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Thomas Gasser

Publications and source records attributed to Thomas Gasser.

At least 55 records · Page 3Linked to original sources
PubMed2005

High-throughput tissue microarray analysis of COX2 expression in urinary bladder cancer.

To investigate whether protein expression of cyclooxygenase 2 (COX2) is associated with tumor phenotype, immunohistochemical alterations, and clinical outcome in urinary bladder cancer (BC). Tissue microarrays (n = 776) were used to analyze COX2, P53 and the Ki-67 labeling index immunohistochemically. A monoclonal mouse antibody was used after heat-induced antigen retrieval. COX2 expression was scored semiquantitatively (0-3+). COX2 expression was detected in 60% (368/617) of urothelial BC. Positive COX2 staining was seen in 77.8% (140/182) of muscle invasive urothelial BC, compared to 35% (7/20) of muscle invasive squamous cell carcinomas (p < 0.001). COX2 protein expression was associated with advanced tumor stage (p < 0.0001), high-grade histology (p < 0.0001), solid growth pattern in invasive BC (pT1-4, p = 0.02), high Ki-67 labeling index (p < 0.0001), and positive P53 IHC (p < 0.001). COX2 expression was not associated with survival, recurrence, and progression in clinically relevant subgroups (pTa, pT1, pT2-4). Expression of COX2 is common in advanced BC with poor prognostic characteristics, supporting efforts to initiate clinical trials on the efficacy of COX2 inhibitors in the adjuvant treatment of high-risk urinary BC.

Aged↗
PubMed2004

Fusion of the cerebellar hemispheres ventral to the brainstem: a rare hindbrain-related malformation.

INTRODUCTION: New variations of cerebellar malformations are being increasingly recognized using modern neuroimaging techniques. Until now only dorsal cerebellar fusion syndromes, such as the rhombencephalosynapsis and its variations have been recognized. CASE REPORT: We report on a 17-month-old male infant presenting with an exceptional hindbrain related malformation characterized by midline fusion of the cerebellar hemispheres ventral to the brainstem and causing symptoms due to brainstem compression. DISCUSSION AND CONCLUSION: A more detailed understanding of the cerebellar embryogenesis is required to unravel the underlying mechanisms leading to this type of cerebellar malformation, which cannot easily be integrated into the common classification systems. Both the morphological features and the clinical presentation are different from those of other cerebellar structural abnormalities. If this type of congenital malformation is detected more frequently in the future, it seems reasonable that it should be added to the list of cerebellar malformations as a distinct type.

Cerebellar Diseases↗
PubMed2004

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

Adult↗
PubMed2004

Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88.

PURPOSE: To determine if immediate hormonal therapy is advantageous compared with deferred treatment in newly diagnosed asymptomatic prostate cancer patients who, for any reason, were not candidates for curative local treatment. PATIENTS AND METHODS: Between February 1988 and February 1992, 197 patients with a median age of 76 years (range, 56 to 86 years) were randomly assigned to receive either immediate or deferred orchiectomy on symptomatic progression. The two groups did not differ significantly in clinical or laboratory parameters; 67% had T3-4 tumors and 20% had lymph node metastases. Patient accrual was stopped prematurely because of a similar competing trial. Therefore, observation time was prolonged to achieve the desired number of events and statistical power. RESULTS: Deferred orchiectomy was necessary in 58% of the patients. Median time to disease progression was 2.8 years less than for patients with immediate orchiectomy. However, overall pain-free time from random assignment to symptomatic progression after immediate or deferred orchiectomy, and performance status, were identical in both groups. Cancer-specific survival tended to be longer in the immediate group (P = .09) but there was no difference in overall survival between the two groups (P = .96). The median hemoglobin value decreased significantly after immediate orchiectomy (P < .001). CONCLUSION: For elderly, asymptomatic patients not undergoing curative local treatment, we were unable to show any major advantage of immediate compared with deferred hormonal treatment regarding quality of life or overall survival in our limited number of patients. Disabling complications were prevented in the deferred-treatment arm by careful follow-up; 42% of these patients never required any tumor-specific treatment.

Aged↗
PubMed2004

E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.

E2F3 is located in the 6p22 bladder amplicon and encodes a transcription factor important for cell cycle regulation and DNA replication. To further investigate the role of E2F3 in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for gene copy number and expression analysis by means of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). E2F3 amplification was strongly associated with invasive tumor phenotype and high tumor grade (P < 0.0001 each). None of 272 pTaG1/G2 tumors, but 35 of 311 pT1-4 carcinomas (11.3%), had E2F3 amplification. A high E2F3 expression level was associated with high grade, advanced stage, and E2F3 gene amplification (P < 0.0001 each). To evaluate whether E2F3 expression correlates with tumor proliferation, the Ki67 labeling index (LI) was analysed for each tumor. There was a strong association between a high Ki67 LI and E2F3 expression (P < 0.0001), which was independent of grade and stage. We conclude that E2F3 is frequently amplified and overexpressed in invasively growing bladder cancer (stage pT1-4). E2F3 expression appears to provide a growth advantage to tumor cells by activating cell proliferation in a subset of bladder tumors.

Cell Division↗
PubMed2004

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease.

An increasing number of studies have shown that an inflammatory process is part of Parkinson's disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.

Adult↗
PubMed2004

An interleukin-6 promoter variant is not associated with an increased risk for Alzheimer's disease.

Recent studies have implicated interleukin-6 (IL-6) in the pathogenesis of Alzheimer's disease (AD). Neuro-inflammatory processes surrounding the amyloid plaques contribute to the progression of AD-related neurodegeneration. IL-6 is a multifunctional inflammatory cytokine which possibly acts as a mediator in the local immune response in the brain of AD patients. In this study we investigated whether the risk of developing AD is altered in carriers of the C allele of a G/C polymorphism at position -174. 113 AD patients and 108 age- and gender-matched nondemented control subjects were analysed. Genotyping of IL-6 was performed using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender and apolipoprotein E epsilon4 status. There was no evidence for an association between the polymorphism and the risk of developing AD. No evidence of an earlier age at onset for carriers of the C allele was evaluated. We conclude that IL-6 (-174) polymorphism does not influence the risk of developing AD in our cohort.

Aged↗
PubMed2004

UCHL1 is a Parkinson's disease susceptibility gene.

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.

Adult↗
PubMed2004

Quantification of oxygen fluxes in a long gravity sewer.

Quantification of the oxygen fluxes in the sewer system is at present the optimal methodology to obtain information about the influence of sewers on transformations and mass balances in the urban drainage system. However, the relative and absolute values of these fluxes are practically unknown. In this work, the oxygen fluxes were quantified experimentally in a full-scale aerobic main sewer. The sewer biofilm respiration was determined with an in situ flow cell, a method that has not been used before in the sewer. The surface reaeration was determined with a gas tracer method based on the inert, non-radio-active and non-toxic gas tracer sulphur hexafluoride. In addition, the wastewater biomass respiration rate was measured. The validity of the applied methods was verified with redundant oxygen balances over a 2-km-long section. Measurement campaigns under different hydrodynamic conditions showed that the relative contribution of the biofilm, the wastewater, the reaeration and the in- and outflow with the water, all contributed significantly. However, the absolute contributions varied extensively and depended especially on the discharge. The COD conversion in the sewer could be estimated from the aerobic activity. The aerobic total degradation in the study reach was 3%. However, when extrapolated to the entire sewer net of the catchment area with 5000 PE, the COD conversion was estimated as high as 30% of the dissolved COD during the night. This indicates that the wastewater composition at the treatment plant will be strongly affected by the sewer system.

Bacteria, Aerobic↗
PubMed2004

TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.

Studies by comparative genome hybridization have suggested that 5p amplification is related to tumor progression in urinary bladder cancer. In this study seven genes (TAS2R, ADCY2, DNAH5, CTNND2, TRIO, ANKH, and MYO10) located to 5p15.31-5p15.1 were analyzed by fluorescence in situ hybridization using a tissue microarray containing samples from tumors and cell lines with known 5p amplification by comparative genome hybridization. Amplification frequency was highest for TRIO, which maps to 5p15.2 and encodes a protein with a putative role in cell-cycle regulation. To further investigate the role of TRIO amplification in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for fluorescence in situ hybridization analysis. TRIO amplification was strongly associated with invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation (Ki67 LI) (P < 0.0001 each). Only 7 of 456 pTaG1/G2 tumors (1.5%) but 62 of 485 pT1-4 carcinomas (12.8%) had TRIO amplification. TRIO amplification was not associated with poor prognosis. Using a frozen bladder tumor tissue microarray RNA in situ hybridization confirmed that TRIO is up-regulated in amplified tumors. It is concluded that TRIO up-regulation through amplification has a potential role in bladder cancer progression.

Carcinoma↗
PubMed2004

New aspects of genetic contributions to Parkinson's disease.

Over the last few years, several genes for rare, monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In dominant families, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in intracellular inclusions (Lewy bodies) may be crucial in the molecular pathogenesis of the disease. Three genes have been identified to cause autosomal-recessive early-onset parkinsonism: parkin, DJ1, and PINK1. These genes are thought to be involved in the proteasomal protein degradation pathway, in the cell's response to oxidative stress, and in mitochondrial function, respectively. It is therefore concluded that these cellular mechanisms may play an important role in the degenerative process of PD. There is also accumulating evidence that genetic factors play a role in the common sporadic form of PD, however their precise nature remains unknown.

Animals↗
PubMed2003

The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval.

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.

Chromosome Mapping↗
PubMed2003

HER-2 and TOP2A coamplification in urinary bladder cancer.

HER-2/NEU is one of the most frequently amplified oncogenes and a potential therapeutic target in bladder cancer. In breast cancer, the adjacent TOP2A gene, the molecular target for several anticancer drugs, is frequently coamplified together with HER-2. To study the amplification and expression of TOP2A and HER-2 and associations with tumor phenotype and clinical outcome in bladder cancer, a tissue microarray containing 2,317 bladder tumor samples was analyzed by FISH and immunohistochemistry. Overall amplification frequencies were 6.3% for HER-2 and 1.5% for TOP2A. Amplifications were most frequently seen in advanced-stage (pT2-4) tumors (HER-2 13.8%, TOP2A 3.4%). Of HER-2-amplified tumors, 56% also had alterations of TOP2A, including 14.7% coamplifications, 33.3% gains and 8% deletions. Only 17.6% of TOP2A amplifications occurred independently of HER-2 alterations. Both HER-2 and TOP2A amplifications were significantly associated with advanced tumor stage (HER-2 p < 0.0001, TOP2A p = 0.0218), high grade (p < 0.0001 for both) and protein overexpression (p < 0.0001 for both). TOP2A amplification and overexpression were linked to shortened survival in muscle-invasive tumors (p = 0.0042 and 0.0077, respectively). In summary, our data suggest that HER-2 amplifications are frequently linked to alterations of the TOP2A gene in bladder cancer. The anatomy of the 17q12-q21 amplicon may be important for response to therapies targeting HER-2 or TOP2A.

Antigens, Neoplasm↗
PubMed2003

Lack of association of interleukin-10 promoter region polymorphisms with Alzheimer's disease.

There is increasing evidence that immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recently, polymorphisms of the interleukin (IL)-1 and IL-6 genes were found to be associated with late-onset AD. The immunoregulatory IL-10 downregulates synthesis of pro-inflammatory cytokines such as IL-1. Current evidence suggests that some polymorphisms in the IL-10 promoter may have functional effects on IL-10 transcription. A total of 406 German AD patients (mean age 70.2+/-10.0 years, range 50-95 years, 42% female) and 251 unrelated non-demented control subjects (mean age 66.8+/-10.6 years, range 50-93 years, 38% female) were investigated for the presence of three polymorphisms in the IL-10 promoter region (-1087A/G, -824C/T, -597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms have been found between AD patients and controls. We conclude that polymorphisms in the IL-10 promoter region do not increase the risk of developing AD.

Aged↗
PubMed2003

Intramedullary spinal cord cavernous malformations: clinical features and risk of hemorrhage.

The aim of this study was to review the natural history of symptomatic intramedullary spinal cord (IMSC) cavernous malformations in order to analyze the underlying mechanisms leading to symptoms and determine the potential risk of lesional hemorrhage. Between January 1990 and June 2001, ten consecutive patients with IMSC cavernous malformations were treated surgically in our institution. Age ranged from 17 to 73 years (mean 34.5). All patients became symptomatic due to one or more hemorrhages leading to neurological deficits of different severity, with a more aggressive course for upper cervical lesions. Pre- and postoperative patient condition was classified according to the Frankel scale. Four patients experienced one hemorrhage, four patients two, one patient three, and another one five repeated hemorrhages. The annual retrospective hemorrhage rate for symptomatic IMSC cavernous malformations was 4.5% per patient/year, with a prospective rehemorrhage risk of 66% per patient/year. The postoperative condition was improved in four patients and unchanged in six, and none grew worse. Detailed analysis of history and clinical course in all patients revealed an acute onset of symptoms with subsequent neurological deterioration after each bleeding episode. Based on the significant risk of rehemorrhage and the gratifying functional results, surgery is indicated for symptomatic IMSC cavernous malformations.

Adolescent↗
PubMed2003

How much phenotypic variation can be attributed to parkin genotype?

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

Adolescent↗