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S Richter

Publications and source records attributed to S Richter.

At least 55 records · Page 3Linked to original sources

A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts.

OBJECTIVES: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity. METHODS AND RESULTS: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models. The superior activity was more evident in PC3 tumour, since BBR 3438 produced an appreciable rate of complete tumour regressions. Under these conditions, the drug-induced antiproliferative activity paralleled delayed apoptosis. Tumour response to in vivo drug treatment was associated with an early down-regulation of Bcl-2, which was somewhat more marked for the aza compound. In fact, the 9-aza-anthrapyrazole induced DNA cleavage in vitro with isolated DNA topoisomerase II (isoform alpha) and DNA strand breaks in prostatic carcinoma cells. Although the molecular effects of losoxantrone and the 9-aza analogue on the enzyme target were comparable, the cytotoxic effects of BBR 3438 could be enhanced by long-term exposure as a consequence of favourable cellular accumulation and prominent DNA-binding affinity. In addition, a lower reduction potential of the 9-aza-anthrapyrazole in comparison with classical anthrapyrazoles suggests an increased ability of the drug to induce oxidative stress following free radical production, which may be a contributing factor in determining the long-term response (i.e. delayed cell death) to genotoxic damage. CONCLUSIONS: BBR 3438 exhibited a unique profile of preclinical activity with a superior efficacy against prostatic carcinoma models compared to reference compounds (doxorubicin and losoxantrone). The antitumour efficacy of BBR 3438 against prostatic carcinoma could be the result of a combination of favourable events, including enhanced intracellular accumulation and an increased DNA-binding affinity favouring the accumulation of multiple sublethal or lethal damage. In spite of its enhanced cytotoxic potency, the 9-aza compound was better tolerated in vivo than losoxantrone, thus improving the therapeutic index. The preclinical profile of efficacy against prostatic carcinoma, a tumour resistant to conventional antitumour drugs, makes the novel 9-aza-anthrapyrazole BBR 3438 a promising candidate for clinical evaluation.

Adenocarcinoma↗

The evolutionary transformation of phyllopodous to stenopodous limbs in the Branchiopoda (Crustacea)--is there a common mechanism for early limb development in arthropods?

Arthropods and in particular crustaceans show a great diversity concerning their limb morphology. This makes the homologization of limbs and their parts and our understanding of evolutionary transformations of these limb types problematical. To address these problems we undertook a comparative study of the limb development of two representatives of branchiopod crustaceans, one with phyllopodous the other with stenopodous trunk limbs. The trunk limb ontogeny of a 'larger branchiopod', Cyclestheria hislopi ('Conchostraca') and the raptorial cladoceran Leptodora kindtii (Haplopoda) has been examined by various methods such as SEM, Hoechst fluorescent stain and expression of the Distal-less gene. The early ontogeny of the trunk limbs in C. hislopi and L. kindtii is similar. In both species the limbs are formed as ventrally placed, elongate, subdivided limb buds. However, in C. hislopi, the portions of the early limb bud end up constituting the endites and the endopod of the phyllopodous filtratory limb in the adult, whereas in L. kindtii, similar limb bud portions end up constituting the actual segments in the segmented, stenopodous, and raptorial trunk limbs of the adults. Hence, the portions of the limbs corresponding to the endites of the phyllopodous trunk limbs in C. hislopi (and other 'larger branchiopods') are homologous to the segments of the stenopodous trunk limbs in L. kindtii. It is most parsimonious to assume that the segmented trunk limbs in L. kindtii have developed from phyllopodous limbs with endites and not vice versa. This study has demonstrated at least one way in which segmented limbs have been derived from phyllopodous, multi-lobate limbs during evolution. Similar pathways can be assumed for the evolution of stenopodous, segmented and uniramous limbs in other crustaceans. Irrespective of the differences in the adult limb morphology, the early patterning of arthropod limbs seems to follow a similar principle.

Animals↗

Transcranial sonography: integration into target volume definition for glioblastoma multiforme.

PURPOSE: Recent studies indicate that transcranial sonography (TCS) reliably displays the extension of malignant brain tumors. The effect of integrating TCS into radiotherapy planning for glioblastoma multiforme (GBM) was investigated herein. METHODS AND MATERIALS: Thirteen patients subtotally resected for GBM underwent TCS during radiotherapy planning and were conventionally treated (54 to 60 Gy). Gross tumor volumes (GTVs) and stereotactic boost planning target volumes (PTVs, 3-mm margin) were created, based on contrast enhancement on computed tomography (CT) only (PTV(CT)) or the combined CT and TCS information (PTV(CT+TCS)). Noncoplonar conformal treatment plans for both PTVs were compared. Tumor progression patterns and preoperative magnetic resonance imaging (MRI) were related to both PTVs. RESULTS: A sufficient temporal bone window for TCS was present in 11 of 13 patients. GTVs as defined by TCS were considerably larger than the respective CT volumes: Of the composite GTV(CT+TCS) (median volume 42 ml), 23%, 13%, and 66% (medians) were covered by the overlap of both methods, CT only and TCS only, respectively. Median sizes of PTV(CT) and PTV(CT+TCS) were 34 and 74 ml, respectively. Addition of TCS to CT information led to a median increase of the volume irradiated within the 80% isodose by 32 ml (median factor 1.51). PTV(CT+TCS) volume was at median 24% of a "conventional" MRI(T2)-based PTV. Of eight progressions analyzed, three and six occurred inside the 80% isodose of the plans for PTV(CT) and for PTV(CT+TCS), respectively. CONCLUSION: Addition of TCS tumor volume to the contrast-enhancing CT volume in postoperative radiotherapy planning for GBM increases the treated volume by a median factor of 1.5. Since a high frequency of marginal recurrences is reported from dose-escalation trials of this disease, TCS may complement established methods in PTV definition.

Adult↗

Warm preflush with streptokinase improves microvascular procurement and tissue integrity in liver graft retrieval from non-heart-beating donors.

BACKGROUND: Apart from the warm ischemic insult, integrity of liver grafts from non-heart-beating donors (NHBD) is additionally affected by microvascular alterations including erythrocyte aggregation and thrombus formation, which might hamper appropriate equilibration of the preservation solution to the grafts' microvasculature precluding cold preservation. Thus, the objective of our study was to characterize microvascular perfusion quality of University of Wisconsin (UW) solution during initial flushout of livers from NHBD rats, and to analyze the effects of an additional warm preflush with Ringer's lactated solution (RL) and with RL containing streptokinase (SK). METHODS: Cardiocirculatory arrest was induced by phrenotomy. Subsequent to 30 min of warm ischemia, livers were perfused via an aortic catheter by gravity of 100 cm H2O either with 4 degrees C 100 ml UW solution (UW, n=7), or with 25 degrees C 30 ml RL preflush followed by 4 degrees C 100 ml UW solution (RL+UW, n=7), or with 25 degrees C 30 ml SK- (7500 IU) containing RL preflush and 4 degrees C 100 ml UW solution (SK/RL+UW, n=6). Liver microperfusion was quantified using in situ fluorescence epi-illumination microscopy. Liver microcirculation of sham-operated living animals (n=4) served as controls. Enzyme release after a 24-hr cold preservation period was used as an indicator of graft integrity. RESULTS: After 30 min of warm ischemia, microvascular perfusion of UW solution was found markedly altered when compared with that of sham-operated living controls, as indicated by a significant reduction (P<0.05) of acinar and sinusoidal perfusion. Preflush with RL (RL+UW) only slightly attenuated the acinar and sinusoidal perfusion deficits, whereas the addition of SK to RL (SK/RL+UW) resulted in a significant improvement of microvascular graft perfusion (P<0.05). Accordingly, the increased enzyme release observed in solely UW-flushed livers after 24 hr cold preseravtion was only slightly influenced by preflush with RL, but markedly attenuated (P<0.05) by pre-flush with RL containing SK. CONCLUSION: The additive fibrinolytic therapy using SK is effective to improve microvascular procurement of livers after warm ischemia and may thus represent a promising approach to attenuate parenchymal cell injury in liver graft retrieval from NHBD.

Adenosine↗

Effect of warm ischemia time and organ perfusion technique on liver microvascular preservation in a non-heart-beating rat model.

BACKGROUND: Current organ shortage has led to a reconsideration of non-heart-beating cadaveric donation. METHODS: We assessed the effectivity of dual, i.e., arterial and portal-venous versus exclusive, arterial gravity perfusion for procurement of rat livers after 30 min and 60 min of cardiac arrest, analyzing the rate and homogeneity of microvascular perfusion by in situ fluorescence microscopy. RESULTS: After 30 min of cardiac arrest, a nearly 100% recovery of acinar perfusion with a sinusoidal density not significantly different from that of normal, nonischemic livers was achieved by dual gravity perfusion. Prolongation of cardiac arrest to 60 min caused an almost 50% deficit of acinar and sinusoidal perfusion (P<0.05) with a concomitant 2-3-fold increase of heterogeneity of hepatic microperfusion. Regardless of the warm ischemic time period, dually perfused livers exhibited significantly (P<0.05) higher rates of both acinar and sinusoidal perfusion with increased homogeneity of microcirculation when compared with exclusive arterial perfusion. CONCLUSION: These data underline the need and benefit of dual perfusion as well as the limitation of warm ischemic tolerance to 30 min for safe liver procurement of non-heart-beating donors.

Animals↗

Influence of treatment technique on dose-volume histogram and normal tissue complication probability for small bowel and bladder. A prospective study using a 3-D planning system and a radiobiological model in patients receiving postoperative pelvic irradiation.

PURPOSE: A prospective study was undertaken to evaluate the influence of pelvic irradiation techniques on the dose-volume histograms of organs at risk and to analyze its possible clinical relevance using radiobiological models. PATIENTS AND METHODS: For 20 patients receiving postoperative pelvic irradiation because of rectal cancer a 3-field technique (3-FT), a 4-field technique (4-FT) and an opposing field technique (OFT) were designed by a 3-D planning system (Helax, TMS). Dose-volume histograms (DVH) of small bowel, urinary bladder and planning target volume (PTV) were analyzed. The normal tissue complication probability (NTCP) was determined by the radiobiological model of Lyman and Kutcher using the tolerance data of Emami. RESULTS: Median dose to the PTV did not differ between the 3 techniques (3-FT/4-FT/OFT: 99.2%/98.6%/98.1% of the prescribed dose; p > 0.05). Although the median dose to the urinary bladder was lower for the 3-FT than for the 4-FT (44.7% vs 60.3%; p < 0.001), there was no difference in the calculated NTCP (0.0% vs 0.0%; p > 0.05). Using multiple field techniques both the dose to and the treated volume of the urinary bladder were significantly lower than using the OFT. As a consequence of this the late NTCP of the bladder was higher for the OFT (5.46%). Although the median dose to the small bowel was lower for the 3-FT than for the 4-FT (30.8% vs 54.5%; p < 0.005), the fractional part of small bowel within the high-dose region (90% isodose) was higher for the 3-FT (10.6% vs 8.2%; p > 0.05). Thus the calculated NTCP was higher for the 3-FT (0.79 vs 0.44) than for 4-FT. For the OFT the median dose to small bowel was 69.9% and the small bowel volume within the high-dose region was 57.8% resulting in a late NTCP of 9.36% (OFT vs 3-FT/4-FT: p < 0.05). CONCLUSION: Using multiple field techniques both the dose to the organs of risk and the fractional part of risk organs within the high-dose region can be reduced significantly. As a consequence of this a lower NTCP was calculated for the 3-FT and the 4-FT than for the OFT. Using the biological model a small, but significant difference between a 3-FT and a 4-FT was demonstrated in favor to the 4-FT.

Adult↗

[Optimized 3-D planning by simple means. An example].

AIM: A treatment technique favorable for linacs with asymmetric jaws, which combines cranio-caudal matching fields with fields enclosing the whole target volume, is investigated with respect to field matching and sparing of normal tissue and organs at risk. PATIENT AND METHODS: For a pelvic target volume rapidly varying in cranio-caudal direction a 5-field technique was planned with individually weighted and blocked fields. Three fields adjoining in cranio-caudal direction were completed by 2 fields enclosing the whole target volume. The matching line was measured and calculated with Helax TMS. Furthermore a 4-field box and opposing fields were planned. The dose-volume histograms for target, bladder, intestine and soft tissue were exported. Normal tissue complication probability and tumor control probability, respectively, were calculated for all techniques. RESULTS: In the region of the matching line the summation of the measured normalized curves resulted in relative dose maxima of 6.0% (caudal) and 4.5% (cranial), respectively. For fields enclosing the whole target volume the dose maxima in the region of the matching line decreased to 2.0% (caudal) and 1.8% (cranial), respectively. For the dose profiles calculated with Helax TMS no overdose was found. The 5-field technique with adjoining fields results in a better sparing of the organs at risk compared to the other techniques, whereas the tumor control remains the same. CONCLUSIONS: In specific cases a technique with cranio-caudal adjoining fields can be recommended with respect to sparing of normal tissue and organs at risk.

Humans↗

Heparin and phentolamine combined, rather than heparin alone, improves hepatic microvascular procurement in a non-heart-beating donor rat-model.

Improvement of organ procurement from non-heart-beating donors (NHBDs) could increase the donor organ pool for liver transplantation. Whether anti-coagulative and anti-vasospastic substances can improve hepatic microvascular preservation from NHBDs is unknown. In donor rats which were pretreated with either heparin (n = 6) or heparin combined with phentolamine (n = 7) 10 min prior to cardiac arrest, the extent and homogeneity of hepatic microvascular reperfusion was assessed at the end of a 60-min period of cardiac arrest using in situ fluorescence microscopy. Non-pretreated animals with cardiac arrest for 60 min served as controls (n = 6). In the non-treated NHBDs, arterial gravity perfusion of 100 cm H2O with HTK-solution led to a hepatic acinar reperfusion of only approximately 22 % with a remarkably diminished sinusoidal density. Application of heparin prior to cardiac arrest resulted in a two-fold, but insignificant increase of acinar perfusion and sinusoidal density with a still considerable heterogeneity of both parameters. Livers of NHBDs that additionally received phentolamine exhibited significantly increased values of both acinar perfusion and sinusoidal density. Phentolamine was found to reduce heterogeneity of organ microperfusion. Thus, our results indicate that the combined application of heparin and phentolamine is a useful additive for optimizing the quality of organs harvested from NHBDs.

Alanine Transaminase↗

Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats.

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-L-phenylalanine (IPA), L-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT < or = IPA). Competitive inhibition experiments using alpha-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.

Alanine↗

Significance of hepatic arterial responsiveness for adequate tissue oxygenation upon portal vein occlusion in cirrhotic livers.

We investigated sinusoidal blood flow and hepatic tissue oxygenation during portal vein occlusion in cirrhotic rat livers to examine the effect of cirrhosis on the properties of hepatic microvascular blood flow regulation. After 8 weeks of CCl4/phenobarbital sodium treatment to induce cirrhosis Sprague-Dawley rats were prepared surgically to allow assessment of portal venous and hepatic arterial inflow using miniaturized flow probes with simultaneous analysis of hepatic microcirculation and tissue oxygenation by fluorescence microscopy and polarographic oxymetry. Age-matched noncirrhotic animals served as controls. Upon portal vein occlusion in cirrhotic livers (flow reduction to < 20%), hepatic arterial blood flow increased 1.5-fold (61 +/- 8 ml/min per 100 g liver) of baseline (40 +/- 7 ml/min per 100 g liver), reflecting an appropriate hepatic arterial buffer response (HABR), similarly as seen in control livers. The net result was a reduction in total liver inflow from 90 +/- 12 to 72 +/- 11 ml/min per 100 g liver, which was associated with a significant decrease in both sinusoidal red blood cell velocity and volumetric blood flow to approx. 71% and 76% of baseline values. However, portal vein occlusion did not cause a deterioration in hepatic tissue pO2 (11 +/- 3 vs. 10 +/- 3 mmHg at baseline). Sinusoidal diameters were found unchanged, disproving a major role of the sinusoidal tone in the regulation of HABR. Microvascular response of cirrhotic livers did not generally differ from that in noncirrhotic livers upon portal inflow restriction. We conclude that HABR in cirrhotic livers operates sufficiently to meet the liver tissue oxygen demand, most probably by an increased relative contribution of arterial perfusion of hepatic sinusoids.

Animals↗

Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death.

We show that following immunoneutralization of endogenous transforming growth factors beta (TGF-beta) in the chick embryo, ontogenetic neuron death of ciliary, dorsal root and spinal motor neurons was largely prevented, and neuron losses following limb bud ablation were greatly reduced. Likewise, preventing TGF-beta signaling by treatment with a TbetaR-II fusion protein during the period of ontogenetic cell death in the ciliary ganglion rescued all neurons that normally die. TUNEL staining revealed decreased numbers of apoptotic cells following antibody treatment. Exogenous TGF-beta rescued the TGF-beta-deprived phenotype. We conclude that TGF-beta is critical in regulating ontogenetic neuron death as well as cell death following neuronal target deprivation.

Animals↗

Scintigraphic study of the major salivary glands in pediatric bone marrow transplant recipients.

Total body irradiation (TBI) at bone marrow transplantation (BMT) is shown to cause salivary gland dysfunction in children. The aim of the investigation was to study the function of major salivary glands in long-term surviving children following treatment with TBI, using salivary gland scintigraphy (SGS). Thirteen patients (seven male, six female), who had received TBI before the age of 13 years and survived more than 4 years, participated in the study. A reference group of 10 patients (nine male, one female) was examined shortly before they were to undergo BMT. The mean age was 14.1 +/- 4.1 years in the TBI-treated group and 12.8 +/- 5.9 years in the reference group. Unstimulated and stimulated whole salivary secretion rates were measured for 15 and 5 min, respectively, before SGS was performed. The percentage of stimulated secretion was 44.7 +/- 18.1% in the TBI-treated group compared to 58.4 +/- 13.0% in the reference group (P = 0.0438). Slower reaccumulation after excretion was found in the TBI-treated patients compared to the reference group (P = 0. 0300). The function of the major salivary glands in long-term survivors treated with TBI at BMT before the age of 13 years was found to be diminished, as shown by the reduced trapping rate and reduced emptying capacity, compared to prior to BMT. Bone Marrow Transplantation (2000) 26, 775-779.

Adolescent↗

Correlation between quantitative salivary gland scintigraphy and salivary secretion rates in children and young adults treated for hematological, malignant and metabolic diseases.

OBJECTIVES: To study the correlation between whole salivary secretion rates and different variables from the radionuclide time-activity curve and to determine a reliable region for background correction in salivary gland scintigraphy. METHODS: Salivary gland scintigraphy (SGS) was performed before bone marrow transplantation or more than 4 years later in 23 patients aged 13.5 (s.d. 4.9) years. Unstimulated and stimulated whole salivary secretion rates were measured before SGS. Six different methods for background correction were evaluated. RESULTS: The unstimulated secretion rate was significantly correlated (P < 0.05) with the percentage stimulated secretion (S) and reaccumulation-slope (RS) after stimulation. The stimulated secretion rate was significantly correlated with RS, S and down-slope (DS). The temporal region above the parotid glands and the area above the thyroid gland was used for subtraction of background radiation for the parotid and submandibular glands respectively showed a strong correlation between repeated measurements of the variables analysed. The mean maximum uptake was 0.73-1.34% of total dose injected. CONCLUSIONS: The salivary scintigraphic variables which correlated more strongly with salivary secretion rates were RS, S and DS. The temporal region above the parotid gland and the area above the thyroid gland can be used reliably for correction background radiation in the analysis of the time-activity curve in SGS of the parotid and submandibular glands respectively.

Adolescent↗

The indwelling ureteric stent: a 'friendly' procedure with unfriendly high morbidity.

OBJECTIVE: To review the morbidity and complications of ureteric stent insertion and to evaluate specifically the effect of an indwelling ureteric stent on the changes in hydronephrosis after stenting. PATIENTS AND METHODS: In a prospective study, 110 renal units with a stent in place were evaluated in 90 patients. Of the 110 stents, 52 were left in place for 3 months, 23 for 6, 11 for 9, 19 for 12 and five (forgotten stents) for 13-30 months. The patients were followed using plain abdominal X-ray at 1 and 30 days after stenting. They were further followed using ultrasonography and plain films every 3 months until the scheduled date for stent removal or the appearance of complications. RESULTS: Thirty-four patients had fever and bacteriuria after stent insertion. Of the 110 stents, 11 (10%) fragmented and nine (8%) migrated. Seventeen patients complained of flank pain on voiding. In 21 renal units (19%) there was no change in the severity of hydronephrosis, whereas in six (5.5%) hydronephrosis developed or worsened after stenting. CONCLUSION: Although ureteric stenting is undoubtedly an important procedure to relieve ureteric obstruction, the indications for stent insertion should be considered carefully in every patient. The close follow-up of stented patients is valuable for the early detection of morbidity or complications and in such cases the stent should be removed or exchanged as soon as possible.

Catheters, Indwelling↗

Chemistry and microbiology of permeable reactive barriers for in situ groundwater clean up.

Permeable reactive barriers (PRBs) are receiving a great deal of attention as an innovative, cost-effective technology for in situ clean up of groundwater contamination. A wide variety of materials are being proposed for use in PRBs, including zero-valent metals (e.g., iron metal), humic materials, oxides, surfactant-modified zeolites (SMZs), and oxygen- and nitrate-releasing compounds. PRB materials remove dissolved groundwater contaminants by immobilization within the barrier or transformation to less harmful products. The primary removal processes include: (1) sorption and precipitation, (2) chemical reaction, and (3) biologically mediated reactions. This article presents an overview of the mechanisms and factors controlling these individual processes and discusses the implications for the feasibility and long-term effectiveness of PRB technologies.

Absorption↗