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Biomedical subjects

M Weller

Publications and source records attributed to M Weller.

At least 37 records · Page 2Linked to original sources
PubMed2003

Expression and functional activity of osteoprotegerin in human malignant gliomas.

Apo2L/TRAIL-based therapy is a promising experimental approach to the treatment of human malignant gliomas. Osteoprotegerin (OPG) is a soluble decoy receptor for Apo2L/TRAIL that antagonizes Apo2L/TRAIL-induced apoptosis. High levels of OPG expressed by tumor cells might therefore abrogate the activity of exogenously added or adenovirally expessed Apo2L/TRAIL. Here we assessed the expression of OPG in human gliomas in vivo, in primary glioma cell cultures and in established glioma cell lines. Immunohistochemistry revealed weak OPG immunoreactivity in up to 5% of the tumor cells in 8 of 13 glioblastomas. Strong OPG labeling was detected in single scattered tumor cells in one of these specimens. Five glioblastomas did not express OPG. High OPG expression was found in 1 of 6 primary glioma cell cultures and in 1 of 12 established glioma cell lines, T98G. OPG released by T98G cells was biologically active in that it inhibited Apo2L/TRAIL-induced apoptosis in sensitive glioma cells. Altogether, however, these data suggest that OPG expression may not be a major pathway of glioma cell resistance to future Apo2L/TRAIL-based therapeutic approaches.

Apoptosis↗
PubMed2003

Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts.

Pseudomonas aeruginosa infection is a serious complication in patients with cystic fibrosis and in immunocompromised individuals. Here we show that P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts. Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells. Failure to generate ceramide-enriched membrane platforms in infected cells results in an unabated inflammatory response, massive release of interleukin (IL)-1 and septic death of mice. Our findings show that ceramide-enriched membrane platforms are central to the host defense against this potentially lethal pathogen.

Animals↗
PubMed2003

[Neurooncology].

The central and peripheral nervous systems give rise to a variety of tumors which differ markedly in their incidence, age preference, and prognosis. The nervous system is also frequently affected by metastatic cancer. The major therapeutic options for tumors of the nervous system include surgical resection, radiotherapy using various strategies of fractionation, total dose, and target volume, and different approaches of chemotherapy such as systemic, intrathecal, and interstitial chemotherapy as well as high-dose chemotherapy with stem cell rescue. An increasing number of therapeutic options in neurooncology are no more merely palliative treatments, but may be curative, indicating that neurooncology is experiencing an era both of controversies regarding previous standards of care and of innovative strategies to combat tumors of the nervous system.

Antineoplastic Agents↗
PubMed2003

A prospective trial of mechanical physiotherapy for lumbar disk prolapse.

Fifty consecutive patients with neuroradiologically confirmed lumbar disk prolapse, who responded to the first five daily physiotherapy sessions with pain centralization, were prospectively treated with mechanical physiotherapy (McKenzie). At a median follow-up of 55 weeks, there were high rates of patient satisfaction, recovery from neurological deficits, and employment, and a low rate of surgical interventions. Mechanical physiotherapy is thus a useful diagnostic tool and an effective treatment strategy for many patients with lumbar disk disease.

Adolescent↗
PubMed2003

Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death.

Hypoxia induces apoptosis in primary and transformed cells and in various tumor cell lines in vitro. In contrast, there is little apoptosis and predominant necrosis despite extensive hypoxia in human glioblastomas in vivo. We here characterize ultrastructural and biochemical features of cell death in LN-229, LN-18 and U87MG malignant glioma cells in a paradigm of hypoxia with partial glucose deprivation in vitro. Electron microscopic analysis of hypoxia-challenged glioma cells demonstrated early stages of apoptosis but predominant necrosis. ATP levels declined during hypoxia, but recovered with re-exposure to normoxic conditions unless hypoxia exceeded 8 h. Longer hypoxic exposure resulted in irreversible ATP depletion and delayed cell death. Hypoxia induced mitochondrial release of cytochrome c, but there was no cleavage of caspases 3, 7, 8 or 9, and no DNA fragmentation. Ectopic expression of BCL-XL conferred protection from hypoxia-induced cell death, whereas the overexpression of the antiapoptotic proteins X-linked-inhibitor-of-apoptosis-protein and cytokine response modifier-A had no effect. These findings suggest that glioma cells resist adverse effects of hypoxia until energy stores are depleted and then undergo necrosis rather than apoptosis because of energy deprivation.

Adenosine Triphosphate↗
PubMed2003

NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells.

Death receptor-mediated apoptosis of human malignant glioma cells triggered by CD95 ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) share several features, including processing of multiple caspases and mitochondrial cytochrome c release. We here report that CD95L-induced cell death is inhibited by sulfasalazine (SS) in all of four human glioma cell lines, both in the absence and presence of cycloheximide (CHX). Coexposure to CD95L and SS prevents the CD95L-evoked processing of caspases 2, 3, 8 and 9, the release of cytochrome c from mitochondria, and the loss of BCL-x(L) protein. This places the protective effect of SS proximal to most known events triggered by the CD95-dependent signaling pathway in glioma cells. CD95L promotes the accumulation of nuclear factor kappa B (NF-kappaB) in the nucleus and induces the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay. The total levels of p50, p65 and IkappaBalpha remain unchanged, but the levels of phosphorylated IkappaBalpha and of nuclear p65 increase, in response to CD95L. IkappaBalpha phosphorylation as well as nuclear NF-kappaB translocation and DNA binding are blocked by SS. However, unlike SS, dominant-negative IkappaBalpha (IkappaBdn) does not block apoptosis, suggesting that SS inhibits CD95L-mediated apoptosis in an NF-kappaB-independent manner. In contrast to CD95L, the cytotoxic effects of Apo2L/TRAIL are enhanced by SS, and SS facilitates Apo2L/TRAIL-evoked caspase processing, cytochrome c release, and nuclear translocation of p65. These effects of SS are nullified in the presence of CHX, suggesting that the effects of SS and CHX are redundant or that enhanced apoptosis mediated by SS requires protein synthesis. IkappaBdn fails to modulate Apo2L/TRAIL-induced apoptosis. Similar effects of SS on CD95L- and Apo2L/TRAIL-induced apoptosis are observed in MCF-7 breast and HCT116 colon carcinoma cells. Interestingly, HCT cells lacking p21 (80S14(p21-/-)) are only slightly protected by SS from CD95L-induced apoptosis, but sensitized to Apo2L/TRAIL-induced apoptosis, indicating a link between the actions of SS and p21. Thus, SS modulates the death cascades triggered by CD95L and Apo2L/TRAIL in opposite directions in an NF-kappaB-independent manner, and SS may be a promising agent for the augmentation of Apo2L/TRAIL-based cancer therapies.

Antineoplastic Agents↗
PubMed2003

March 2003: a 41 -year-old female with a solitary lesion in the liver.

The March COM. A 41-year-old woman presented in 1997 with diffuse abdominal pain, meteorism and intermittent diarrhea. Imaging studies revealed a focal rounded lesion in the liver. Although there was no history of progesterone or estrogen therapy, the radiographic appearance was considered to be suggestive of adenoma. The lesion was monitored by ultrasound until October 2000 when a resection was performed because of the presumed risk of a malignant transformation. H&E stained sections revealed an ectopic ependymoma that was strongly positive for GFAP. The surrounding hepatic tissue was negative for GFAP. An extensive search for a CNS manifestation or any other extraspinal localization was unrevealing. We believe we have encountered the first case of an ectopic ependymoma presenting as a solitary hepatic lesion in the absence of CNS disease. Ependymomas generally arise in the CNS in relation to the ventricular system. Extraneural metastasis from ependymomas may occasionally occur even years after detection and treatment of the primary lesion and have been the subject of several reports. In contrast, there are only anecdotal reports of primary extraneural "ectopic" ependymomas. So far those rare cases have only been found in close vicinity to the neural axis, eg, in the sacrococcygeal region, the posterior mediastinum or the ovaries and are there thought to originate from embryonic remnant cells around the neural tube. Distant metastases of ependymomas invading or arising within the extraneural lumbosacral soft tissue may occur in this situation. Here, we report what appears to be the first case of a primary ectopic ependymoma originating in the liver, with no signs of CNS or other systemic involvement.

Abdominal Pain↗
PubMed2002

Primary central nervous system (CNS) lymphoma in immunocompetent patients.

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Primary CNS lymphoma in the spinal cord: clinical manifestations may precede MRI detectability.

We report a 36-year-old woman whose first MRI after developing symptoms of cervical nerve root irritation was normal. Eight months later, after progression to tetraparesis and demonstration of an extensive contrast-enhancing intramedullary lesion giving high signal on T2-weighted images, the diagnosis of lymphoblastic non-Hodgkin's lymphoma was made by biopsy. The lesion responded for a short time to corticosteroid medication, but later rapidly extended to the epidural soft tissues, probably due to a cerebrospinal fluid fistula. Despite radio-and chemotherapy, the patient survived only 7 months from histological diagnosis and 15 months from the onset of symptoms.

Adult↗
PubMed2002

Ocular manifestation of primary nervous system lymphoma: what can be expected from imaging?

Primary ocular lymphoma, which affects the posterior parts of the eye, is an ocular manifestation of primary central nervous system lymphoma (PCNSL). It used to be the ocular disease with the shortest time of survival, even worse than ocular melanoma. Death ensues by CNS dissemination. Unfortunately, ocular lymphoma may be the initial manifestation of PCNSL and diagnosis is frequently difficult, even if vitreal biopsy is performed. Therefore, it should be determined whether cross sectional imaging may be helpful in detection and differential diagnosis of ocular lymphoma. MRI of seven patients (female = 6, male = 1, median age 62 years) with biopsy proven ocular lymphoma were retrieved from the files of our hospital and of a multicenter PCNSL study. In four patients, ocular lymphoma was the first manifestation of PCNSL, in three a cerebral lesion had occurred in the first place. Progression to cerebral lymphoma was seen in three of the four patients with initial eye manifestation. Imaging was performed using a dedicated thin section protocol in four patients. An intraocular abnormality was found in four cases, always in T1-weighted images after contrast injection. Differential diagnosis from uveitis or ocular melanoma was not possible by imaging alone. The examination was falsely negative in the remaining three patients.Hence, imaging has a low sensitivity for ocular lymphoma and does not facilitate differential diagnosis against uveitis or ocular melanoma.

Aged↗
PubMed2002

Myelopathy in primary Sjögren's syndrome: diagnostic and therapeutic aspects.

We report a patient with a myelopathy in primary Sjögren's syndrome, proven by salivary gland biopsy and specific antibodies. Under steroid medication, the patient had a remitting and relapsing clinical course. The severity of clinical symptoms correlated with a transient contrast uptake in spinal magnetic resonance imaging. Under a treatment with azathioprine and prednisone the patient has suffered no relapse within the last 20 months. Although this is only a case report, the combination of azathioprine and prednisone may be a valuable medication in chronic cases of Sjögren's syndrome with neurologic symptoms.

Aged↗
PubMed2002

Identification of inhibitor-of-differentiation 2 (Id2) as a modulator of neuronal apoptosis.

Inhibitor-of-differentiation 2 (Id2) belongs to a family of transcriptional modulators that are characterized by a helix loop helix region but lack the basic amino acid domain. During development, Id2 antagonizes differentiation mediated by the retinoblastoma protein, probably by scavenging downstream E-box basic helix-loop-helix proteins. Here, using differential display RT-PCR, we identify Id2 as an induced gene during serum and potassium deprivation-induced apoptosis of cerebellar granule neurons. Consistent with a biological role for induced Id2 messenger RNA and protein expression in neuronal cell death, expression of Id2 antisense RNA, or targeted deletion of the Id2 gene in neurons from Id2 knock-out mice, protect from apoptosis. Further, gene transfer- mediated overexpression of Id2 induces neuronal cell death both in high potassium and low potassium conditions. Thus, the present study defines a role for Id2 in the modulation of neuronal apoptosis.

Animals↗
PubMed2002

Irradiated homozygous TGF-beta1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF-beta1 wild-type fibroblasts.

PURPOSE: To study the role of transforming growth factor beta1 (TGF-beta1) on cellular radiation sensitivity by analysing mouse lung fibroblasts of different TGF-beta1 genotypes. MATERIALS AND METHODS: Heterozygous TGF-beta1 knock-out mice were mated to produce offspring of different TGF-beta1 genotypes as confirmed by PCR-genotyping. Primary lung fibroblast populations were established from new-born animals of specific genotypes (TGF-beta1(+/+), TGF-beta1(+/-), TGF-beta1(-/-)). Production of TGF-beta1 was tested by ELISA. TGF-beta1 receptor-II mRNA expression was analysed by RT-PCR. Colony formation of untreated, TGF-beta1-treated and/or irradiated primary lung fibroblasts was determined under different medium conditions. RESULTS: Plating efficiencies under different medium conditions were independent of TGF-beta1 genotype. Production of TGF-beta1 correlated with the genotype: heterozygous TGF-beta1 knock-out fibroblasts (TGF-beta1(+/-)) produced 60-65% of wild-type (TGF-beta1(+/+) cells). As expected, homozygous TGF-beta1 knock-out fibroblasts (TGF-beta1(-/-)) did not produce TGF-beta1. Radiation exposure significantly enhanced TGF-beta1 production in TGF-beta1(+/+) cells by a factor of 2. No such stimulation was observed in TGF-beta1(+/-) cells. TGF-beta1(+/-) and especially TGF-beta1(-/-) cells were significantly more radioresistant than TGF-beta1(+/+) cells. TGF-beta1 treatment significantly reduced clonogenic survival for both TGF-beta1(+/+) and TGF-beta1(-/-) cells. TGF-beta1 treatment of TGF-beta1(-/-) cells resulted in an enhancement of radiation sensitivity. CONCLUSION: The data are the first direct evidence that TGF-beta1 is a major autocrine regulator of intrinsic radiation sensitivity of mouse lung fibroblasts.

Activin Receptors, Type I↗
PubMed2002

CD95/CD95 ligand-independent potentiation of treosulfan cytotoxicity by BSO in malignant glioma cells in vitro and in vivo.

The glutathione synthase inhibitor, buthionine sulfoximine (BSO), specifically enhances the cytotoxic effects of treosulfan in human glioma cells. BSO depletes glutathione and greatly enhances treosulfan cytotoxicity in all the 12 human malignant glioma cell lines examined. None of these cell lines showed enhanced susceptibility to CD95L- or tumor necrosis factor (TNF)-alpha-induced apoptosis when glutathione is depleted. The combination of serial systemic BSO applications (300 mg/kg) and a single systemic dose of treosulfan (2.5 g/kg) reduced the growth of intracranially growing rat C6 gliomas in vivo by 73% whereas treosulfan alone reduced tumor growth by 16% and BSO alone had no effect. BSO lowered glutathione levels to 25-30% in peripheral blood mononuclear cells (PBMC) and to 50% in the glioma tissue. The glutathione levels in the non-tumor-bearing contralateral hemisphere were unaffected by systemic BSO treatment. The main side effects of treosulfan, gastrointestinal and bone marrow toxicity, were not significantly enhanced by BSO.

Animals↗
PubMed2001

Diva/Boo is a negative regulator of cell death in human glioma cells.

Diva is a novel proapoptotic member of the Bcl-2 protein family which binds apoptosis activating factor-1 (APAF-1). Diva is identical with Boo which was identified as a novel antiapoptotic Bcl-2 family protein. Here, we report that Diva promotes the cell cycle exit of human glioma cells in response to serum deprivation and inhibits apoptosis of these cells induced by CD95 ligand or chemotherapeutic drugs. In glioma cells, Diva interferes with apoptotic signaling downstream of cytochrome c release, but upstream of caspase activation, consistent with an inhibitory effect on the mitochondrial amplification step involving the apoptosome and APAF-1.

Apoptotic Protease-Activating Factor 1↗
PubMed2001

Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease.

Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP(+)) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP(+) led to the sequential phosphorylation and activation of JNK kinase (MKK4), JNK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the JNK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of JNK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the JNK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.

Adaptor Proteins, Signal Transducing↗