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Biomedical subjects

K Lauber

Publications and source records attributed to K Lauber.

At least 19 recordsLinked to original sources
PubMed2005

Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form.

African trypanosomes produce some prostanoids, especially PGD2, PGE2 and PGF2alpha (Kubata et al. 2000, J. Exp. Med. 192: 1327-1338), probably to interfere with the host's physiological response. However, addition of prostaglandin D2 (but not PGE2 or PGF2alpha) to cultured bloodstream form trypanosomes led also to a significant inhibition of cell growth. Based on morphological alterations and specific staining methods using vital dyes, necrosis and autophagy were excluded. Here, we report that in bloodstream form trypanosomes PGD2 induces an apoptosis-like programmed cell death, which includes maintenance of plasma membrane integrity, phosphatidylserine exposure, loss of mitochondrial membrane potential, nuclear chromatin condensation and DNA degradation. The use of caspase inhibitors cannot prevent the cell death, indicating that the process is caspase-independent. Based on these results, we suggest that PGD2-induced programmed cell death is part of the population density regulation as observed in infected animals.

Animals↗
PubMed2005

STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis.

Classical Hodgkin lymphoma (cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the biology of cHL, the transforming events remain to be elucidated. Recently, we demonstrated that the Janus kinase inhibitor AG490 blocked cellular proliferation and STAT3 phosphorylation in cHL. To explore the potential of constitutively activated STAT3 as a drug target and its role in cHL pathogenesis, different cHL cell lines were analyzed. Treatment of cHL cells by the protein tyrosine kinase inhibitor AG17 was associated with inhibition of cellular proliferation and cell cycle arrest. AG17 treatment was accompanied by decreased levels of STAT3 phosphorylation, whereas NF-kappaB and p38/SAPK2 signaling were not inhibited. Incubation with AG17 or AG490 sensitized cHL cells to CD95/Fas/Apo-1 or staurosporine-mediated apoptosis. Coincubation of tyrphostins with staurosporine was accompanied by rapid complete inhibition of STAT3 phosphorylation. RNA interference directed against STAT3 in L428 and L1236 cHL cells demonstrated that STAT3 is essential for cell proliferation of these cHL cells. In conclusion, these findings support the concept that STAT3 signaling is important in the pathogenesis of cHL and tyrphostins are agents for developing new therapeutic strategies.

Apoptosis↗
PubMed2003

Urinary iodine concentration during pregnancy in an area of unstable dietary iodine intake in Switzerland.

We prospectively investigated urinary iodine concentration (UIC) in pregnant women and in female, non-pregnant controls in the canton of Berne, Switzerland, in 1992. Mean UIC of pregnant women [205 +/- 151 microg iodine/g creatinine (microg l/g Cr); no. = 153] steadily decreased from the first (236 +/- 180 microg l/g Cr; no. = 31) to the third trimester (183 +/- 111 microg l/g Cr, p < 0.0001; no. = 66) and differed significantly from that of the control group (91 +/- 37 microg l/g Cr, p < 0.0001; no. = 119). UIC increased 2.6-fold from levels indicating mild iodine deficiency in controls to the first trimester, demonstrating that high UIC during early gestation does not necessarily reflect a sufficient iodine supply to the overall population. Pregnancy is accompanied by important alterations in the regulation of thyroid function and iodine metabolism. Increased renal iodine clearance during pregnancy may explain increased UIC during early gestation, whereas increased thyroidal iodine clearance as well as the iodine shift from the maternal circulation to the growing fetal-placental unit, which both tend to lower the circulating serum levels of inorganic iodide, probably are the causes of the continuous decrease of UIC over the course of pregnancy. Mean UIC in our control group, as well as in one parallel and several consecutive investigations in the same region in the 1990s, was found to be below the actually recommended threshold, indicating a new tendency towards mild to moderate iodine deficiency. As salt is the main source of dietary iodine in Switzerland, its iodine concentration was therefore increased nationwide in 1998 for the fourth time, following increases in 1922, 1965 and 1980.

Adult↗
PubMed2001

The adapter protein apoptotic protease-activating factor-1 (Apaf-1) is proteolytically processed during apoptosis.

Apoptotic protease-activating factor-1 (Apaf-1), a key regulator of the mitochondrial apoptosis pathway, consists of three functional regions: (i) an N-terminal caspase recruitment domain (CARD) that can bind to procaspase-9, (ii) a CED-4-like region enabling self-oligomerization, and (iii) a regulatory C terminus with WD-40 repeats masking the CARD and CED-4 region. During apoptosis, cytochrome c and dATP can relieve the inhibitory action of the WD-40 repeats and thus enable the oligomerization of Apaf-1 and the subsequent recruitment and activation of procaspase-9. Here, we report that different apoptotic stimuli induced the caspase-mediated cleavage of Apaf-1 into an 84-kDa fragment. The same Apaf-1 fragment was obtained in vitro by incubation of cell lysates with either cytochrome c/dATP or caspase-3 but not with caspase-6 or caspase-8. Apaf-1 was cleaved at the N terminus, leading to the removal of its CARD H1 helix. An additional cleavage site was located within the WD-40 repeats and enabled the oligomerization of p84 into a approximately 440-kDa Apaf-1 multimer even in the absence of cytochrome c. Due to the partial loss of its CARD, the p84 multimer was devoid of caspase-9 or other caspase activity. Thus, our data indicate that Apaf-1 cleavage causes the release of caspases from the apoptosome in the course of apoptosis.

Adenosine Triphosphate↗
PubMed2001

Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation.

Apoptosis can be induced by various stimuli including DNA-damaging anticancer drugs and the protein kinase inhibitor staurosporine. It is generally believed that the molecular events during execution of apoptosis are shared, as both anticancer drugs and staurosporine derivatives induce mitochondrial damage, cytochrome c release and the activation of the caspase-9 proteolytic cascade. In the present study we show that overexpression of a dominant-negative caspase-9 mutant abolished the activation of endogenous caspase-9, caspase-3 and the cleavage of the caspase substrate Bid in response to anticancer drug treatment. Surprisingly, however, only marginal effects were observed during staurosporine-induced apoptosis. Furthermore, we describe a Jurkat T-cell clone that is completely resistant towards different anticancer drugs, but remains sensitive towards staurosporine-induced apoptosis. In these cells only staurosporine, but neither anti-CD95 nor anticancer drugs were able to trigger caspase activity and the cleavage of caspase substrates. Our results therefore suggest that the mechanism of staurosporine-induced apoptosis is more complex and at least partially differs from anticancer drug-induced caspase activation. These distinct features of staurosporine may allow to bypass chemoresistance of tumor cells and may encourage further clinical trials for the use of staurosporine derivatives in antitumor therapy.

Antineoplastic Agents↗
PubMed2001

Human mature red blood cells express caspase-3 and caspase-8, but are devoid of mitochondrial regulators of apoptosis.

Although proteases of the caspase family are essential mediators of apoptosis in nucleated cells, in anucleate cells their presence and potential functions are almost completely unknown. Human erythrocytes are a major cell population that does not contain a cell nucleus or other organelles. However, during senescence they undergo certain morphological alterations resembling apoptosis. In the present study, we found that mature erythrocytes contain considerable amounts of caspase-3 and -8, whereas essential components of the mitochondrial apoptotic cascade such as caspase-9, Apaf-1 and cytochrome c were missing. Strikingly, although caspases of erythrocytes were functionally active in vitro, they failed to become activated in intact erythrocytes either during prolonged storage or in response to various proapoptotic stimuli. Following an increase of cytosolic calcium, instead the cysteine protease calpain but not caspases became activated and mediated fodrin cleavage and other morphological alterations such as cell shrinkage. Our results therefore suggest that erythrocytes do not have a functional death system. In addition, because of the presence of procaspases and the absence of a cell nucleus and mitochondria erythrocytes may be an attractive system to dissect the role of certain apoptosis-regulatory pathways.

Apoptosis↗
PubMed2000

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis.

Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either deficient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-x(L) prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less effective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

Adenocarcinoma↗
PubMed1997

[Why is iodine deficiency once again present in the Berne region?].

Owing to the progressive iodination of salt in Switzerland (5, 10, 20 mg KI/kg in the years 1922, 1965, 1980), iodine deficiency in former endemic goiter regions had nearly disappeared. In several areas of the country, urinary iodine had increased from below 30 micrograms/24 h (1920) to > 100 micrograms/g creatinine (1981-1990). In 1991-1992, however, the 24-h-iodinuria in a subgroup of 160 examinations out of a total of 289 persons in Berne was again insufficient (norm > 150 micrograms J/24 h): mean 121 micrograms/24 h (82 micrograms/l), median 107.8 micrograms/24 h (67 micrograms/l). Follow-up of one proband in 1991-1992 (n = 9) and 1996 (n = 11) yielded average 24-h-iodinurias in the slightly deficient domain of (mean +/- SD) 104 +/- 57 micrograms/ 24 h (75 +/- 30 micrograms/l) and 103 +/- 27 micrograms/24 h (44 +/- 17 micrograms/l) respectively, with a wide range (45-258 micrograms l/24 h globally). Possible reasons for the decreasing iodide intake in recent years, resulting in the 1990s in a marginally deficient supply, are reduced intake of salt in recent decades, increased consumption of foodstuffs prepared with non-iodized salt, dietary diversification, and frequent meals away from the family table. Therefore, intake of non-iodized salt should be avoided in Switzerland.

Adult↗
PubMed1995

The instability of dietary iodine supply over time in an affluent society.

In the Bernese region, where goiter was formerly endemic, alimentary salt has been supplemented by increasing amounts of potassium iodide (KI): 5, 10, 20 mg KI/kg in 1922, 1965 and 1980 respectively. Ioduria rose from < 30 micrograms I/g creatinine in 1920 to > 100 micrograms I/g creatinine in the 1980s. In 1992 ioduria was estimated in 55 healthy volunteers (group A and individual B) and 234 thyroid carcinoma patients after thyroidectomy: hypothyroid patients with (C) and without thyroid remnants (D) and euthyroid patients on T4 substitution (E). The arithmetic mean iodine excretion of the healthy volunteers in group A and individual B was found to be 87 +/- 40 micrograms I/g creatinine. This is insufficient according to the recommendations of the WHO. In all groups, the iodine excretion reached the recommended level only in some members: 24% (A, B), 19% (C), 38% (D) and 81% (E). It was thought in the 1980s that in a formerly iodine-deficient society, iodinated salt would continue to provide an adequate supply of iodine. However, iodine intake in this affluent society has proved to be unstable. This can be attributed to modifications of eating habits, which include a reduction of total salt consumption, combined with a growing consumption of manufactured food of cosmopolitan origin, prepared using salt containing little or no iodine.

Adolescent↗
PubMed1994

Low intrathyroidal iodine concentration in non-endemic human goitres: a consequence rather than a cause of autonomous goitre growth.

Iodine may have an inhibitory and, in some circumstances, a stimulatory effect on thyroid follicular cell growth. Exogenous iodine deficiency causes the growth of endemic goitres and it has been claimed that low intrathyroidal iodine stores stimulate growth. On the other hand, the role of iodine, if any, in regulating the growth of human nodular goitres exposed to an ample supply of iodine has not been studied systematically. Very few data on intrathyroidal iodine concentration in this type of goitre are available. In the present work we have investigated total iodine content in 24 samples from 11 clinically and histomorphologically well-defined fast and autonomously growing human nodular goitres from a non-endemic area. Iodine was fractionated into thyroglobulin-iodine and non-thyroglobulin-iodine. The regional distribution of intrathyroidal iodo-compounds was also assessed in three goitres. Total iodine concentration, as well as its sub-fractions, i.e. thyroglobulin-iodine and non-thyroglobulin-iodine, were significantly lower than in normal thyroids. Furthermore, there was large inter- and intraindividual heterogeneity of all iodo-compounds as well as of thyroglobulin. Total iodine concentration varied by a factor of almost 40 between different goitre samples and by a factor of 20 between samples taken from the same goitre. Total non-thyroglobulin-iodine, the only fraction comprising possible cell growth-regulating iodo-compounds, varied by a factor of > 60 between different goitres and by a factor of > 6 between different samples of the same goitre. The low iodine concentration in all our goitre samples did not differ from values reported in the literature for endemic iodine-deficient goitres. Since all goitres studied here were actively growing while exposed to an ample supply of iodine, iodine shortage cannot be a primary and causal factor for the growth of this type of sporadic goitre. Rather, the low concentration and the large inter- and intraindividual heterogeneity of all iodo-compounds appear to be secondary incidental events well explained by the recently developed concept of autonomous thyroid growth.

Goiter↗
PubMed1990

T3 plus high doses of beta-blockers: effects on energy intake, body composition, bat and heart in rats.

The effects of a combined treatment with supraphysiological doses of the thyroid hormone T3 (15 micrograms/kg BW/day, s.c.) and high doses of a predominant beta 1-blocker (atenolol, 12.5 and 25 mg/kg BW, 3X/day, s.c.) or a non-specific beta-blocker (propranolol, 5 mg/kg BW s.c. and 33 mg/kg BW p.o., each 3X/day) on energy intake, body composition and the heart were studied in overfed rats with an increased body fat content. The goal of the study was to investigate whether the above treatment constitutes a therapy for obesity in that T3 causes weight and fat loss and the beta-blockers prevent the unwanted T3-effects on the heart (tachycardia and increased heart weight). T3 did not increase energy intake above the level seen in overfed animals. It caused loss of body weight due to loss of fat but not protein, an increase in interscapular brown adipose tissue (IBAT) weight and fat, tachycardia and an increase in heart weight. Atenolol and propranolol blocked T3-induced tachycardia. With the exception of the highest propranolol dose which abolished the T3-induced increase in IBAT fat content, the beta-blockers did not modify the other T3 effects. Thus, in spite of the weight and fat loss and the lack of significant protein loss and tachycardia observed under T3/high dose beta-blockers treatment, the T3-induced increase in heart weight makes this treatment unsuitable as a therapy for obesity.

Adipose Tissue↗
PubMed1985

Crystallization conditions in urine of patients with idiopathic recurrent calcium nephrolithiasis and with hyperparathyroidism.

The highest degree of urinary supersaturation with respect to calcium oxalate monohydrate (COM) and brushite at which secondary nucleation and growth of small amounts of COM and hydroxyapatite (HAP) are inhibited was determined by new and simple methods. There were 39 subjects who produced 24 h-urine collections (11 idiopathic stone formers (ISF), 12 patients suffering from primary hyperparathyroidism (HPT) and 16 healthy controls (HC). These subjects had a moderate calcium and low oxalate intake. The results obtained were compared with the state of urinary saturation and with urine chemistry. The measurements of crystallization conditions with respect to COM were repeated in 26 subjects (11 ISF, 5 HPT, 10 HC) after a dietary oxalate load. In 24 h-urines of HC diluted to 2.4 1/24 h the degree of supersaturation necessary to induce crystallization of COM and HAP was 2-5 times higher than the state of urinary saturation measured under the same test conditions. ISF showed a decreased pyrophosphate concentration and a decreased inhibitory activity to HAP crystallization in their 24 h-urine. The urinary inhibitory activity towards crystallization of HAP showed a positive correlation to urinary pyrophosphate concentration. In the 24 h-urine of HPT hypercalciuria and increased saturation with respect to brushite which reached values to induce HAP crystallization were found. After a dietary oxalate load urinary supersaturation with respect to COM reached values to induce COM crystallization in ISF and HPT but not in HC.

Adult↗
PubMed1984

Pregnancy-associated plasma protein-A (PAPP-A) and immunosuppressive activity in split ejaculates.

Pregnancy-associated plasma protein-A (PAPP-A) and phytohemagglutinin (PHA)-induced lymphocyte transformation were measured in split ejaculates of 17 normal volunteers. The concentration of PAPP-A was identical in both fractions of the ejaculate but the first fraction was twice as immunosuppressive as the second fraction. The origin of PAPP-A in men as well as its possibility of being an immunosuppressor is discussed.

Ejaculation↗
PubMed1983

Human seminal plasma contains a protein that shares physicochemical, immunochemical, and immunosuppressive properties with pregnancy-associated plasma protein-A.

Pregnancy-associated plasma protein-A (PAPP-A) was detected by RIA in human seminal plasma. This was not due to interference with proteases or binding to seminal plasma proteins, since immunoreactivity was not affected by treatment with protease inhibitors, and the elution of [125I]PAPP-A was not altered by preincubation with seminal plasma. The major component of the seminal plasma PAPP-A coeluted with pure PAPP-A or plasma PAPP-A from pregnant and nonpregnant women. In the RIA, serial dilutions of seminal plasma gave parallel displacement curves to pregnancy plasma. Removing PAPP-A-like material from seminal plasma by adsorbtion to heparin-Sepharose reduced the inhibitory effect of seminal plasma on phytohemagglutinin-induced lymphocyte transformation. The source of seminal plasma PAPP-A-like immunoreactive material remains to be elucidated, but it is unlikely to be the testis, since PAPP-A levels in semen of vasectomized men were similar to those in nonvasectomized men.

Female↗
PubMed1983

Circulating levels of pregnancy proteins and depression of lymphoblastogenesis during pregnancy.

Plasma was obtained from 287 normal pregnant women at different times of gestation. Alpha-foetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL) and pregnancy associated plasma protein-A (PAPP-A) were measured by radioimmunoassay. The capacity of those plasmas to inhibit phytohaemagglutinin (PHA) induced lymphocyte transformation was also tested. Between the 7th and the 12th week, pregnancy plasma has a relatively small inhibitory effect on lymphoblastogenesis. Plasmas taken between the 13th week and term pregnancy inhibit much more lymphocyte transformation. The factor which increases this inhibition is unknown. None of the proteins measured were significantly correlated with the inhibitory effect. Two explanations are proposed: either AFP, hCG, hPL and PAPP-A are not responsible for the in vitro inhibition of lymphoblastogenesis or else these factors exert a combined effect so that the concentration of each protein taken separately cannot account for the overall inhibitory effect observed with pregnancy plasma.

Female↗
PubMed1982

Inhibition of lymphocyte transformation by pregnancy-associated plasma protein-A (PAPP-A).

A third trimester pregnancy plasma pool was divided into 2 aliquots, one of them was depleted of pregnancy-associated plasma protein-A (PAPP-A) by absorption onto a monospecific antiserum to PAPP-A. These plasmas as well as pure PAPP-A (isolated from pregnancy plasma) were tested for their ability to inhibit mitogen induced lymphocyte transformation. Pregnancy plasma containing PAPP-A exerted a significantly higher inhibition of phytohemagglutinin (PHA) induced lymphoblastogenesis than did pregnancy plasma devoid of PAPP-A. Pure PAPP-A added to normal human AB serum was also inhibitory. Since PAPP-A (pregnancy plasma with PAPP-A) is inhibitory even if it is preincubated in absence of PHA (and this mitogen added after washing the cells) one can conclude that the inhibitory effect of PAPP-A is specific and is not due to the binding of PHA to PAPP-A (glycoprotein). The fact that PAPP-A is active on prestimulated cells in absence of PHA seems to indicate that PAPP-A inhibits lymphoblastogenesis by acting on the secretion products of lymphocytes.

Female↗
PubMed1980

[Determination of serum iron; a comparison of two methods: Teepol/dithionite/bathophenanthroline versus guanidine/ascorbic acid/Ferrozine (author's transl)].

Two spectrophotometric methods for the assay of serum iron without deproteinisation are compared: 1. Liberation of iron by a detergent (Teepol SHELL), reduction by dithionite, chelation by bathopehanthroline disulfonate; 2. Liberation of iron by 6 mol/l guanidine, reduction by ascorbic acid, chelation by 3-(2-pyridyl)-5,6-bis-(4-phenyl sulfonic acid)-1,2,4-triaxine (Ferrozine).

Ascorbic Acid↗