Search PubMed⌕ Search

Biomedical subjects

M Schutte

Publications and source records attributed to M Schutte.

34 records · Page 2Linked to original sources
PubMed1996

DPC4 gene in various tumor types.

We recently identified a novel tumor-suppressor gene, DPC4, at chromosome 18q21.1 and found that both alleles of DPC4 were inactivated in nearly one-half of the pancreatic carcinomas. Here, we analyzed 338 tumors, originating from 12 distinct anatomic sites, for alterations in the DPC4 gene. Sixty-four specimens were selected for the presence of the allelic loss of 18q and were further analyzed for DPC4 sequence alterations. An alteration of the DPC4 gene sequence was identified in one of eight breast carcinomas and one of eight ovarian carcinomas. These results indicate that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (< 10%) in the other tumor types examined. The tissue restriction of alterations in DPC4, as in many other tumor-suppressor genes, emphasizes the complexity of rate-limiting checkpoints in human tumorigenesis.

Chromosomes, Human, Pair 18↗
PubMed1996

Homozygous deletion map at 18q21.1 in pancreatic cancer.

Absolute genetic differences between neoplastic and nonneoplastic cells can be discerned at sites of homozygous deletions. These deletions are of critical interest because they might be useful in the identification of defective biochemical pathways in neoplastic cells, and subsequently for the development of new treatment strategies in human cancer. We identified an area at 18q21.1 involved by homozygous deletions in 30% of pancreatic carcinomas. To characterize the homozygous deletions, we constructed a detailed physical map of nearly 2 Mb, containing yeast artificial chromosomes, P1-derived artificial chromosomes, cosmids and 24 sequence-tagged sites. The homozygously deleted are contained a new candidate tumor-suppressor gene (DPC4). To date, 23 (64%) of 35 pancreatic carcinomas carry at least one homozygous deletion at a published locus. The study of the total gene content of these loci, facilitated by the sequence-tagged site markers and maps of these regions, should help to reveal the absolute biochemical differences between neoplastic and nonneoplastic cells for a common human tumor.

Alleles↗
PubMed1996

DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.

About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

Alleles↗
PubMed1996

Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.

Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours.

Alleles↗
PubMed1995

Isolation of YAC insert sequences by representational difference analysis.

We present a method for the isolation of YAC insert sequences by representational difference analysis (RDA). To achieve maximal representation of the sequences, the amplicons were generated from a Mbol digestion product. RDA was performed using a 970 kb insert YAC clone. After two rounds of re-association and selective amplification 92% of the difference product represented sequences derived from the YAC insert. Twenty insert-specific sequence-tagged sites were readily defined. The difference product was also successfully used to isolate microsatellite markers, to identify clones from a human PAC library and as a chromosome painting probe in fluorescence in situ hybridization.

Base Sequence↗
PubMed1995

An integrated high-resolution physical map of the DPC/BRCA2 region at chromosome 13q12.

We identified a homozygous deletion in a pancreatic carcinoma (DPC) that localized to a 1-cM region at chromosome 13q12.3, which lay within the 6-cM locus of familial breast cancer susceptibility (BRCA-2). Here we present a physical map of the region, consisting of YAC, PAC, and cosmid contigs. The YAC contig comprises 16 clones that together span the entire BRCA2 region. The PAC contig comprises 22 clones that together span the DPC region. Seventy cosmid clones were localized within and near the DPC region. Thirty-five sequence-tagged sites were defined and localized within the map. The map indicates the size of the DPC region to be near 250 kb, and provides mapped and cloned resources for the search for the putative tumor suppressor gene(s) in the region.

Base Sequence↗
PubMed1995

Allelotype of pancreatic adenocarcinoma using xenograft enrichment.

p53 and MTS1 are known to be mutationally inactivated in pancreatic adenocarcinoma. Other tumor suppressor genes are likely also to play a role. To define chromosomal arms which may harbor additional tumor suppressor genes, we performed an extensive allelotype on pancreatic cancer utilizing a xenograft enrichment technique. Eighty-eight percent (28/32) of primary tumors gave rise to xenografts. Eighteen cases were used in a PCR-based allelotype using 283 polymorphic markers, over 2800 informative assays, and an average coverage of 4.1 informative markers per chromosomal arm per case. Highly frequent allelic loss (> 60%) was seen at chromosomes 1p, 9p, 17p, and 18q. Moderately frequent allelic loss (40-60%) was seen at 3p, 6p, 6q, 8p, 10q, 12q, 13q, 18p, 21q, and 22q. The average fractional allelic loss was 0.36. Allelic and sequence stability was demonstrated among 64 parallel and second-passage xenografts derived from 12 cases of pancreatic adenocarcinoma with the ascertainment of over 3000 single alleles. The findings were confirmed in primary tumors. In only two instances were discrepancies revealed between the allelic loss data obtained from corresponding parallel xenografts, probably due to the xenografting of minor subpopulations, reflecting genetic heterogeneity of the primary tumor.

Adenocarcinoma↗
PubMed1995

Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.

Homozygous deletions have been central to the discovery of several tumor-suppressor genes, but their finding has often been either serendipitous or the result of a directed search. A recently described technique [Lisitsyn, N., Lisitsyn, N. & Wigler, M. (1993) Science 259, 946-951] held out the potential to efficiently discover such events in an unbiased manner. Here we present the application of the representational difference analysis (RDA) to the study of cancer. We cloned two DNA fragments that identified a homozygous deletion in a human pancreatic adenocarcinoma, mapping to a 1-centimorgan region at chromosome 13q12.3 flanked by the markers D13S171 and D13S260. Interestingly, this lies within the 6-centimorgan region recently identified as the BRCA2 locus of heritable breast cancer susceptibility. This suggests that the same gene may be involved in multiple tumor types and that its function is that of a tumor suppressor rather than that of a dominant oncogene.

Adenocarcinoma↗
PubMed1994

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Adenocarcinoma↗
PubMed1994

Symptom perception: psychological correlates of symptom reporting and illness behavior of women with medically unexplained gynecological symptoms.

Medically unexplained (gynecological) symptoms can be viewed as an indication of the somatization of negative emotions. Most studies regarding psychological correlates of medically unexplained gynecological symptoms have paid attention only to certain personality characteristics of women with these symptoms. In this study the reporting of physical symptoms and the resulting illness behavior is explained in terms of information processing or a perception process, i.e. the process by which people detect and interpret physical sensations as symptoms of illness (symptom perception). Symptom perception is in part determined by environmental characteristics and cognitive and emotional processes, such as variation in daily life, (coping with) emotional threat and the use of cognitive illness schemes. Differences in symptom perception and illness behavior of women with medically unexplained and explained gynecological symptoms, compared to women with medically explained gynecological symptoms and a control group, were established with the help of a questionnaire, containing a number of scales. As expected, women with medically unexplained gynecological symptoms had higher reports of common symptoms and sensations and showed also more other illness behavior than the other two groups. They reported less variation and more threat in daily life than the other two groups. These variables together with the use of illness schemes contributed most to symptom reporting of women with medically unexplained symptoms. It is concluded that defence against threat is probably an important determinant. Suggestions for further research and some practical implications are discussed.

Adolescent↗
PubMed1988

[Adverse effects of antihistaminics].

Of most antihistamines more or less pronounced sedative effects are known. In recently developed substances this effect is said to be less or absent. After some days of application the sedative effect may decrease, but it can be enhanced by simultaneous intake of psychotropic drugs, sedatives or alcohol. There are important interindividual differences. The Drug Commission of the German Medical Profession (AKdA) received reports concerning tiredness, somnolence (even with new antihistamines), CNS-stimulation, nervousness, insomnia and paroniria have also been observed. Furthermore cases of dyskinesia have been reported, which are already described in the literature after long term intake, as well as anticholinergic reactions. Despite of their use as antiallergic drugs, reports on hypersensitivity reactions due to antihistamines, up to anaphylactic reaction have been not infrequently received by the AKdA. In rare cases disturbances of blood cell formation have been reported besides observations of gastrointestinal disorders, increase of appetite and weight. Abuse of antihistamine containing drugs was reported mainly for combinations with psychotropic agents.

Histamine Antagonists↗
PubMed1986

Mechanoreceptors in the human anterior cruciate ligament.

This study was undertaken to identify and quantitate mechanoreceptors in the human anterior cruciate ligament (ACL). Ligaments from six human subjects were obtained at autopsy, cut into cross-sectional segments 1.0-1.5 cm thick, and kept oriented as to the femoral and tibial attachments. The segments were stained in bulk by using a modified gold chloride method, frozen, and sectioned on a sliding microtome at 100 microns. The sections were floated in alcoholic gelatin, mounted on slides, dehydrated, and coverslipped. Serial sections were studied with the light microscope and receptors were photographed. Cross-sectional maps of every tenth section were made outlining the periphery of the ACL and the receptors within that section. With these maps, a computerized, morphometric analysis of the ACL was done, thus obtaining the percentage of receptors in each section and in each ACL. In addition to free nerve endings, two morphologically distinct mechanoreceptors were identified: (1) Ruffini end organs and (2) Pacinian corpuscles. Preliminary morphometric analyses show that populations of mechanoreceptors are greater at the femoral and tibial ends of the ligament and constitute approximately 2.5% of the ligament. Based on these findings the human ACL has the anatomic basis for a discriminating afferent outflow to the central nervous system.

Humans↗
PubMed1975

Effects of anesthesia, surgery and inflammation upon host defense mechanisms. I. Effects upon the complement system.

Complement protein levels and C7 hemolytic activity were measured in four individuals following anesthesia and surgery, and in a group of 20 patients with inflammatory diseases. Seven of the eight complement components studied characteristically were elevated, most dramatically C1s and C3PA. Elevation of C1s often was greater than elevation of C1q, displaying an independent variation of C1s and C1q in both postoperative and inflammatory disease patient groupds. The major increases of C components were seen subsequent to the peak C-reactive protein response, as was the occurrence of the 'reactor state', a propensity to formation of C56 which surprisingly was associated with increased levels of C7. Levels of properdin frequently were reduced postoperatively. It is concluded that multiple complement components, with the notable exception of properdin, respond as acute phase reactants which are elevated and changed in proportion postoperatively and during inflammatory disease.

Anesthesia, General↗
PubMedDate not supplied

Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials.

Preclinical studies with murine tumor models have demonstrated that tumor cell vaccines engineered to secrete certain cytokines in a paracrine fashion elicit systemic immune responses capable of eliminating small amounts of established tumor. In particular, tumors that express the cytokine GM-CSF produce potent systemic antitumor immune responses against poorly immunogenic murine tumors. These results have encouraged the development of paracrine-cytokine secreting tumor vaccines for gene therapy of human cancer. GM-CSF recruits professional antigen-presenting cells, which in turn activate effector T cells. These findings suggest that allogeneic as well as autologous tumor cells can be used as the tumor source for developing cancer vaccines. A major obstacle to creating genetically modified human allogeneic tumor vaccines is the absence of stable cell lines required for efficient gene transfer, because most human tumors isolated from primary surgical specimens fail to proliferate in long-term culture. We have developed a method for the routine generation of in vitro cell lines from primary tumors of the pancreas. This method overcomes the common problem of stromal and fibroblast overgrowth that can inhibit the in vitro expansion of many histologic types of tumors. In addition, we have analyzed 12 of these cell lines for cytokeritin and mutated K-ras expression to demonstrate that they derive from the original epithelial tumor tissue. The lines can be genetically modified to stably express the cytokine GM-CSF. These methods should be helpful to investigators attempting to establish cell lines from other histologic tumor types for the development of allogeneic genetically modified tumor vaccines.

Adenocarcinoma↗