| 1: AJNR Am J Neuroradiol. 2004 Sep;25(8):1318-24. |
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Method for combining information from white matter fiber
tracking and gray matter parcellation.
Park HJ, Kubicki M, Westin CF, Talos IF, Brun A, Peiper S, Kikinis R,
Jolesz FA, McCarley RW, Shenton ME.
Clinical Neuroscience Division, Laboratory of Neuroscience, Boston VA Health
Care System-Brockton Division, Department of Psychiatry, Harvard Medical
School, Boston, MA 02301, USA.
We introduce a method for combining fiber tracking from diffusion-tensor
(DT) imaging with cortical gray matter parcellation from structural
high-spatial-resolution 3D spoiled gradient-recalled acquisition in the
steady state images. We applied this method to a tumor case to determine the
impact of the tumor on white matter architecture. We conclude that this new
method for combining structural and DT imaging data is useful for
understanding cortical connectivity and the localization of fiber tracts and
their relationship with cortical anatomy and brain abnormalities.
Publication Types:
PMID: 15466325 [PubMed - indexed for MEDLINE]
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| 2: Cancer Res. 2004 Dec 15;64(24):9160-6. |
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Specific recognition and killing of glioblastoma
multiforme by interleukin 13-zetakine redirected cytolytic T cells.
Kahlon KS, Brown C, Cooper LJ, Raubitschek A, Forman SJ, Jensen MC.
Division of Molecular Medicine, Beckman Research Institute, Departments of
Pediatric Hematology-Oncology, City of Hope National Medical Center, Duarte,
California, USA.
The interleukin (IL) 13 receptor alpha2 (IL13Ralpha2) is a glioma-restricted
cell-surface epitope not otherwise detected within the central nervous
system. Here, we describe a novel approach for targeting glioblastoma
multiforme (GBM) with IL13Ralpha2-specific cytolytic T cells (CTLs) by their
genetic modification to express a membrane-tethered IL13 cytokine chimeric
T-cell antigen receptor, or zetakine. Our prototype zetakine incorporates an
IL13 E13Y mutein for selective binding to IL13Ralpha2. Human
IL13-zetakine(+)CD8(+) CTL transfectants display IL13Ralpha2-specific
antitumor effector function including tumor cell cytolysis, T(C)1 cytokine
production, and zetakine-regulated autocrine proliferation. The E13Y amino
acid substitution of the IL13 mutein of the zetakine endows CTL
transfectants with the capacity to discriminate between IL13Ralpha2(+) GBM
targets from targets expressing IL13Ralpha1. In vivo, the adoptive transfer
of IL13-zetakine(+)CD8(+) CTL clones results in the regression of
established human glioblastoma orthotopic xenografts. Pilot clinical trials
have been initiated to evaluate the feasibility and safety of local-regional
delivery of autologous IL13-zetakine redirected CTL clones in patients with
recurrent GBM. Our IL13-zetakine is a prototype of a new class of chimeric
immunoreceptors that signal through an engineered immune synapse composed of
membrane-tethered cytokine muteins bound to cell-surface cytokine receptors
on tumors.
PMID: 15604287 [PubMed - in process]
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| 3: Cancer Res. 2004 Dec 15;64(24):9131-8. |
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The human glutathione S-transferase P1 protein is
phosphorylated and its metabolic function enhanced by the Ser/Thr protein
kinases, cAMP-dependent protein kinase and protein kinase C, in glioblastoma
cells.
Lo HW, Antoun GR, Ali-Osman F.
Department of Surgery and the Comprehensive Cancer Center, Duke University
Medical Center, Durham, North Carolina, USA.
We report here that the human glutathione S-transferase P1 (GSTP1) protein,
involved in phase II metabolism of many carcinogens and anticancer agents
and in the regulation of c-Jun NH(2)-terminal kinase-mediated cell
signaling, undergoes phosphorylation by the Ser/Thr protein kinases,
cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), resulting in
a significant enhancement of its metabolic activity. GSTP1 phosphorylation
by PKA was glutathione (GSH)-dependent, whereas phosphorylation by PKC did
not require but was significantly enhanced by GSH. In the presence of GSH,
the stoichiometry of phosphorylation was 0.4 +/- 0.03 and 0.53 +/- 0.02 mol
incorporated phosphate per mole of dimeric GSTP1 protein. The GSTP1 protein
was phosphorylated, in the presence of GSH, by eight different PKC isoforms
(alpha, betaIota, betaIotaIota, delta, epsilon, gamma, eta, and zeta),
belonging to the three major PKC subclasses, albeit with various
efficiencies. The catalytic efficiency, k(cat)/K(m), of the phosphorylated
GSTP1 was more than double that of the unphosphorylated protein. In MGR3
human glioblastoma cells, PKA and PKC activation resulted in a significant
increase in the level of phosphorylation of the GSTP1 protein and was
accompanied by a 2.1- and 2.7-fold increase, respectively, in specific GSTP1
activity in the cells. Peptide phosphorylation analyses and both
phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at
candidate amino acid residues established Ser-42 and Ser-184 as putative
phospho-acceptor residues for both kinases in the GSTP1 protein. Together,
these findings show PKA- and PKC-dependent phosphorylation as a significant
post-translational mechanism of regulation of GSTP1 function. The
GSH-dependence of the phosphorylation suggests that under high intracellular
GSH conditions, such as is present in most drug-resistant tumors, the GSTP1
protein will exist in a hyper-phosphorylated and enzymatically more active
state. In normal cells, the functional activation of the GSTP1 protein by
PKA- and PKC-dependent phosphorylation could represent a potentially
important mechanism of cellular protection, whereas in tumors, increased
phase II metabolism of anticancer drugs by the more active phosphorylated
GSTP1 protein could contribute to the drug resistance and therapeutic
failure frequently associated with increased activities of these Ser/Thr
kinases.
PMID: 15604283 [PubMed - in process]
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| 4: Cancer Res. 2004 Dec 15;64(24):9115-23. |
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Agents with selective estrogen receptor (ER) modulator
activity induce apoptosis in vitro and in vivo in ER-negative glioma cells.
Hui AM, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA.
Neuro-Oncology Branch, National Cancer Institute, National Institute of
Neurological Disorders and Stroke, National Institutes of Health, Bethesda,
Maryland, and Celgene, San Diego, California, USA.
Tamoxifen, a member of the selective estrogen receptor modulator (SERM)
family, is widely used in the treatment of estrogen receptor (ER)-expressing
breast cancer. It has previously been shown that high-dose tamoxifen has
cytotoxic activity against glioma cells, but whether this effect is drug
specific or represents a general property of SERMs is unknown. In this
study, we demonstrate that tamoxifen and CC-8490, a novel benzopyranone with
SERM activity, induce glioma cell apoptosis in a dose- and time-dependent
manner. Moreover, administration of tamoxifen and CC-8490 suppresses tumor
growth in vivo and extends animal survival in glioma xenograft models. None
of the eight glioma cell lines examined express either ER-alpha or -beta,
suggesting the mechanism for tamoxifen- and CC-8490-induced glioma cell
apoptosis is independent of the ER signaling pathway. Complementary DNA
microarray expression profiling allowed us to identify a subset of genes
specifically regulated by tamoxifen and CC-8490, and not by other apoptotic
stimuli, including nuclear factor (NF)-kappaB with its target genes IEX-3,
SOD2, IL6, and IL8. We demonstrate that suppression of NF-kappaB activation
markedly enhances SERM-induced apoptosis, suggesting a role for NF-kappaB in
protecting glioma cells from SERM-induced cytotoxicity. These findings
demonstrate for the first time that a SERM other than tamoxifen can induce
glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of
SERMs for the treatment of malignant gliomas could potentially be enhanced
by simultaneous inhibition of the NF-kappaB pathway.
PMID: 15604281 [PubMed - in process]
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| 5: Int J Cancer. 2004 Dec 17; [Epub ahead of print] |
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Reproductive and hormonal factors and risk of brain
tumors in adult females.
Hatch EE, Linet MS, Zhang J, Fine HA, Shapiro WR, Selker RG, Black PM,
Inskip PD.
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, NIH, DHHS, Rockville, MD, USA.
Causes of brain tumors are largely unknown, and there is an urgent need to
identify possible risk factors. Several observations point to a possible
role of reproductive hormones, but few epidemiologic studies have examined
whether reproductive factors, such as age at menarche and parity, are
associated with brain tumor risk. We conducted a multi-center case-control
study of newly diagnosed glioma (n = 212) and meningioma (n = 151) and
frequency-matched controls (n = 436) in women from hospitals in Phoenix,
Arizona; Boston, Massachusetts; and Pittsburgh, Pennsylvania between 1994
and 1998. Research nurses interviewed patients regarding potential risk
factors for brain tumors, including reproductive factors and hormone use.
Unconditional logistic regression analyses were used to calculate odds
ratios (ORs) and 95% confidence intervals (CIs). Risk of glioma increased
with older age at menarche [OR = 1.90 (95% CI = 1.09-3.32) for age at
menarche >/=14 vs. <12 years]. Early age at first birth was associated
with reduced risk of glioma [OR = 0.43 (95% CI = 0.23-0.83) for a first
birth before age 20 vs. nulliparity], but there was little effect of number
of births. Exogenous hormone use was also associated with a lower risk of
glioma, but risks did not vary systematically according to duration of use
or age at first use. Possibly owing to low statistical power, there were few
noteworthy associations between meningioma and reproductive factors, other
than a nonsignificant (p = 0.09) trend of increasing risk with increasing
age at menopause. The findings suggest that hormonal exposures early in life
may be associated with risk of glioma, but the evidence is inconsistent and
does not point clearly to a specific causal or protective hypothesis. (c)
2004 Wiley-Liss, Inc.
PMID: 15609304 [PubMed - as supplied by publisher]
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| 6: J Clin Oncol. 2004 Dec 15;22(24):4881-7. |
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Feasibility and response to induction chemotherapy
intensified with high-dose methotrexate for young children with newly
diagnosed high-risk disseminated medulloblastoma.
Chi SN, Gardner SL, Levy AS, Knopp EA, Miller DC, Wisoff JH, Weiner HL,
Finlay JL.
Dana-Farber Cancer Institute, 44 Binney St, SW331, Boston, MA 02115; e-mail:
susan_chi@dfci.harvard.edu.
PURPOSE To evaluate the feasibility of and response rate to an intensified
induction chemotherapy regimen for young children with newly diagnosed
high-risk or disseminated medulloblastomas. PATIENTS AND METHODS From
January 1997 to March 2003, 21 patients with high-risk or disseminated
medulloblastoma were enrolled. After maximal surgical resection, patients
were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses
per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4
mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per
cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin
rescue. Following induction chemotherapy, eligible patients underwent a
single myeloablative chemotherapy cycle with autologous stem-cell rescue.
Results Significant toxicities of this intensified regimen, including
gastrointestinal and infectious toxicities, are described. Among the 21
patients enrolled, there were 17 complete responses (81%), two partial
responses, one stable disease, and one progressive disease. The 3-year
event-free survival and overall survival are 49% (95% CI, 27% to 72%) and
60% (95% CI, 36% to 84%), respectively. CONCLUSION This intensified
induction chemotherapy regimen is feasible and tolerable. With the majority
of patients with disseminated medulloblastoma having M2 or M3 disease at
diagnosis, the encouraging high response rate of this intensified induction
regimen suggests that such an addition of methotrexate should be explored in
future studies.
PMID: 15611503 [PubMed - in process]
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| 7: J Neurochem. 2005 Jan;92(1):1-9. |
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Activated JNK brings about accelerated apoptosis of
Bcl-2-overexpressing C6 glioma cells on treatment with tamoxifen.
Moodbidri MS, Shirsat NV.
Neuro-oncology, Advanced Centre for Treatment, Research & Education in
Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
Abstract Tamoxifen causes apoptosis of malignant glial cells at a
concentration that does not kill normal astrocytes. C6 glioma cells were
stably transfected with a vector expressing Bcl-2 under the control of
metallothionin promoter. Low leaky Bcl-2 expression offered complete
protection against tamoxifen-induced apoptosis. High Bcl-2 levels, on the
other hand, accelerated the apoptosis, with Bcl-2-overexpressing clones
dying within 48 h of tamoxifen treatment as compared to 6 days for parental
C6 cells. Overexpressed Bcl-2 is localized primarily in mitochondria and to
a much lower extent in endoplasmic reticulum (ER). Only a minor fraction of
the overexpressed Bcl-2 gets phosphorylated in tamoxifen-treated cells and
the phosphorylation does not affect its binding to Bax. Tamoxifen treatment
of Bcl-2-overexpressing clones was found to result in activation of c-Jun
N-terminal kinase (JNK) and p38 kinase. Inhibition of JNK but not p38 kinase
completely abrogated the accelerated apoptosis. Constitutively expressed
endogenous c-Jun was found to be phosphorylated, resulting in increased
activator protein 1 (AP-1) DNA-binding activity. Expression of Fas ligand
(FasL), an AP-1 transcriptional target, increased during accelerated cell
death. This presumably brought about activation of caspase 8, as inhibition
of caspase 8 blocked the apoptosis. The JNK/c-Jun/AP-1/FasL pathway could be
considered as a potential target for the therapy of gliomas.
PMID: 15606891 [PubMed - in process]
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| 8: Neurology. 2004 Jul 13;63(1):167-9. |
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Clonal evolution as pathogenetic mechanism in relapse of
primary CNS lymphoma.
Pels H, Montesinos-Rongen M, Schaller C, Van Roost D, Schlegel U,
Wiestler OD, Deckert M.
Department of Neurology, University of Bonn, Germany.
Comparative investigation of immunoglobulin (Ig) heavy chain gene
rearrangements and DNA sequence analyses of a primary lymphoma of the CNS
(PCNSL) and its recurrence revealed that both tumors used the same Ig gene
segment. In addition to shared somatic mutations, the primary and the
recurrent PCNSLs harbored somatic mutations unique to each tumor. Clonal
evolution rather than subclone selection appears to underlie the development
of tumor recurrence in this case.
Publication Types:
PMID: 15249632 [PubMed - indexed for MEDLINE]
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| 9: Neurology. 2004 Jun 8;62(11):2025-30. |
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Stroke in patients with cancer: incidence and etiology.
Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM.
Department of Neurology, Weill College of Medicine of Cornell University,
New York, USA.
OBJECTIVE: To assess the incidence and type of strokes in patients with
cancer at Memorial Sloan-Kettering Cancer Center. METHODS: Retrospective
review of all ischemic strokes diagnosed by a neurologist and confirmed by
neuroimaging between February 1997 and April 2001 was conducted. Age,
gender, cancer diagnosis and stage, and vascular risk factors were recorded.
NIH Stroke Scale and modified Rankin Scale scores were calculated
retrospectively. Stroke etiology was assigned independently by two
neurologists using the Trial of Org 10172 in Acute Stroke Treatment (TOAST)
criteria. RESULTS: Ninety-six patients with a confirmed stroke were
identified. The median age was 67, and 61.5% were men. The distribution of
vascular risk factors was comparable with that seen in large stroke trials.
Lung cancer (30%) was the most common primary tumor followed by brain and
prostate cancer (9% each). Strokes were embolic in 52 (54%) and nonembolic
in 44 (46%). Eleven of 12 tested patients had an elevated D-dimer level, but
in only 3 patients could a definitive diagnosis of nonbacterial thrombotic
endocarditis be made. The median survival was 4.5 months (95% CI 2.8 to 9.5)
from the diagnosis of stroke; 25% of patients died within 30 days. Treatment
had no effect on survival. CONCLUSIONS: Embolic strokes are the commonest
cause of stroke in patients with cancer, due partially to
hypercoagulability, whereas atherosclerosis accounted for only 22% of stroke
in this population. Outcome was primarily determined by the underlying
malignancy and the patient's neurologic condition.
Publication Types:
PMID: 15184609 [PubMed - indexed for MEDLINE]
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| 10: Oncogene. 2004 Nov 25;23(55):8908-19. |
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TMF/ARA160 is a BC-box-containing protein that mediates
the degradation of Stat3.
Perry E, Tsruya R, Levitsky P, Pomp O, Taller M, Weisberg S, Parris W,
Kulkarni S, Malovani H, Pawson T, Shpungin S, Nir U.
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
TMF/ARA160 is a Golgi resident protein whose cellular functions have not
been conclusively revealed. Herein we show that TMF/ARA160 can direct the
proteasomal degradation of the key cell growth regulator - Stat3. TMF/ARA160
was dispersed in the cytoplasm of myogenic C2C12 cells that were grown under
low-serum conditions. The cytoplasmic distribution of TMF/ARA160 was
accompanied by its transient association with the tyrosine kinase Fer and
with Stat3, which underwent proteasomal degradation under those conditions.
Moreover, serum deprivation induced the association of ubiquitinated
proteins, with the TMF/ARA160 complex. However, TMF/ARA160 did not bind
Stat1, whose cellular levels were increased in serum-starved C2C12 cells.
Amino-acid sequence analysis identified a BC-box element in TMF/ARA160 that
mediated the binding of this protein to elongin C. Ectopic expression of
TMF/ARA160 in serum-starved C2C12 cells drove the ubiquitination and
proteasomal degradation of Stat3, an effect that was not caused by
TMF/ARA160 devoid of the BC-box motif. Thus, the Golgi apparatus harbors a
novel BC-box-containing protein that can direct Stat3 to proteasomal
degradation. Interestingly, the level of TMF/ARA160 was significantly
decreased in malignant brain tumors, implying a suppressive role of that
protein in tumor progression.
PMID: 15467733 [PubMed - indexed for MEDLINE]
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| 11: Pediatr Neurosurg. 2004 Jul-Aug;40(4):196-202. |
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Delayed persistent hyperthermia after resection of a
craniopharyngioma.
Chatzisotiriou AS, Selviaridis PK, Kontopoulos VA, Kontopoulos AV,
Patsalas IA.
Department of Neurosurgery, AHEPA University Hospital, Aristotle University
of Thessaloniki, Thessaloniki, Greece.
OBJECTIVE AND IMPORTANCE: Disorders of thermoregulation are occasionally
noticed after operations in the region of the third ventricle. Various
factors are usually implicated, but the actual contribution of each of them
is rather vague. Apart from the presumed derangement in the functional
connections of the hypothalamic region, mechanical reasons of compression
should be thoroughly considered. CLINICAL PRESENTATION: An 8.5-year-old
patient was subjected to a radical excision of a craniopharyngioma
compressing the third ventricle. Three months after the operation, he
presented with a febrile syndrome of unknown origin. All usual
investigations proved negative. INTERVENTION: A chronic subdural hygroma was
evacuated, an encapsulated CSF cyst of the suprachiasmatic cistern was
drained and the lamina terminalis incised resulting in a moderate control of
pyrexia. The administration of chlorpromazine contributed to the final
resolution of hyperthermia. CONCLUSION: Postoperative hyperthermia may
result following resection of tumors of the hypothalamic floor. It should
not be blindly attributed to hypothalamic dysfunction as surgical causes
could be implicated as well. Chlorpromazine could be a useful adjunct to the
correction of the disorder. Copyright 2004 S. Karger AG, Basel.
PMID: 15608494 [PubMed - in process]
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Volume 3, Supplement 21 - 28 December 2004