Neurosci Lett. 2003; 346: 33-36
Pouleau H.B.
Rynkowski M.
Voltage-dependent K+ channels as oncotargets in malignant gliomas.
Oncotarget. 2012; 3: 516-517
Arvind S.
Arivazhagan A.
Santosh V.
Differential expression of a novel voltage gated potassium channel–Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma.
Br J Neurosurg. 2012; 26: 16-20
], Kv10.1 [
Bai Y.
Liao H.
Liu T.
MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-à-go-go (EAG1).
Eur J Cancer. 2013; 49: 710-724
Eag1: an emerging oncological target.
Martínez R.
Analysis of the expression of Kv10.1 potassium channel in patients with brain metastases and glioblastoma multiforme: impact on survival.
BMC Cancer. 2015; 15: 839
Masi A.
Becchetti A.
Restano-Cassulini R.
hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines.
], KCa1.1 [
Ransom C.B.
Liu X.
BK channels in human glioma cells have enhanced calcium sensitivity.
Glia. 2002; 38: 281-291
Bomben V.C.
Expression and function of calcium-activated potassium channels in human glioma cells.
] and KCa3.1 [
Ruggieri P.
Mangino G.
Fioretti B.
The inhibition of KCa3.1 channels activity reduces cell motility in glioblastoma derived cancer stem cells.
] (Fig. 2).
The Kv1.3, Kv10.1, and Kv11.1 channels are the best studied voltage-gated K channels in the context of cell migration. They are of particular importance for cells of the immune system and tumor cells, including glioblastoma cells, constituting potential diagnostic or prognostic markers or even therapeutic targets [
Kv10.1 (also known as EAG1, ether-à-go-go and KCNH1), a voltage-gated potassium channel that is virtually absent from normal cells outside the central nervous system, is expressed in limited areas of the brain (hypothalamus, hippocampus, cerebral cortex, cerebellum and olfactory nerve) but highly expressed in different cancers, including brain metastases and gliomas [
]. Bai et al. also observed Kv10.1 overexpression in both glioma cell lines and clinical glioma samples [
]. In several different cancers, Kv10.1 enhances proliferation. It has also been shown to be required for the maintenance of growth associated with the p53/miRNA34/E2F1 regulatory pathway in SHSY5Y human dopaminergic neuroblastoma cells [
Lin H.
Li Z.
Chen C.
Transcriptional and post-transcriptional mechanisms for oncogenic overexpression of ether à go-go K+ channel.
]; this channel up-regulates HIF-1 and VEGF in the tumor environment [
Downie B.R.
Sánchez A.
Knötgen H.
Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumors.
] and increases migration [
Toral C.
Mendoza-Garrido M.E.
Azorín E.
Effect of extracellular matrix on adhesion, viability, actin cytoskeleton and K+ currents of cells expressing human ether à go-go channels.
Life Sci. 2007; 81: 255-265
]. Kv10.1 expression in Chinese Hamster Ovary (CHO) cells affects cytoskeletal organization, which might influence cancer cell proliferation, migration and metastasis [
A correlation between dismal prognosis and Kv10.1 expression in patients with brain metastasis from different carcinomas has been observed, and metastatic cancer patients receiving tricyclic antidepressants (such as imipramine, chlorimipramine, citalopram and amitriptyline) showed a significantly longer median overall survival than patients not treated with these agents [
Kv11.1 (also known as HERG or KCNH2) was among the first voltage-gated channels directly associated with cancer [
Bianchi L.
Wible B.
Arcangeli A.
herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells?.
Cancer Res. 1998; 58: 815-822
]. Further, Kv11.1 blockers impair the proliferation of tumor cells [
Crociani O.
Guasti L.
Balzi M.
Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells.
J Biol Chem. 2003; 278: 2947-2955
]. Kv11.1 physically interacts with β1 integrin at the plasma membrane of human cancer cells to regulate survival and migration [
Crescioli S.
Zanieri F.
The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression.
Sci Signal. 2017; 10
] (Fig. 2), and this channel has also been implicated in the regulation of apoptosis of human glioblastoma cells (see below) [
Staudacher I.
Jehle J.
Staudacher K.
HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
The Kv1.3 and Kv1.5 channels modulate Ca2+ signaling and cell volume and have been analyzed in a number of cancer cell types [
Bielanska J.
Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention.
Curr Med Chem. 2012; 19: 661-674
]. The levels of expression of the Kv1.5 and Kv1.3 channel subtypes vary between different glioma groups, and differential expression of Kv1.5 according to malignancy grade has been noted [
]. Kv1.5 also contributes to the resistance to pro-apoptotic stimuli of cancer cells, including gliomas (see below).
The calcium-activated potassium channels KCa1.1 and KCa3.1 are important for the migration of glioma and glioma stem cells [
Turner K.L.
Honasoge A.
A Proinvasive Role for the Ca2+-Activated K+ Channel KCa3.1 in Malignant Glioma.
D'Alessandro G.
Catalano M.
Sciaccaluga M.
KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo.
Cell Death Disease. 2013; 4: e773
]. The REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT) database allowed to determine that the gene KCNN4, which encodes KCa3.1, is overexpressed in 32% of gliomas, and that its expression correlated with short survival [
]. Turner et al. generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression [
]. Subjecting these cells to a combination of in vitro and in situ invasion assays revealed that KCa3.1 expression may enhance glioma invasion and either specific pharmacological inhibition with TRAM-34 or elimination of this channel by gene silencing impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA from U251 cells resulted in a significant reduction in tumor invasion into the surrounding brain [
Migration of glioblastoma cells can be stimulated by ionizing radiation (IR) [
Wild-Bode C.
Rimner A.
Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma.
]. Steinle et al. accordingly analyzed the IR-induced increase in Ca2+-activated potassium channel activity and its effect on the migration of T98G and U87MG cells [
Steinle M.
Palme D.
Misovic M.
Ionizing radiation induces migration of glioblastoma cells by activating BK K channels.
Radiother Oncol. 2011; 101: 122-126
]. IR dose-dependently stimulated migration of glioblastoma cells, which in turn was sensitive to the channel inhibitor paxilline. These authors concluded that IR stimulates potassium channel activity, resulting in the activation of Ca2+/calmodulin-dependent protein kinase II and enhanced glioblastoma cell migration [
Approximately 20 years ago, Sontheimer proposed that the invasive migration of human glioma cells into the normal brain parenchyma requires shape and/or volume changes [
Soroceanu L.
Manning Jr, T.J.
Modulation of glioma cell migration and invasion using Cl(-) and K(+) ion channel blockers.
]. Chloride currents may contribute to such shape-volume changes by affecting net salt fluxes across glioma cell membranes, with accompanying water efflux, resulting in cell shrinkage that is conducive to glioma cell migration through minute extracellular spaces of the brain [
O'Neal J.T.
Volume-activated chloride currents contribute to the resting conductance and invasive migration of human glioma cells.
]. Sontheimer and collaborators subsequently performed a direct examination of Cl- dynamics in human glioma cells and its functional relationship to cell biology [
Habela C.W.
Ernest N.J.
Swindall A.F.
Chloride accumulation drives volume dynamics underlying cell proliferation and migration.
J Neurophysiol. 2009; 101: 750-757
]. First, these authors observed that invasive tumor cells become morphologically polarized and develop membrane protrusions (Fig. 2). During this process, invasive glioma cells alter their cell shape and volume to fit into the narrow extracellular spaces available and invade the brain parenchyma. These features include secretion of Cl- and K+ through ion channels localized to lipid raft domains on invadopodia and water passively flowing through water channels or aquaporins [
]. In addition, the interplay between Na+-K+-Cl- cotransporters and Na+/K+ ATPase leads to active accumulation of K+ and Cl-, establishing a gradient for KCl efflux (Fig. 2) [
Here, we do not review the roles of other channels involved in glioma migration, such as transient receptor potential (TRP) calcium channels, which also contribute to changes in Ca2+ by modulating the driving force for Ca2+ entry as Morrone et al. recently summarized this subject [
Morrone F.B.
Gehring M.P.
Nicoletti N.F.
Calcium channels and associated receptors in malignant brain tumor therapy.
Mol Pharmacol. 2016; 90: 403-409
Microtubes
Osswald et al. reported that astrocytomas but not oligodendrogliomas develop functional multicellular network structures through ultra-long membrane protrusions and that astrocytoma cells use these distinct tumor microtubes as routes for brain invasion, proliferation, and interconnections over long distances [
Osswald M.
Jung E.
Sahm F.
Brain tumour cells interconnect to a functional and resistant network.
Nature. 2015; 528: 93-98
]. The resulting network facilitates multicellular communication through microtube-associated gap junctions. Confocal microscopy revealed punctate connexin 43 (Cx43) gap junction immunoreactivity, particularly at the tumor microtubes of astrocytoma cells, which was not observed for other connexins. When damage to the network occurs, tumor microtube is used for repair. Moreover, microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumor progression, were protected from cell death inflicted by radiotherapy. Osswald et al. hypothesized that intercellular tumor microtubes can serve as an individual tumor cell to distribute critical elevations of small molecules, such as calcium, within the large network (Fig. 3), achieving nonlethal levels for radiotherapy-induced cytotoxicity and for intrinsic apoptotic cell death in glioma cells [
]. Neuronal growth-associated protein 43 (GAP-43) is important for microtube formation and function and drives microtube dependent tumor cell invasion, proliferation, interconnection, and radioresistance. The disconnection of astrocytoma networks by disrupting their tumor microtubes may emerge as a new principle to reduce the treatment resistance of this disease, but clinical applications have not been introduced [
Fig. 3Pathways of intercellular communication in glioblastoma. Glioblastoma demonstrates intratumoral heterogeneity and contains a population of glioma stem cells (GSC) that contributes to tumor propagation, maintenance and therapeutic resistance. After secretion, glioblastoma EV microRNAs are taken up by other tumor cells or normal cells in the microenvironment to change their phenotype and support tumor progression. Structures called microtubes connect tumor cells, enabling these cells to act as a single, organism-like unit. Tumor microtubes facilitate invasion into healthy brain tissue, permitting the spread of toxic molecules, such as Ca2+, which build up during radiotherapy enabling the whole unit to share the burden of toxicity. Furthermore, if tumor tissue is surgically removed, then newly synthesized nuclei donated by tumor cells can travel down the microtube to the cell-free site to form new tumor cells.
Extracellular MicroRNAs
Over the past decade, there has been increased awareness of the possible role of microRNAs (miRNAs) in the development of cancer, including glioblastoma [
Lin S.
Gregory R.I.
MicroRNA biogenesis pathways in cancer.
Nat Rev Cancer. 2015; 15: 321-333
]. miRNAs are small non-coding RNAs of approximately 20–23 nucleotides that act as post-transcriptional regulators of gene expression. miRNAs repress gene expression by binding to complementary sequences in the 3′ untranslated region (3′ UTR) of mRNAs and targeting these molecules for degradation, thereby preventing their translation, resulting in a decreased level of encoded proteins that affect an array of cellular processes, e.g., differentiation, proliferation, migration, metabolism, apoptosis and stem cell maintenance [
Fu J.
Rodova M.
Nanta R.
NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200.
]. Aberrant miRNA biogenesis in cancer occurs at different steps during miRNA maturation [
], and a single miRNA can regulate the expression of many genes. Depending on its target genes, miRNA can act as a tumor suppressor or tumor promoter. The accumulation of specific miRNAs in glioblastoma samples from patients and in glioblastoma cell lines was initially demonstrated a decade ago [
Ciafrè S.A.
Galardi S.
Mangiola A.
Extensive modulation of a set of microRNAs in primary glioblastoma.
Biochem Biophys Res Commun. 2005; 334: 1351-1358
Chan J.A.
Krichevsky A.M.
Kosik K.S.
MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.
]. Since then, numerous reviews have highlighted the involvement of miRNAs in glioblastoma progression, migration and radio-chemotherapy resistance and suggested their potential as therapeutic targets [
Sana J.
Hajduch M.
Michalek J.
MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications.
J Cell Mol Med. 2011; 15: 1636-1644
Karsy M.
Arslan E.
Moy F.
Current progress on understanding MicroRNAs in glioblastoma multiforme.
Genes Cancer. 2012; 3: 3-15
Møller H.G.
Rasmussen A.P.
Andersen H.H.
A systematic review of microRNA in glioblastoma multiforme: micro-modulators in the mesenchymal mode of migration and invasion.
Mol Neurobiol. 2013; 47: 131-144
Costa P.M.
Cardoso A.L.
Mano M.
MicroRNAs in glioblastoma: role in pathogenesis and opportunities for targeted therapies.
CNS Neurol Disord: Drug Targets. 2015; 14: 222-238
Pal D.
Mukhopadhyay D.
Ramaiah M.J.
Regulation of cell proliferation and migration by miR-203 via GAS41/miR-10b axis in human glioblastoma cells.
PLoS One. 2016; 11e0159092
Godlewski J.
Johnson M.D.
Belonging to a network-microRNAs, extracellular vesicles, and the glioblastoma microenvironment.
Stojcheva N.
Schechtmann G.
Sass S.
MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM.
Oncotarget. 2016; 7: 12937-12950
Recently, microRNAs have also been localized to the extracellular space, often encapsulated in secreted extracellular vesicles (EV), nanometer size membrane-enclosed particles formed either from the fusion of an endosome with the plasma membrane (exosomes) or directly from the cell membrane (microvesicles) and released from numerous cell types, including glioblastoma cells, to mold the tumor microenvironment to their advantage (Fig. 3) [
Fanini F.
Fabbri M.
Cancer-derived exosomic microRNAs shape the immune system within the tumor microenvironment: state of the art.
Semin Cell Dev Biol. 2017; 67: 23-28
Naito Y.
Yoshioka Y.
Yamamoto Y.
How cancer cells dictate their microenvironment: present roles of extracellular vesicles.
Cell Mol Life Sci. 2017; 74: 697-713
Rooj A.K.
Mineo M.
MicroRNA and extracellular vesicles in glioblastoma – Small but powerful.
Brain Tumor Pathol. 2016; 33: 77-88
]. Neighboring or distant recipient normal and tumor cells can take up EVs containing tissue-specific expressed/secreted microRNAs [
Bronisz A.
Chiocca E.A.
Extracellular vesicles and MicroRNAs: their role in tumorigenicity and therapy for brain tumors.
Cell Mol Neurobiol. 2016; 36: 361-376
]. In a recent review, Rooj et al. discussed the current knowledge regarding the multifaceted roles of both cellular and EV microRNAs in shaping the glioblastoma microenvironment [
]. Glioblastoma EVs are enriched in several oncogenic microRNAs, including miR-21, miR-23a, miR-30a, miR-221 and miR-451 [
Li C.C.
Eaton S.A.
Young P.E.
Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells.
RNA Biol. 2013; 10: 1333-1344
]. However, the functions of most of these microRNAs remain unknown. Hoshino and colleagues elegantly demonstrated that tumor-derived EVs are internalized in organ-specific cells, and this process plays an important role in the preparation of the pre-metastatic niche [
Hoshino A.
Costa-Silva B.
Shen T.L.
Tumour exosome integrins determine organotropic metastasis.
]. EVs containing miRNA were also detected in the blood or the cerebrospinal fluid of glioblastoma patients [
Akers J.C.
Hua W.
Li H.
A cerebrospinal fluid microRNA signature as biomarker for glioblastoma.
]. Thus, microRNAs circulating in complexes with tumor-originated EVs represent a potential source of biomarkers for the early detection and monitoring of tumor responses to treatment and could be utilized for glioblastoma therapy using therapeutic mi-RNA [
]. Arscott et al. showed that irradiation increases the abundance of exosomes released by glioblastoma cell lines and normal astrocytes [
Arscott W.T.
Tandle A.T.
Zhao S.
Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration.
Transl Oncol. 2013; 6: 638-648
]. These authors showed that exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration, including activation of neurotrophic tyrosine kinase receptor type 1 (TrkA) and FAK signaling [
Relationship between cell migration and resistance to pro-apoptotic stimuli
Intracellular signaling pathways involved in the acquisition of resistance to pro-apoptotic stimuli by migrating glioma cells, including the PTEN/PI3K/Akt/mTOR and NF-kB pathways, were already an important topic more than 10 years ago [
]. These pathways are not all constitutively activated at the same time in all cells in any one glioma. Many inhibitors of these pathways have been developed, and numerous clinical trials have investigated these agents alone or in conjunction with conventional radiotherapy or chemotherapy. Several recent publications have provided an update on the state of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials for glioblastoma [
Li X.
Wu C.
Chen N.
PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma.
Zhao H.F.
Wang J.
Shao W.
Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development.
Mol Cancer. 2017; 16: 100
]. So far, targeted therapy directed to central intracellular signal pathways has not yet achieved satisfactory results in glioblastoma. A future perspective for glioblastoma therapy may be the combined inhibition of multiple targets and more tumor-tailored strategies.
As indicated above, potassium channels may be involved both in the migratory processes and resistance to pro-apoptotic stimuli of glioblastoma cells. A volume change and decrease in intracellular K+ concomitantly occur with the initiation of apoptosis in glioma cells [
McFerrin M.B.
Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death.
Am J Physiol Cell Physiol. 2012; 303: C1070-C1078
]. Kv1.3, expressed at the plasma membrane, is also expressed at the inner membrane of mitochondria, where it is directly inhibited by the proapoptotic protein BAX, resulting in cytochrome c release and initiation of apoptosis [
Leanza L.
Henry B.
Sassi N.
Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells.
EMBO Mol Med. 2012; 4: 577-593
]. Similar mechanisms are shared by other K+ channels implicated in apoptosis [
Checchetto V.
Azzolini M.
Peruzzo R.
Mitochondrial potassium channels in cell death.
Biochem Biophys Res Commun. 2017; (pii:S0006-291X(17)31226-3)
]. Staudacher et al. showed that the small molecule Kv11.1 ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 and U87MG glioma cells, accompanied by cell cycle arrest in G0/G1 [
In addition, compared with normal cells, several human cancers exhibit a high mitochondrial membrane potential and low expression of the Kv1.5 channel, which both contribute to the apoptosis resistance of cancer cells, including glioma cells [
Bonnet S.
Archer S.L.
Allalunis-Turner J.
A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
]. Closing K+ channels or decreasing their expression in cancer cells increases the intracellular K+ concentration, which in turn increases the tonic inhibition that cytosolic K+ exerts on caspases [
Burg E.D.
Remillard C.V.
Yuan J.X.
K+ channels in apoptosis.
J Membr Biol. 2006; 209: 3-20
As indicated above, glioma cells can extend tumor microtubes for brain invasion, proliferation, and interconnection of single cells to a syncytium that is resistant to radiotherapy [
]. Recently Weil et al. evidenced using patient-derived glioblastoma stemlike cell lines (GBMSCs) implanted into the brain of mice that after a surgical lesion GBMSCs increasingly extended tumor microtubes toward the lesion area [
Weil S.
Solecki G.
Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas.
Neuro Oncol. 2017; 19: 1316-1326
]. In fact, an excessive "healing response" was observed in which tumor cell densities significantly exceeded those of unlesioned brain regions. Moreover, inhibition of tumor microtube formation and function by genetic targeting of growth associated protein-43 robustly suppressed this surgery-induced tumor growth reaction, in contrast to standard postsurgical anti-inflammatory treatment with dexamethasone. After one cycle of TMZ chemotherapy, intra- and intertumoral heterogeneity of tumor microtube formation and interconnection was strongly associated with therapy response: when tumor cells were integrated in tumor microtube networks, they were more likely to resist chemotherapy [
New anti-glioblastoma drugs related to migration, invasion and resistance to apoptosis
Targeting glutamate
The multitude of effects of glutamate in glioma biology has supported the rationale for the pharmacological targeting of glutamate receptors and transporters in the treatment of glioblastoma ([
Glutamate and the biology of gliomas.
Glia. 2011; 59: 1181-1189
] for review). Using the web site http://www.clinicaltrials.gov/ as a reference, we analyzed the few clinical trials completed with therapies targeting glutamate (see also [
Blecic S.
De Witte O.
Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications.
Bull Cancer. 2013; 100: 829-835
]).
Glutamate release can be inhibited by sulfasalazine, an FDA-approved drug for the treatment of inflammatory bowel disease, through inhibition of the CXC network. This drug may also facilitate death receptor-mediated apoptosis of glioma cells [
Hermisson M.
NF-kB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signalling pathways in human malignant glioma cells.
Cell Death Differ. 2003; 10: 1078-1089
]. Sulfasalazine could be considered a therapeutic agent for glioma patients to reduce seizure activity and control invasive growth in patients, although a preliminary study of ten patients with recurrent glioblastoma indicated lack of clinical efficacy [
Robe P.A.
Martin D.H.
Nguyen-Khac M.T.
Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults.
BMC Cancer. 2009; 9: 372
] (Table 1). Yet, small series of 10 patients are insufficient to draw definitive conclusions about the potential therapeutic benefit of any given drug. Accordingly, Huberfeld and Vecht have discussed the potential for single therapeutic agents, such as the CXC system blocker sulfasalazine or histone deacetylase inhibitor valproic acid, to treat both gliomas and associated epilepsy [
Huberfeld G.
Vecht C.J.
Seizures and gliomas–towards a single therapeutic approach.
Nat Rev Neurol. 2016; 12: 204-216
]. However, the same year valproic acid was definitively excluded as a useful therapeutic approach after the analysis of survival of a pooled patient cohort (n = 1869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma patients that received the antiepileptic drug at the start of chemoradiotherapy with temozolomide [
Happold C.
Gorlia T.
Chinot O.
Does valproic acid improve survival in glioblastoma? A meta-analysis of randomized trials in newly diagnosed glioblastoma.
Table 1Potential treatment approaches in clinical study.
Glutamate release by CXC network Sulfasalazine Recurrent glioblastoma Phase I/II
AMPA receptors Talampanel Newly diagnosed glioblastoma Phase II in association with radio- and temozolomide
Iwamoto F.M.
Kreisl T.N.
Kim L.
Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas.
Grossman S.A.
Ye X.
Chamberlain M.
Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial.
Piantadosi S.
Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States.
NMDA receptors Memantine Glioblastoma Phase I in association with temozolomide On going
Cl-channel TM-601 Anaplastic astrocytoma and glioblastoma Phases I/II and III intracavitary
Mamelak A.N.
Rosenfeld S.
Bucholz R.
Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma.
Talampanel, an allosteric inhibitor of AMPA receptors, entered phase II clinical trials, and it has been speculated that this drug may provide a survival advantage when used in combination with standard chemoradiotherapy [
] (Table 1). However, Grossman and colleagues challenged their own conclusions one year later [
]. Overall survival of 244 patients with newly diagnosed glioblastoma accrued to three consecutive therapeutic trials conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium was significantly higher than is reported with radiation and temozolomide alone [
]. The improvement in survival was evident as early as 6 months after study initiation (94% vs 86% survival, p < 0.003) and continued over two years (37% vs 27%, p < 0.02). In each of these trials a novel agent including talampanel for 72 patients was combined with standard radiation and temozolomide [
]. This report documents significant improvements in the survival of patients with newly diagnosed glioblastoma. However, Grossman et al. emphasized that it remains uncertain if these results are attributable to the novel therapies themselves or reflect evolving patterns of care in this patient population [
]. This argues strongly against the overinterpretation of survival data from uncontrolled phase II studies in newly diagnosed glioblastoma, as has recently been confirmed with the negative outcome of the phase III ACT IV trial [
Butowski N.
Tran D.D.
ACT IV trial investigators: Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial.
Memantine, a noncompetitive inhibitor of NMDA receptors approved for dementia treatment, is a candidate for modulating the effects of glutamate at the infiltrative rim of gliomas [
]. Indeed, a phase I factorial trial of temozolomide, memantine, mefloquine, and metformin for post-radiation therapy glioblastoma is ongoing (https://clinicaltrials.gov/ct2/show/NCT01430351?term=memantine&cond=glioma&rank=3) (Table 1).
The goal of this study is to identify the highest tolerable dose of TMZ in combination with a mixture of memantine, mefloquine, and/or metformin that can be administered to glioblastoma patients who have previously undergone radiation and chemotherapy in combination. The safety of these drug combinations will also be studied (https://clinicaltrials.gov/ct2/show/NCT01430351?term=memantine&cond=glioma&rank=3). However, whether such complex trials advance standards of care in glioblastoma remains doubtful, and exploring the addition of high doses of memantine alone to standard chemoradiotherapy might have been preferable. Yohay et al. demonstrated that the local polymer-based delivery of riluzole, a glutamate uptake blocker approved for the treatment of amyotrophic lateral sclerosis, or memantine improved survival in a rat intracranial glioma model when the polymer wafers were placed at the time of tumor engraftment [
Yohay K.
Weaver K.D.
Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models.
J Neurosurg. 2014; 120: 854-863
We speculate that normal neurons might be protected against the high glutamate microenvironment by specific inhibitors of ionotropic receptors but further research is warranted [
Chen H.S.
Lipton S.A.
The chemical biology of clinically tolerated NMDA receptor antagonists.
J Neurochem. 2006; 97: 1611-1626
Catarzi D.
Colotta V.
Varano F.
Competitive AMPA receptor antagonists.
Med Res Rev. 2007; 27: 239-278
Targeting ion channels
One Cl- channel inhibitor, TM-601, a synthetic version of the peptide chlorotoxin, a small 36 amino acid neurotoxin isolated from the venom of the giant yellow Israeli scorpion Leiurus quinquestriatus [
DeBin J.A.
Maggio J.E.
Strichartz G.R.
Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion.
Am J Physiol. 1993; 264: C361-C369
] that is covalently linked to iodine 131, has completed phase I and II clinical trials for the treatment of anaplastic astrocytomas and glioblastomas through repeated local intracavitary administrations (NCT00591058) [
] (Table 1). Intracavitary-administered 131I-TM-601 is well tolerated, remains highly localized to the treatment site, and preliminarily appears safe for repeated injections. As no major toxicity and no death due to 131I-TM-601 have been reported, the FDA allowed the trial to go to Phase III [
Jacoby D.B.
Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601).
Expert Opin Drug Deliv. 2007; 4: 175-186
]. An FDA approval has also been obtained to investigate the effect of TM601 in newly diagnosed gliomas. TM601 appears to be stable, is not immunogenic and lacks toxicity in humans upon local administration. Parallel to this trial, the same team has worked on an intravenous injection protocol of this product but this time with an imaging application in perspective [
Hockaday D.C.
Shen S.
Fiveash J.
Imaging glioma extent with 131I-TM-601.
J Nucl Med. 2005; 46: 580-586
]. However, to our knowledge no study has been published recently. Interestingly, intracranial injection of 131I-CTX detects brain tumors by gamma-ray scintigram scans in vivo, but also labels the stomach, indicating that the molecular target of chlorotoxin is also expressed in this organ. So far, TM-601 is the only derivative of chlorotoxin for which human clinical studies have been partially published. Besides the clinical trial of 131I-TM-601, many other chlorotoxin applications have been described that may be potentially useful to treat glioma. A large proportion of them rely on the administration of therapeutic agents, cDNA or siRNA to block oncogene expression, thanks to the use of nanoparticles [
Veiseh O.
Kievit F.M.
Fang C.
Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery.
Biomaterials. 2010; 31: 8032-8042
Huang R.
Ke W.
Han L.
Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration.
Molecular targets for chlorotoxin include voltage gated chloride channels, calcium-dependent phospholipid-binding protein annexin-2, and matrix metalloproteinase-2 (MMP-2) [
Deshane J.
Garner C.C.
Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2.
]. Among these targets, MMP-2 has most anti-neoplastic potential [
According to Pardo and Stühmer [
] and our previous study [
], inhibition of potassium channels also has therapeutic potential for glioblastoma patients. Wulf et al. have previously discussed the pharmacological strategies for targeting potassium channels with venom peptides, antibodies or small molecules [
Wulff H.
Castle N.A.
Voltage-gated potassium channels as therapeutic targets.
Nat Rev Drug Discov. 2009; 8: 982-1001
]. The Kv10.1 and Kv11.1 inhibitors have been proposed for the treatment of various types of cancers. Two potent blockers of Kv10.1, the antihistamine, astemizole, and the tricyclic antidepressant, imipramine, have been shown to decrease tumor cell proliferation in vitro and, in the case of astemizole, also in vivo [
García-Quiroz J.
Camacho J.
Astemizole: an old anti-histamine as a new promising anti-cancer drug.
Anticancer Agents Med Chem. 2011; 11: 307-314
]. Imipramine binds to the intracellular pocket and consequently inhibits the current of Kv10.1 [
Gómez-Varela D.
Major F.
Approaches targeting K(V)10.1 open a novel window for cancer diagnosis and therapy.
]. Desipramine and imipramine have been demonstrated to inhibit PI3K/Akt/mTOR signaling and induce autophagic cell death in vitro in murine C6 and human U87MG glioma cells [
Ma J.
Hou L.N.
Rong Z.X.
Antidepressant desipramine leads to C6 glioma cell autophagy: implication for the adjuvant therapy of cancer.
Jeon S.H.
Kim S.H.
Kim Y.
The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells.
Recently, Sales et al. showed that in vitro suppression of the Kv10.1 channel using astemizole or silencing using a short-hairpin RNA expression vector sensitized U87MG glioma cells to temozolomide [
Sales T.T.
Resende F.F.
Chaves N.L.
Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide.
Oncol Lett. 2016; 12: 2581-2589
Kv11.1 is affected by drugs that cause acquired long QT syndrome [
Kalyaanamoorthy S.
Barakat K.H.
Development of Safe Drugs: The hERG Challenge.
Med Res Rev. 2017; (May 3 [Epub ahead of print])
]. Even if the intracellular channel pore openings of Kv10.1 and Kv11.1 are similar, although not identical, all of the known Kv10.1 blockers are also effective blockers of Kv11.1 and therefore share cardiac safety problems. For these reasons, the antihistamine astemizole was withdrawn from the market in 2000 [
Gottlieb S.
Antihistamine drug withdrawn by manufacturer.
BMJ. 1999; 319: 7
]. Because the risk benefit profile of an anticancer drug is radically different from that of compounds developed for the treatment of benign conditions, the potential for these compounds should be reconsidered for repositioning. Moreover, there are at least three alternative transcripts of Kv11.1, which are differentially expressed in heart versus tumor cells, suggesting the option of selective inhibition of this type of ion channel in tumors while preserving heart function. A specific peptide toxin that can achieve this result has yet to be reported. However, a monoclonal antibody (mAb56) has been developed that specifically blocks Kv10.1 without affecting Kv11.1 or its close relative Kv10.2 [
Napp J.
Hartung F.
In vivo imaging of tumour xenografts with an antibody targeting the potassium channel Kv10.1.
Eur Biophys J. 2016; 45: 721-733
]. This antibody showed efficacy in vitro against human melanoma MDA-MB-435S and human pancreatic carcinoma AsPC-1 cell lines as well as in vivo in nude mice subcutaneously grafted with these tumor models, but the required doses were high, whereas the reduction of tumor growth was modest [
]. The experiments were performed in immunodeficient mice, so that the antibody could, in principle, act exclusively as a channel blocker. Finally, the anticancer compound roscovitine, a cyclin-dependent kinase inhibitor that has terminated phase II clinical trials for non-small cell lung cancer [
Ganapathi S.B.
Kester M.
Elmslie K.S.
State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy.
], is an efficient blocker of Kv11.1, but does not induce arrhythmia, likely due to its low affinity for closed and inactivated states of the channel.
Staudacher et al. recently identified the Kv11.1 ligand doxazosin as a small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human glioblastoma cells in vitro [
]. Doxazosin and future derivatives have therefore been proposed as novel options for more effective glioblastoma treatment [
Citalopram (Cipramil®), a selective serotonin reuptake inhibitor used for its antidepressive activity, acts on Kv1.5 currents as an open-channel blocker [
]. Because both imipramine and citalopram have been commonly used to treat depression, which commonly occurs in glioma patients, the European Organization for Research and Treatment of Cancer (EORTC) conducted a large epidemiological study to investigate the actual benefit that these two drugs may provide for glioblastoma patients. D'Alessandro et al. demonstrated that (i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34, a high affinity blocker of KCa3.1, exhibits good selectivity for these channels and increases the TMZ antitumor effects, reducing GL-261 glioma cell migration, invasion and colony forming activity, increasing apoptosis and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; (ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; (iii) the combination of TMZ and TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures through a microglia-dependent mechanism since the effect is abolished by clodronate-induced microglia killing; (iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); and (v) TMZ/TRAM-34 co-treatment reduces the cell viability of glioblastoma cells and cancer stem cells freshly isolated from patients [
D'Alessandro G.
Grimaldi A.
Chece G.
KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment.
]. Taken together, these data demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglial cells, resulting in an overall reduction of tumor cell progression. Furthermore, calcium activated potassium channel blockade by paxilline, a toxin of the fungus Penicillium paxilli, inhibited ionizing radiation-induced migration in vivo in an orthotopic model of the human glioblastoma model [
Edalat L.
Stegen B.
Klumpp L.
BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells.
]. Additionally, ophiobolin-A, a sesterterpenoid phytotoxin produced by pathogenic fungi of the genus Bipolaris, induced marked changes in the dynamic organization of the F-actin cytoskeleton and inhibited proliferation and migration of glioblastoma cells, likely by inhibiting conductance Ca(2+)-activated potassium channel activity [
Bury M.
Girault A.
Mégalizzi V.
Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.
Cell Death Dis. 2013; 4: e561
Targeting extracellular miRNAs
MicroRNAs are secreted into the extracellular space, at least in part by EV, and are subsequently taken up by normal and cancer cells to sustain and promote tumor growth (Fig. 3). Glioblastoma EVs transport several tumor-specific microRNAs; however, the functions of most of these microRNAs remain unknown. A better understanding of the role of secreted microRNAs may unveil a novel mechanism of glioblastoma progression and resistance to current treatments and may provide novel diagnostic and prognostic biomarkers. Rooj et al. suggested that these biomarkers can be used for the development of targeted therapies aimed at improving glioblastoma patient outcomes [
Conclusion and perspectives
Glioblastoma is an incurable neoplasm characterized by diffusely infiltrative growth. Given the highly invasive nature of glioblastoma, it remains unlikely that any single therapeutic approach will be able to specifically target and eliminate residual heterogeneous tumor cells. New therapeutic strategies to fight both migrating apoptotic resistant and proliferating glioma cells are necessary to effectively counteract glioblastoma progression. Novel treatment approaches have to integrate the intracellular perspective of the complex intracellular signaling pathways with the microenvironmental orchestral machinery, including connections between heterogeneous tumoral and nontumoral cells, potentially also through channels, microtubes, and extracellular miRNA, generating different messages at different times. New avenues for glioblastoma treatment must not ignore the very specific and peculiar interactions between tumor cells and their host tissue, and the prime targets currently appear to be glutamate- and ion channel-controlled processes.
The authors declared that there is no conflict of interest.
Published online: June 26, 2018
Accepted: June 21, 2018
Received in revised form: June 19, 2018
Received: January 14, 2018
DOI: https://doi.org/10.1016/j.ctrv.2018.06.017
© 2018 The Author(s). Published by Elsevier Ltd.
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redpajama_set_name: RedPajamaCommonCrawl


text:
Statewide Rankings | Climate at a Glance
Statewide Mapping
Statewide Time Series
Statewide Rankings
Statewide Haywoods
Statewide Data Info
Statewide Data Information
Statewide data come from the U.S. Climate Divisional Database, which have data from 1895 to the present.
State: Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming
Please note, Degree Days and Palmer Indices are not available for Alaska. Palmer Drought Severity Index (PDSI), Palmer Hydrological Drought Index (PHDI), and Palmer Modified Drought Index (PMDI) are not offered for multiple-month time scales.
Minimum Temperature Rankings, December 1993
(-2.3°C) 2.1°F
Nov–Dec 1993
Oct–Dec 1993
Sep–Dec 1993
Aug–Dec 1993
Jul–Dec 1993
Jun–Dec 1993
May–Dec 1993
Apr–Dec 1993
Mar–Dec 1993
Feb–Dec 1993
Jan–Dec 1993
Jul 1992–Dec 1993
Jan 1992–Dec 1993
NOAA National Centers for Environmental information, Climate at a Glance: Statewide Rankings, published January 2023, retrieved on January 26, 2023 from https://www.ncei.noaa.gov/access/monitoring/climate-at-a-glance/statewide/rankings


text:
Tech Manager Guides
Crimson AV Display Mounting Accessories
By AVNetwork Staff (AV Network) 29 May 2014
Crimson AV is releasing new mounting solutions engineered to affix to round and rectangular pipes, on walls, on counter tops, and other challenging attachment points often found in retail, point of sale, digital signage and other commercial installations. Expanding on the Company's mission to deliver professional-grade AV mounting solutions that are simple to specify, order, and install, Crimson will demonstrate at InfoComm 2014 a host of new mounting solutions specifically designed for hospitality, retail, entertainment, education, government, healthcare facilities, houses of worship, venues of any size, and a wide variety of commercial applications.
Crimson AV has a unique value proposition and fills a much-needed niche. In addition to a comprehensive TV and projector mount lineup of more than 400 off-the-shelf solutions, the Company also specializes in custom-configured solutions that are designed to specification and suitable for virtually every type of audio-visual installation. Two new models in the line are a product of this solution-oriented approach and are being shown to InfoComm attendees for the first time:
New CLAMP3 Display Mounting Accessory
Benefit: Quick and easy to install, attaches to unistrut, truss, pipe, or any round or rectangular structure up to 3.5 inches in diameter. Extremely adjustable; monitor display height adjustment is limited only by the range of the drop length. Creates a unique and versatile display mounting solution that's compatible with a variety of flat, tilt, pivoting and articulating mounts.
Application: Digital signage, retail, point of sale, trade shows, exhibits, studios, warehouses, venues, and other challenging environments.
New PR30 Display Mounting Accessory
Benefit: Versatile mounting solution for monitors up to 30 inches in size. Interfaces with the CLAMP3 to create a pivoting display mounting solution. Attached monitors can be set in either landscape or portrait orientation, and then rotated, tilted, and locked into place after installation, providing end-users significant flexibility in both location and use.
Application: 100x100mm hole pattern. Ideal for retail point of sale, hospitality, venues, and other challenging environments.
"Our new PR30 and CLAMP3 were developed for customers that needed to mount displays for point of sale and digital signage use in retail, warehouses, venues, and other challenging commercial environments," said Crimson president, Vlad Gleyzer. "They're genuine problem-solvers and serve as prime examples of Crimson's ability to react to the unique needs of commercial systems integrators."
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Facebook is finally banning ads for coronavirus 'cures'
Image source: SHAWN THEW/EPA-EFE/REX/Shutterstock
By Mike Wehner @MikeWehner
Facebook has a massive problem with fake news flooding its platform. It's an issue that has existed for years — and may have influenced a presidential election in the process — but the company has yet to fully squash it. Instead, Facebook addresses individual issues as they pop up, and with the current worldwide panic over the coronavirus, ads promoting "cures" for the infection are becoming a serious concern.
Now, as Business Insider reports, the company is paying more attention to ads and promoted posts related to the coronavirus COVID-19 and everything related to the virus and the outbreak. Put simply, the company is going to ban anything that claims to offer a cure for the infection.
"We recently implemented a policy to prohibit ads that refer to the coronavirus and create a sense of urgency, like implying a limited supply, or guaranteeing a cure or prevention," the company said in a statement to Business Insider. "We also have policies for surfaces like Marketplace that prohibit similar behavior."
It's sad but not entirely surprising that people are using Facebook to exploit some of the concern and panic regarding the coronavirus outbreak. It's not been hard to find ads or Marketplace listings claiming to offer supplements or even "cures" for the infection, despite the fact that no such treatment is publicly available.
The good news is that a vaccine for coronavirus is actually in the works. In fact, a US company called Moderna recently announced that it had provided samples of the vaccine to the government and could have human testing in the works within a couple of months. Even still, making that vaccine widely available (if it indeed works) might not be possible until early 2021. In any case, anything you see on Facebook promising a cure or vaccine for the virus right now is total bunk, and it's nice to see that Facebook is finally taking action against it.
Tags: coronavirus, facebook, health
Mike Wehner has reported on technology and video games for the past decade, covering breaking news and trends in VR, wearables, smartphones, and future tech. Most recently, Mike served as Tech Editor at The Daily Dot, and has been featured in USA Today, Time.com, and countless other web and print outlets. His love of reporting is second only to his gaming addiction.
Coronavirus outbreak reaches scary new milestone
You might miss your stimulus check if you don't realize this one thing


Jim is a former staff attorney at the Michigan Court of Appeals and Michigan Supreme Court, and also served as Settlement Director at the Court of Appeals (the Court's mediation office). He served on the Supreme Court's committee that drafted the trial court mediation rules in Michigan and helped modify court rules and court forms at the Court of Appeals. He has served as a seminar faculty member teaching attorneys, court staff, and judges about mediation and appellate procedures, and taught legal research and writing to law students. Jim specializes in research and appellate representation, and can handle the entire appeal or segments of your research and representation needs as part of your team.
Why should you consult an appellate attorney?
► Appellate practice is an increasingly specialized segment of the law. Every day, lawyers are embarrassed in front of their clients when appellate courts dismiss appeals for procedural matters – or issue an opinion rejecting arguments because the lawyer did not cite adequate authority or properly identify the facts relevant to the appeal.
► Appeals require a special candor with the tribunal that some advocates cannot comfortably provide when they come from the "bulldog" intensity of a trial practice. What works in front of juries does not work in front of judges.
► Appeals require familiarity with complicated procedural issues of a specialty court.
► Most clients benefit from a second set of eyes reviewing a trial court's action.
► If the trial attorney made a mistake, it is better to try and resolve it early than to push for a baseless appeal where the Court of Appeals might point a public finger of blame.
January 2016: Jim successfully defended against an appeal in the Michigan Court of Appeals involving the appointment of a special personal representative. The court ruled in Jim's client's favor on all issues in an 11-page decision.


It might only cover 49 square miles, but San Francisco is one of the most visited cities in the United States. Iconic landmarks like the vivid Golden Gate Bridge, crooked Lombard Street and photogenic Telegraph Hill captivate visitors from all over the world. The city is one of the nation's most densely populated urban centers (with an estimated population of around 865,000) yet still feels close to nature. It's located on the tip of a peninsula that's bordered by a sparkling bay to the east and the vast Pacific ocean to the west, with majestic California landscapes to the north and south—wild headlands, rugged coastline, virgin redwood groves and the towering peak of Mount Tamalpais. The city's population started exploding in 1848, when it became the epicenter of the California Gold Rush. After a massive fire and earthquake nearly leveled the city in 1906, it quickly rebuilt itself from the ashes. San Francisco weather is mild year round. The summers are unusually foggy and cool, with daytime highs usually peaking in the '60s. September and October are the warmest and sunniest months, and winter is typically the wettest season.
San Francisco has long been considered a bastion of progressive culture in the United States, leading the nation in a number of progressive social movements throughout the second half of the 20th century. Today visitors will see hundreds of cyclists commuting on Market Street, dedicated compost bins in food establishments, LEED certified architecture and neighborhood farmers' markets throughout the week. The city has had subsidized healthcare for nearly a decade and provides the country's highest minimum wage and fiercest tenants rights. In the 1950s, the city saw the birth of Beat culture, which rebelled against mainstream values. The next decade brought the Summer of Love to the Haight-Asbury District and Golden Gate Park. The city's LGBT activist legacy took off in the 1960s, and the local gay community went on to survive the brutal AIDS crisis during the 1980s-90s. Today the city is home to one of the world's biggest and most prominent LGBT communities. Nearly 36 percent of San Francisco's ethnically diverse population is of Asian descent, and the city has the largest Chinatown outside of Asia. In recent years, the city has experienced a boom in development and an influx of young people moving in for jobs in the tech sector.
A trip to the city isn't complete without seeing (and perhaps walking or biking across) the Golden Gate Bridge. Almost anyone would enjoy the trip to Alcatraz Island (the views of the city are worth the trip alone). Chugging up one of the city's famous hills on a cable car is a quintessential San Francisco experience, as is walking up or down lushly landscaped Lombard, "the crookedest street in the world." Visit the epicenter of the hippie movement in the Haight-Ashbury District and look up at towering redwood trees in Muir Woods across the Golden Gate Bridge. Climbing up Telegraph Hill via the Filbert Steps to reach Coit Tower is a feast for the senses, with the squawks of parrots, the scent of blooming gardens and the views soaring across the bay. Golden Gate Park is packed with photogenic attractions like the Japanese Tea Garden and a world-class science and art museum. An entire day could be spent at the newly renovated SFMOMA, the largest modern art museum in the nation. Any itinerary should include a few special meals since San Francisco might be the most food-obsessed city in the country. Locals expect restaurants to use fresh, local ingredients. The city has the highest number of restaurants per capita of any American city, and many of these restaurants have earned national accolades. It's worth the effort to venture to multiple neighborhoods to sample the diversity of the epicurean scene. For those limited on time, the Ferry Building Marketplace offers an impressive sampling.


Silver jacket, shirt and pant, all by Payal Khandwala; white sneakers, from Camper; stone ring, by Niharika Khan; watch, from Chanel.
I don't follow any one label.
Clothes with labels plastered all over.
According to my mood — our profession allows a lot of freedom.
In the '80s, when I combined highlights and a perm — disaster!
A gown by Shahab Durazi.
When picking colours for clothes, make-up or hair, make sure that they complement skin tone and eye colour.


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text:
Richmond Barthé
Richmond Barthé (1901-1989) was a pioneer in American sculpture in the 1930s and 1940s in that he was one of the first African American artists to focus thematically on the lives of blacks, both in the United States and in Africa.
Trailblazing artist Richmond Barthé's sculpted works were seminal in that they focused on the lives of his fellow African Americans. He depicted African Americans at work in the fields of the South (Woman with Scythe, 1944), African Americans of distinction, and, in Mother and Son (1939), African Americans as victims of racial violence. He also sculpted images of African warriors and ceremonial participants.
Barthé was born on January 28, 1901, in Bay St. Louis, Mississippi, to Richmond Barthé, Sr., and Marie Clementine Robateau. His father died before Barthé was a year old, and his mother's sewing supported the family. She later remarried, to William Franklin, an old friend and Barthé's godfather. Franklin worked in various odd jobs, including as an ice man, delivering ice throughout the rural community. According to Barthé, he was artistically inclined from a very young age. In A History of African American Artists, he is quoted as saying, "When I was crawling on the floor, my mother gave me paper and pencil to play with. It kept me quiet and she did her errands. At six years old I started painting. A lady my mother sewed for gave me a set of watercolors. By that time I could draw pretty well."
As a teenager, Barthé's artistic talent had attracted attention among several of his mother's clients, and among his stepfather's ice customers as well. Barthé used to help in the delivery during the summer. One of the customers, who knew of and admired Barthé's work, told the young boy that he would injure himself carrying such large chunks of ice all day long. She arranged for him to get a job with the Pond family in New Orleans, a very wealthy family with several homes and an interest in supporting the arts. Barthé stayed with the Ponds for several years, working as their houseboy while being encouraged to continue drawing and painting. Around this time, Barthé met Lyle Saxon, a writer working for the New Orleans Times-Picayune, and the two men became good friends. Saxon was very interested in Barthé's work and remained a champion of the artist after he became a well-known novelist.
Around 1923, a Catholic priest took an interest in Barthé's work and began looking for a local art school for him to attend. In the South, however, no school would admit a black, so the priest paid for Barthé to attend the prestigious Art Institute of Chicago. Here, Barthé rapidly developed as an artist, studying with several important teachers. Barthé's most influential teacher was Charles Schroeder. It was ultimately Schroeder who suggested that Barthé try sculpture. Schroeder did not intend to suggest that Barthé, who was mainly a painter then, shift his medium, but for him to incorporate three dimensions into his art. It turned out, however, that Barthé was a gifted sculptor, as was immediately apparent from the creation of his first busts in art school. An Art Institute show included three of his works. From that show, Barthé received his first commission as a sculptor. The Lake County Children's Home in Gary, Indiana, saw Barthé's work and hired him to do busts of Henry O. Tanner and Toussaint L'Ouverture for its home. Barthé, who had taken no classes in sculpting, thus began a career as a sculptor. His talents so impressed his teachers at the Institute that they advised him not to take any classes, fearing that formal training might ruin the creative spark in his work.
Having taken up sculpture, Barthé's began drawing the kind of critical attention artists dream about but rarely achieve at such a young age. In 1929, just out of art school, Barthé received an offer for a one-man show in New York, a tremendous honor. Barthé, however, was reluctant to accept, feeling he had not fully developed yet, not wanting to show in an important art center such as New York until he had refined his form more. Barthé declined the offer and spent a year studying at the Art Students League in New York. In 1930, after returning to Chicago, he had a large show at the Women's City Club. The show was a major success and it won him a Julius Rosenwald Fund fellowship.
In 1931, Barthé felt he was finally ready for a New York show and one was arranged at the Caz-Delbo Gallery, a prestigious showcase. Barthé's work at this show drew high praise and Barthé moved to the city when his Rosenwald fellowship was continued. In 1933, he exhibited at the Chicago World's Fair and, in 1934, Xavier University in New Orleans awarded him an honorary master of arts degree. In 1934, Barthé had a show at the Whitney Museum of American Art in New York, the preeminent contemporary art museum in the country. After the show, the museum purchased three of Barthé's sculptures for its permanent collection. By this time, Barthé was selling so much work that for the first time he could abandon side jobs and devote himself entirely to art.
Later in 1934, he went to Europe where the cultural heritage he observed fascinated him and where he also made several important sales to private collectors. In 1939, Barthé held his second one-man show in New York. It was his largest exhibition to date, including 18 bronze works, and was held at the Arden Galleries. Again, critical response was enthusiastic and on the strength of the work exhibited at these shows, Barthé was awarded a Guggenheim fellowship in 1940 and in 1941. In 1943, The Boxer was purchased by the Metropolitan Museum of Art in New York, America's largest and most important museum.
After the Second World War, the world of art began to change drastically, focusing on abstraction or distorted representations of reality. Barthé was not interested in these trends and was increasingly forgotten by the artistic establishment. As a result, Barthé began devoting much of his time to making portrait busts for wealthy New York clients, especially people involved in the theater. During and after the war, Barthé made busts of John Gielgud and Maurice Evans. Later works were of Lawrence Olivier, Katharine Cornell, and Judith Anderson. In 1946, he was inducted into the National Institute of Arts and Letters. By the end of the 1940s, Barthé had grown tired of the art scene in New York (and depressed over his exclusion from it) and he bought a house in Jamaica on the advice of his doctor who told him that living in the city was hurting his health.
Over the next several years, Barthé became a tourist attraction on the island, while continuing to work. In 1953, he completed a forty-foot statue for the city of Port au Prince, Haiti, depicting Jean Jacques Dessalines, leader of the 1804 revolution. He also designed several Haitian coins that are still in use. At first, Barthé enjoyed the prestige of being an expatriate black artist living in seclusion on a small Caribbean island, but by 1969 he had grown restless and decided to move to Europe. He first went to Switzerland and then, in 1970, he moved to Florence. He stayed in Italy for the next seven years, then sold everything he owned and moved to California, where he rented an apartment from an admirer. Growing increasingly impoverished and old, and getting sick as well, Barthé became a charity case. The actor James Garner, who had only recently met him, was shocked that he should be living so poorly and began secretly paying his rent and medical expenses. Other artists and actors began to help Barthé too. The city of Pasadena renamed Barthé's street Barthé Drive. A fund-raising drive was also mounted to found the Barthé Historical Society and to fund thirty Barthé scholarships for artists.
Barthé's last known work was a bust of James Garner, made in appreciation for all of Garner's help late in Barthé's life. Barthé died on March 5, 1989.
Further Reading on Richmond Barthé
Bearden, Romare, A History of African American Artists, from 1792 to the present, Pantheon Books, 1993.
Fine, Elsa Honig, "A Search for Identity, " in The Afro-American Artists, Hacker Art Books, 1982.
New York Times, March 6, 1989.