PubMed Health⌕ Search

Biomedical subjects

B Pasche

Publications and source records attributed to B Pasche.

At least 19 recordsLinked to original sources
PubMed2005

TGFBR1*6A is not associated with prostate cancer in men of European ancestry.

The TGFBR1*6A (*6A) variant in exon 1 of the TGFBR1 gene has been postulated as a putative tumor susceptibility allele in several studies. We have performed a case-control study in 537 men with histologically verified prostate cancer and in 488 unrelated controls to investigate the association of *6A with prostate cancer. Our results revealed that the frequency of the (*)6A allele does not differ in men with prostate cancer compared to healthy controls, even in a subset of age-matched cases and controls. There is no compelling evidence for an association of the *6A variant with prostate cancer.

Activin Receptors, Type I↗
PubMed2001

MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells.

The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

Anaphase↗
PubMed2001

Role of transforming growth factor beta in cancer.

Transforming growth factor beta (TGF-beta) is an effective and ubiquitous mediator of cell growth. The significance of this cytokine in cancer susceptibility, cancer development and progression has become apparent over the past few years. TGF-beta plays various roles in the process of malignant progression. It is a potent inhibitor of normal stromal, hematopoietic, and epithelial cell growth. However, at some point during cancer development the majority of transformed cells become either partly or completely resistant to TGF-beta growth inhibition. There is growing evidence that in the later stages of cancer development TGF-beta is actively secreted by tumor cells and not merely acts as a bystander but rather contributes to cell growth, invasion, and metastasis and decreases host-tumor immune responses. Subtle alteration of TGF-beta signaling may also contribute to the development of cancer. These various effects are tissue and tumor dependent. Identifying and understanding TGF-beta signaling pathway abnormalities in various malignancies is a promising avenue of study that may yield new modalities to both prevent and treat cancer. The nature, prevalence, and significance of TGF-beta signaling pathway alterations in various forms of human cancer as well as potential preventive and therapeutic interventions are discussed in this review.

Animals↗
PubMed2001

Isolation and characterization of the human forkhead gene FOXQ1.

We have isolated a human genomic and cDNA clone that encodes a protein of 403 amino acids and belongs to the family of the FOX transcription factors (previously called HNF-3/forkhead transcription factors). The 2.7-kb transcript of the human FOXQ1 gene is expressed predominantly in the stomach, trachea, bladder and salivary gland. Additionally, overexpression of human FOXQ1 was shown in colorectal adenocarcinoma and lung carcinoma cell lines. The FOXQ1 gene is located on chromosome 6p23-25. Databank analysis shows 82% homology with the mouse Foxq1 gene (formerly Hfh-1L) and with a revised sequence of the rat FoxQ1 gene (formerly HFH-1). The DNA-binding motif, named HNF-3/forkhead domain, is well conserved, showing 100% identity in human, mouse, and rat. The human protein sequence contains two putative transcriptional activation domains, which share a high amino acid identity with the corresponding mouse and rat domains.

Amino Acid Sequence↗
PubMed1999

TbetaR-I(6A) is a candidate tumor susceptibility allele.

We have previously described a type I transforming growth factor (TGF)-beta receptor (TbetaR-I) polymorphic allele, TbetaR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TbetaR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TbetaR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TbetaR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TbetaR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TbetaR-I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TbetaR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TbetaR-I, we established stably transfected TbetaR-I and TbetaR-I(6A) cell lines. We found that, compared to TbetaR-I, TbetaR-I(6A) was impaired as a mediator of TGF-beta antiproliferative signals. We conclude that TbetaR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-beta-mediated growth inhibition.

Activin Receptors, Type I↗
PubMed1999

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Abnormalities, Multiple↗
PubMed1998

Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract.

In a search for mutations of the type I transforming growth factor beta receptor (TbetaR-I), we mapped the gene to 9q22 and found a common polymorphism [TbetaR-I(6A)] and a rare variant [TbetaR-I(10A)] of TbetaR-I, causing an in-frame deletion of three alanines and an in-frame insertion of one alanine, respectively, in the receptor's extracellular domain. The biological relevance of the polymorphism TbetaR-I(6A) was investigated. When TbetaR-I(6A) was transiently transfected into TbetaR-I-deficient cells, the growth-inhibitory effects of transforming growth factor beta were restored. TbetaR-I(6A) and TbetaR-I(10A) frequency were assessed in 108 tumor samples and 80 nontumor samples from patients with a diagnosis of cancer, as well as in 118 normal blood donors of comparable ethnic composition. The frequency of TbetaR-I(6A) heterozygotes was fairly similar in normal blood donors (8%), in nontumor DNA of patients with a diagnosis of cancer (10%), and in tumor samples (14%). However, the frequency of TbetaR-I(6A) homozygotes among nontumor (4%) and tumor (8%) samples obtained from patients with a diagnosis of cancer was higher than that predicted by the Hardy-Weinberg law. The clinical and biological significance of TbetaR-I(6A) homozygosity needs to be further investigated.

Acute Disease↗
PubMed1997

Bright light and LEET effects on circadian rhythms, sleep and cognitive performance.

Shift work and jet lag can disrupt cicadian rhythms, with detrimetnal effects on alertness, performance and sleep. This study examined the effects of two interventions to adapt circadian rhythms, sleep and performance to a 10-h phase delay of the work-rest cycle. Bright light was administered from 2200 to 0200 each night to promote phase delay of circadian rhythms. Low energy emission therapy (LEET) was administered for 20 min prior to daytime sleep periods to promote sleep. Twelve subjects received bright light, 12 subjects received LEET, 11 received both interventions and 10 control subjects received only placebo treatments. Bright light accelerated phase delay of the circadian melatonin rhythms after the work-rest schedule shift. Further, subjects who received bright light had greater total sleep time (TST) and improved sleep continuity. LEET treatment produced a trend (p = 0.16) for increased TST, but LEET did not affect the melatonin circadian rhythm. After the schedule shift, cognitive performance measures showed few significant differences. Some minor improvements in cognitive performance were producced by light treatments but not by LEET.

Adult↗
PubMed1996

Effects of low energy emission therapy in chronic psychophysiological insomnia.

The treatment of chronic psychophysiological insomnia presents a challenge that has not been met using currently available pharmacotherapy. Low energy emission therapy (LEET) has been developed as a potential alternative therapy for this disorder. LEET consists of amplitude-modulated electromagnetic fields delivered intrabuccally by means of an electrically conducting mouthpiece in direct contact with the oral mucosa. The effect of LEET on chronic psychophysiological insomnia was assessed with polysomnography (PSG) and sleep rating forms on a total of 106 patients at two different centers. Active or inactive LEET was administered for 20 minutes in late afternoon three times a week for a total of 12 treatments. Primary efficacy endpoints evaluating the results were changes from baseline in PSG-assessed total sleep time (TST) and sleep latency (SL). Secondary endpoints were changes in sleep efficiency (SE), sleep stages, and reports by the subjects of SL and TST. There was a significant increase in TST as assessed by PSG between baseline and post-treatment values for the active treatment group (76.0 +/- 11.1 minutes, p = 0.0001). The increase for the inactive treatment group was not statistically significant. The TST improvement was significantly greater for the active group when compared to the inactive group (adjusted for baseline TST; p = 0.020. R1 = 0.20). There was a significant decrease in SL as assessed by PSG between baseline and post-treatment values for the active treatment group (-21.6 +/- 5.9 minutes, p = 0.0006), whereas the decrease noted for the inactive treatment group was not statistically significant. The difference in SL decrease between the two treatment groups was marginally significant (adjusted for baseline SL and center, p = 0.068, R2 = 0.60). The number of sleep cycles per night increased by 30% after active treatment (p = 0.0001) but was unchanged following inactive treatment. Subjects did not experience rebound insomnia, and there were no significant side effects. The data presented in this report indicate that LEET administered for 20 minutes three times a week increased TST and reduced SL in chronic psychophysiological insomnia. LEET is safe and well tolerated and it effectively improved the sleep of chronic insomniacs given 12 treatments over a 4-week period by increasing the number of sleep cycles without altering the percentage of the various sleep stages during the night. The therapeutic action of LEET differs from that of currently available drug therapies in that the sleep pattern noted in insomniacs following LEET treatment more closely resembles nocturnal physiological sleep. This novel treatment may offer an attractive alternative therapy for chronic insomnia.

Adult↗
PubMed1995

Platelets and plasminogen activation.

Platelets serve as a site for assembly of the proteins of the plasminogen activator system. Once bound to the platelet surface, tissue-type plasminogen activator manifests enhanced catalytic activity. Plasmin, once formed, also binds to the platelets surface and, at low concentrations, renders the platelet dysfunctional by cleaving glycoprotein IIIa selectively in the presence of bound fibrinogen. At higher concentrations (approximately 1 caseinolytic unit/ml), plasmin activates the platelet directly. Activated platelets also bind plasminogen and tissue-type plasminogen activator, and manifest enhanced catalytic efficiency of plasminogen activation. These observations suggest that plasminogen activation by tissue-type plasminogen activator is an autocatalytic process on the platelet surface, and that unique reciprocating mechanisms govern the interaction between platelets and the components of the plasminogen activator system.

Blood Platelets↗
PubMed1994

Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences.

Plasmin exposure modulates platelet aggregation responses, but a direct effect of plasmin on the platelet fibrinogen receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), has never been conclusively shown in a plasma milieu. To examine this issue, we incubated platelets in platelet-rich plasma with plasmin and measured the effect of this treatment on platelet aggregation, fibrinogen binding, and the structural integrity of GPIIb/IIIa. Plasmin treatment reduced maximal reversible fibrinogen binding in a dose-dependent fashion, and this reduction in binding was accompanied by a correlative reduction in the maximal rate of aggregation. Immunoblots performed with polyclonal antibodies against GPIIb/IIIa showed that GPIIIa had been cleaved by plasmin, but this cleavage was detected only after subsequent degradation of the solubilized GPIIb/IIIa with Staphylococcus aureus V8 (Glu-C) endoprotease. Peptide sequence analysis showed that cleavage occurred at the lys444-pro445 bond in the first cysteine-rich repeat domain of GPIIIa a unique proteolytic event observed only in the presence of plasma fibrinogen. These observations suggest that plasmin modifies GPIIIa by a unique proteolytic event in plasma that is dependent on fibrinogen binding and, consequently, is accompanied by significant reductions in fibrinogen binding and aggregation response.

Amino Acid Sequence↗
PubMed1994

Sleep inducing effect of low energy emission therapy.

The sleep inducing effect of a 15 min treatment with either an active or an inactive Low Energy Emission Therapy (LEET) device emitting amplitude-modulated electromagnetic (EM) fields was investigated in a double-blind cross-over study performed on 52 healthy subjects. All subjects were exposed to both active and inactive LEET treatment sessions, with an interval of at least 1 week between the two sessions. LEET consists of 27.12 MHz amplitude-modulated (sine wave) EM fields emitted intrabuccally by means of an electrically conducting mouthpiece in direct contact with the oral mucosa. The estimated local peak SAR is less than 10 W/kg in the oral mucosa and 0.1 to 100 mW/kg in brain tissue. No appreciable sensation is experienced during treatment, and subjects are therefore unable to tell whether they are receiving an active or an inactive treatment. In this study the active treatment consisted of EM fields intermittently amplitude-modulated (sine wave) at 42.7 Hz for 3 s followed by a pause of 1 s during which no EM fields were emitted. During the inactive treatment no EM fields were emitted. Baseline EEGs were obtained and 15 min post-treatment EEGs were recorded and analyzed according to the Loomis classification. A significant decrease (paired t test) in sleep latency to stage B2 (-1.78 +/- 5.57 min, P = 0.013), and an increase in the total duration of stage B2 (1.15 +/- 2.47 min, P = 0.0008) were observed on active treatment as compared with inactive treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

The platelet function defect of cardiopulmonary bypass.

The use of cardiopulmonary bypass (CPB) during cardiac surgery is associated with a hemostatic defect, the hallmark of which is a markedly prolonged bleeding time. However, the nature of the putative platelet function defect is controversial. In this study, blood was analyzed at 10 time points before, during, and after CPB. We used a whole-blood flow cytometric assay to study platelet surface glycoproteins in (1) peripheral blood, (2) peripheral blood activated in vitro by either phorbol myristate acetate, the thromboxane (TX)A2 analog U46619, or a combination of adenosine diphosphate and epinephrine, and (3) the blood emerging from a bleeding-time wound (shed blood). Activation-dependent changes were detected by monoclonal antibodies directed against the glycoprotein (GP)Ib-IX and GPIIb-IIIa complexes and P-selectin. In addition, we measured plasma glycocalicin (a proteolytic fragment of GPIb) and shed-blood TXB2 (a stable breakdown product of TXA2). In shed blood emerging from a bleeding-time wound, the usual time-dependent increase in platelet surface P-selectin was absent during CPB, but returned to normal within 2 hours. This abnormality paralleled both the CPB-induced prolongation of the bleeding time and a CPB-induced marked reduction in shed-blood TXB2 generation. In contrast, there was no loss of platelet reactivity to in vitro agonists during or after CPB. In peripheral blood, platelet surface P-selectin was negligible at every time point, demonstrating that CPB resulted in a minimal number of circulating degranulated platelets. CPB did not change the platelet surface expression of GPIb in peripheral blood, as determined by the platelet binding of a panel of monoclonal antibodies, ristocetin-induced binding of von Willebrand factor, and a lack of increase in plasma glycocalicin. CPB did not change the platelet surface expression of the GPIIb-IIIa complex in peripheral blood, as determined by the platelet binding of fibrinogen and a panel of monoclonal antibodies. In summary, CPB resulted in (1) markedly deficient platelet reactivity in response to an in vivo wound, (2) normal platelet reactivity in vitro, (3) no loss of the platelet surface GPIb-IX and GPIIb-IIIa complexes, and (4) a minimal number of circulating degranulated platelets. These data suggest that the "platelet function defect" of CPB is not a defect intrinsic to the platelet, but is an extrinsic defect such as an in vivo lack of availability of platelet agonists. The near universal use of heparin during CPB is likely to contribute substantially to this defect via its inhibition of thrombin, the preeminent platelet activator.

Blood Coagulation Disorders↗
PubMed1991

Heparin cofactor II significance for the inhibition of thrombin at the injured vessel wall.

The thrombin inhibitory role of antithrombin III (ATIII) and heparin cofactor II (HCII) was studied in vitro using intact and injured rabbit aortae. When intact vessels were loaded with thrombin and then exposed to either heat defibrinogenated human plasma (HDHP) or ATIII the same degree of thrombin inhibition was achieved demonstrating that ATIII was the only plasma component involved in thrombin inhibition on the intact vessel wall. When the media of the vessel wall was loaded with thrombin and then exposed to ATIII or HCII a significantly higher thrombin activity remained on the surface than when it was exposed to defibrinogenated plasma. A mixture of ATIII and HCII resulted in a greater inhibition of thrombin than ATIII or HCII alone. It is concluded that, contrary to what happens on the endothelium, HCII and ATIII inhibit additively thrombin on the injured vessel wall. HCII thus plays an essential role for the inhibition of thrombin at the injured vessel wall. It is also concluded that an additional plasma component participates in thrombin inhibition on the media but its contribution is negligible as compared with ATIII or HCII.

Animals↗
PubMed1991

Thrombin-inhibitory capacity of the injured vessel wall.

The present study examined the appearance of thrombin activity in vitro after single and repeated in vivo balloon injury of the rabbit aorta. The in vitro ability of the injured vessel wall to bind and subsequently inhibit thrombin in the presence of defibrinogenated plasma was also assessed. Thrombin activity was assayed by measuring the levels of fibrinopeptide A generated in the presence of fibrinogen. These findings were correlated with the changes observed in light and electron microscopy. Thrombin activity on the vessel wall was increased five minutes and three hours after the initial and the repeated injury, and returned to control values one week after the initial injury. When the inhibition of thrombin was assayed in the presence of defibrinogenated plasma, a diminished inhibition capacity was observed after the repeated injury, which correlated with deposition of fibrin and an enhanced inflammatory reaction as measured by the density of granulocytes covering the injured neointima. Decreased thrombin inhibitory capacity of the injured neointima appears to be linked with its increased thrombogenicity.

Angioplasty, Balloon↗
PubMed1991

Binding of antithrombin to immobilized heparin under varying flow conditions.

Rheologic factors are likely to influence the balance between thrombotic and antithrombotic forces at the level of the vascular wall. In this study, the effects of flow-velocity/wall shear stress on the interaction of antithrombin (AT) with surface-immobilized heparin were investigated. The binding of AT to low-affinity and high-affinity heparin could be discriminated by measurements at physiological of elevated ionic strength. Under low shear stress conditions, substantial binding of AT to both high- and low-affinity heparin was observed, in relative quantities largely reflecting the proportion of these polysaccharide populations on the surface. With increasing shear stress, the binding to high-affinity sites was relatively constant, while total low-affinity binding decreased. Furthermore, under the highest shear stress (greater than 1,000 N/m2), the binding of AT to low-affinity heparin completely disappeared while binding to the high-affinity fraction persisted. These results were related to values obtained in a mathematical model, describing the theoretical maximum transport of AT from the liquid phase to the surface under the conditions used in the experimental system.

Animals↗
PubMed1990

The use of a commercial ELISA for assay of thrombin-antithrombin complexes in purified systems.

Inhibition of thrombin by antithrombin III (AT) results in the formation of stable thrombin-AT complexes (TAT). An enzyme-linked immunosorbent assay (ELISA) following the sandwich principle is available for the determination of TAT complexes in human plasma, however, this ELISA method could not be used in purified systems containing thrombin and AT. It has therefore been modified for use in purified systems and an excellent correlation was found between the disappearance of thrombin and AT and the recovery of TAT complexes. Addition of thrombin inhibitor hirudin and heparin inhibitor polybrene into the reacting thrombin-AT mixture did not interfere with the assay of TAT. It was found that the use of siliconised tubes was necessary for the conservation of the TAT complexes.

Antithrombin III↗