PubMed Health⌕ Search

Biomedical subjects

T van der Kwast

Publications and source records attributed to T van der Kwast.

8 recordsLinked to original sources
PubMed2001

Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques.

Modified vaccinia virus Ankara (MVA)-based recombinant viruses have been shown to be potent vaccine candidates for several infectious and neoplastic diseases. Since a major application of these live, replication-deficient vectors would be their use in immunocompromised or potentially immunocompromised individuals, a preclinical safety study was carried out. Macaques were inoculated with high doses of MVA (10(9)) via various routes, after immune-suppression by total-body irradiation, anti-thymocyte globulin treatment, or measles virus (MV) infection. No clinical, haematological or pathological abnormalities related to MVA inoculation were observed during a 13-day follow-up period. The presence of MVA genomes was demonstrated by nested PCR during the course of the experiment in all macaques, but from none of these animals replication competent MVA could be reisolated. These data suggest that MVA can safely be used as a basis for recombinant human vaccines, and that it is also safe for use in immunocompromised individuals.

Animals↗
PubMed2001

Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors.

We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. All 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0.0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0.0001). FGFR3 mutations were detected in 27 of 32 (84%) G1, 16 of 29 (55%) G2, and 5 of 71 (7%) G3 tumors. This association between FGFR3 mutations and low grade was highly significant (P < 0.0001). FGFR3 is the first gene found to be mutated at a high frequency in pTa tumors. The absence of FGFR3 mutations in CIS and the low frequency of FGFR3 mutations in pT1 and pT2-4 tumors are consistent with the model of bladder tumor progression in which the most common precursor of pT1 and pT2-4 tumors is CIS.

Carcinoma in Situ↗
PubMed2001

Prostate-specific antigen-based early detection of prostate cancer--validation of screening without rectal examination.

OBJECTIVES: The evaluation of the screening procedures for prostate cancer (PCa) was a part of the protocol of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, The Netherlands. We sought to establish an improved strategy for the early detection of PCa using a prostate-specific antigen (PSA) cutoff of 3.0 ng/mL or greater as the only indication for prostate biopsy with omission of the digital rectal examination (DRE). METHODS: In June 1996, 8612 men, 55 to 74 years old, were randomized to screening and were screened within the ERSPC Rotterdam by a PSA level of 4.0 ng/mL or greater or positive DRE or transrectal ultrasound findings as the indication for biopsy. Four hundred thirty men had PCa. Those treated by radical prostatectomy provided the tumor characteristics considered essential for a change in the screening strategies. Various options were evaluated and predictions made by logistic regression analyses. The protocol change was implemented in February 1997. Another 7943 men were screened according to the new protocol (PSA 3.0 ng/mL or greater). The resulting data were used to compare the two protocols. RESULTS: The detection rate (proportion of PCa in those screened) turned out to be very similar, with rates of 5.0 and 4.7 at a PSA cutoff of 4.0 ng/mL or greater and 3.0 ng/mL or greater, respectively. This was due to a much larger number of cases of PCa per biopsy in the PSA range of 3 to 3.9 ng/mL than expected. The positive predictive value of the PSA range 3.0 to 3.9 ng/mL in the two protocols was 18.0% and 6.4%, respectively. Tumor characteristics were studied on radical prostatectomy specimens from the original protocol. PCa detected with the new screening regimen had a similar distribution of Gleason scores but a larger proportion of confined disease. Tumor volumes were smaller in patients with PSA levels of less than 2.9 ng/mL; the proportion of "minimal disease" in that group was 50% compared with 28% in the group with a PSA level between 3.0 and 3.9 ng/mL. CONCLUSIONS: Lowering the biopsy indication to a PSA cutoff of 3.0 ng/mL or greater without a DRE improved the positive predictive value from 18.2% to 24.3%. The number of biopsies necessary to detect 1 case of PCa accordingly changed from 5.2 to 3.4. The overall characteristics of the cases detected at that PSA cutoff differed very little from those detected with the regimen based on PSA, DRE, and transrectal ultrasound.

Aged↗
PubMed2000

Fixation-dependent immunolocalization shift and immunoreactivity of intracellular growth factors in cartilage.

The effects of fixation on immunolocalization and immunoreactivity in cartilage tissues were studied using monoclonal antibodies against peptides that can effectively stimulate chondrocytes in vitro and have been shown to play a role in musculoskeletal tissue regeneration: transforming growth factor beta1, transforming growth factor beta3, insulin-like growth factor I, insulin-like growth factor II and fibroblast growth factor 2. Paraffin sections fixed in buffered formalin, buffered paraformaldehyde, Carnoy and methacarn, as well as cryosections, were tested. A strong immunoreaction was observed in tissue fixed in formaldehyde-based fixatives, with a resemblance to that in cryopreserved tissues. Immunoreactivity was reduced in alcohol-fixed tissues. Furthermore, a striking intracellular immunolocalization shift from cytoplasm to nucleus was observed using alcohol-based fixatives as compared to cryopreserved or formaldehyde-based fixatives. We concluded that, for the detection and localization of growth factors in cartilage tissues, fixation in buffered formalin or paraformaldehyde is optimal.

Animals↗
PubMed2000

Cellular and molecular pathology of prostate cancer precursors.

Prostate cancer is usually heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Current understanding of the molecular basis for this heterogeneity is limited, particularly for prostatic intraepithelial neoplasia (PIN), the only putative precursor which can be identified according to morphologic criteria. However, it is likely that prostatic adenocarcinoma might arise from precursor lesions other than PIN, although these cannot be recognized with certainty at the present time. In this review, we summarize the current state of knowledge regarding the cell-biological and genetic bases for linking PIN and prostatic adenocarcinoma. It is conceivable that a stem cell of basal phenotype, or an amplifying cell, is the target of prostatic carcinogenesis. Prominent genetic heterogeneity is characteristic of both PIN and carcinoma; and multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect probably underlies prostatic neoplasia. Multiple foci of cancer also often arise independently, lending additional support to this hypothesis. The strong genetic similarities between PIN and cancer strongly suggest that evolution and clonal expansion of PIN, or other precursor lesions, may account for the multifocal etiology of carcinoma. Uncertainties with respect to identification of those precursor lesions which are most likely to progress to invasive and metastatic prostate cancer reinforce the requirement for objective immunohistochemical or molecular biological markers of the aggressive phenotype.

Adenocarcinoma↗
PubMed1996

Functions of fibroblast and transforming growth factors in primary organoid-like cultures of normal human urothelium.

Previous studies have indicated that growth factors such as epidermal growth factor, transforming growth factor alpha, and fibroblast growth factor 1 (FGF-1) have important regulatory functions in murine urothelial wound healing and tumorigenesis. Immunocytochemical analyses suggest that these factors are also involved in human urothelium. Yet, little is known about the functional effects of these growth factors on human urothelial cells. We established organoid-like primary cultures of normal human urothelium on porous membranes. Direct functional effects of growth factors were examined on confluent cultures reflecting intact urothelium. Immunocytochemistry was performed with a panel of specific antibodies against growth factors and their receptors on both cultures and the corresponding tissue sections. Lacking the appropriate antibodies, we performed reverse transcriptase PCR to detect FGF receptor mRNA in cultures and dissected tissue. The proliferation was stimulated by transforming growth factor alpha, FGF-1, and weakly by FGF-7, but not by FGF-2. TGF beta 1 inhibited proliferation. In contrast to mouse urothelium, none of the growth factors showed an effect on differentiation. The functional data correlate with the urothelial expression of epidermal growth factor receptors, TGF beta receptor types I and II, the (low) protein expression of FGF receptor 1, and the presence of FGF-7 receptor (FGF receptor 2 (IIIb)) mRNA. The organotypic nature of the cultures permits the study of growth factor interactions between urothelial cells. The data indicate that FGF-1, transforming growth factor alpha, and TGF beta 1 contribute differently to the maintenance of human urothelium.

Base Sequence↗