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Biomedical subjects

R Bukowski

Publications and source records attributed to R Bukowski.

At least 19 recordsLinked to original sources
PubMed2006

Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors.

INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.

Administration, Oral↗
PubMed2006

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors.

PURPOSE: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. METHODS: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS: Five dose levels of MAC-321 ranging from 25 to 75 mg/m(2) were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m(2)). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m(2); one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m(2) had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C (max) value of less than 1 h. Mean C (max) and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). CONCLUSIONS: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was neutropenic fever. Four subjects had disease stabilization.

Administration, Oral↗
PubMed2006

Intrauterine growth restriction.

This study reviewed the screening, diagnosis, prophylaxis, and treatment of intrauterine growth restriction using the PubMed database for key words and the Cochrane database for systematic reviews. Identification of risk factors and measurement of symphysis-fundus height are currently the screening standards. Diagnosis is verified by ultrasonography. Accuracy of diagnosis may be improved by using customized fetal growth curves, symphysis-fundus height charts, and 3-dimensional ultrasonographic evaluation and measuring umbilical artery Doppler dimensional ultrasonographic evaluation measuring umbilical artery Doppler impedance. Prophylaxis with acetylsalicylic acid, started in the first or second trimester or combined with heparin before conception, may reduce the incidence of growth restriction in specific groups at high risk. Active management may reduce incidence in patients with mild to moderate asthma, and targeted treatment of infections may also be beneficial. Antenatal corticosteroid treatment also reduces the perinatal morbidity and mortality associated with IUGR. Bed rest has no demonstrated beneficial effects.

Adrenal Cortex Hormones↗
PubMed2005

Re-examination of the topographical localization of facial nucleus in the pig.

Previous publications have provided different descriptions of the topographical organization of the facial nucleus of the pig. Since swine is used in biomedical research due to its embryological, anatomical and physiological similarities to human, we have reinvestigated the anatomical organization of the facial nucleus with application of fluorescent retrograde tracer Fast Blue, antibody to choline acetyltransferase and acetylcholinesterase histochemistry. Our findings demonstrate that in the porcine medulla facial motoneurons constitute a large cellular group occupying the ventro-lateral medulla. The neuronal group is interposed rostro-caudally between the superior and inferior olive, and located ventro-medially to the spinal nucleus of the trigeminal nerve. The present results clarify the anatomical description of this important brain stem nucleus in the pig.

Acetylcholinesterase↗
PubMed2003

Amniotic fluid index measured with the aid of color flow Doppler.

OBJECTIVE: To determine whether using color flow Doppler to identify the umbilical cord affects amniotic fluid index (AFI) measurements. METHODS: A total of 2236 AFI measurements between 24 and 42 weeks in singleton gestations with no known or suspected fetal anomalies and < 14 days' discrepancy between menstrual and ultrasonographic dating were included. Color flow Doppler was used to identify loops of umbilical cord; these were excluded from the measurement. Polynomial regression was used to generate means and centiles. Data were grouped according to completed weeks of gestation and descriptive statistics were calculated. At each week of gestation, the number and percentage of pregnancies diagnosed as < or = 2.5th, < or = 5th, > or = 95th, and > or = 97.5th centile according to a 'standard' nomogram derived without using color flow Doppler were calculated. RESULTS: The AFI decreased significantly over gestational age, starting at 31 weeks (p < 0.05 by ANOVA). The relationship between AFI and gestational age was best modeled by a second-degree polynomial (p < 0.001). The median and range of the proportion of AFIs that fell outside the ranges of the standard nomogram at each completed gestational age was: 6.0 (2.3-35.4)% for the < or = 2.5th centile, 9.9 (3.1-37.5)% for the < or = 5th centile, 3.8 (0-30)% for the > or = 95th centile, and 1.8 (0-20)% for the > or = 97.5th centile. The 2.5th and 5th centiles using the current data were lower than those of the 'standard', and the difference increased with advancing gestation. Upper centiles were also different. CONCLUSION: The AFI measured using color flow Doppler overestimates oligohydramnios and may underestimate polyhydramnios when a standard AFI table obtained without color flow Doppler is used. Normal values specific for measurement method should be used for reference.

Amniotic Fluid↗
PubMed2001

Inhibition of NFkappaB induces caspase-independent cell death in human T lymphocytes.

Nuclear factor kappaB (NFkappaB) regulates the expression of various genes essential for cell survival. Here we demonstrate that suppression of NFkappaB nuclear import with SN50 peptide carrying the nuclear localization sequence (NLS) of the NFkappaB p50 subunit induces apoptosis in human peripheral blood T lymphocytes (T-PBL), which can be blocked with the pan-caspase inhibitor Z-VAD.fmk. However, even when caspase function is blocked, the addition of SN50 induces irreversible cell loss due to the reduction in the mitochondrial transmembrane potential (DeltaPsim) followed by disruption of the cell membrane, hallmarks of necrosis. These observations demonstrate that although inhibition of NFkappaB nuclear translocation by SN50 peptide can induce caspase-dependent apoptosis in T-PBL, cell death may still proceed in the absence of functional caspase activity. The availability of downstream caspases appears to determine the mode of cell death in NFkappaB defective cells.

Active Transport, Cell Nucleus↗
PubMed2001

Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics.

PURPOSE: The present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated. METHODS: A total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients. RESULTS: The toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h. CONCLUSIONS: The combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.

Administration, Oral↗
PubMed2001

Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes.

Alterations in intracellular Zn(2+) concentrations are believed to play a crucial role in modulating apoptosis. The observation that Zn(2+) deficiency can induce cell death both in vivo and in vitro has been attributed to the fact that exchange of Zn(2+) for Ca(2+) and Mg(2+) within the nuclei may directly activate endogenous endonucleases therefore inducing DNA fragmentation independent of cytoplasmic factors. Here we show that the membrane-permeable zinc chelator, N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces translocation of cytochrome c from the mitochondrial intramembranous space into the cytosol in human peripheral blood T lymphocytes (PBL) with subsequent activation of caspases-3, -8, and -9. Pretreatment of T lymphocytes with caspase inhibitors Z-VAD.fmk or DEVD.fmk prevented DNA fragmentation in response to TPEN indicating that apoptosis triggered by zinc deficiency is entirely dependent on activation of caspase family members. The release of cytochrome c and activation of downstream caspases precedes changes in the mitochondrial transmembrane potential (Delta Psim). Therefore, cytoplasmic and mitochondrial events are critical to this process.

Amino Acid Chloromethyl Ketones↗
PubMed2001

New developments in the management of preterm labor.

Current management of preterm labor has not changed the incidence of preterm delivery; therefore, significant research effort has been concentrated on the search for new methods of management. New tocolytics like inhibitors of cyclooxygenase 2 and nitric oxide donors have been tested in animal models and in preliminary clinical trials with promising results. Inhibition of cervical ripening may be one alternative to tocolysis. This new approach has a potential to be a valuable method of management of preterm labor if human studies confirm the promising results reported in animals. Growing evidence suggests that premature delivery may be associated with infection or fetal growth abnormalities, with dire consequences to the fetus. If these associations are to be included in risk and benefit assessment, then inhibition of preterm labor may prove to be detrimental to the fetus.

Cerebral Palsy↗
PubMed2001

Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer.

Anaemia is a common haematologic disorder in patients with cancer and has a multifactorial aetiology, including the effects of the malignancy itself and residual effects from previous therapy. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa), a protein with additional sialic acid compared with erythropoietin (EPO), stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO) but it is biochemically distinct. NESP, with its approximately 3-fold greater serum half-life, can maintain haemoglobin levels as effectively as rHuEPO in anaemic patients with chronic renal failure and do so with less frequent dosing. We investigated the ability of NESP to safely increase haemoglobin levels of anaemic patients with non-myeloid malignancies not receiving chemotherapy. NESP was administered under the supervision of a physician at doses of 0.5, 1.0, 2.25 or 4.5 mcg kg(-1)wk(-1)for a maximum of 12 weeks. This report includes 89 patients completing the study by November 2000. NESP was well tolerated, with no reported dose-limiting toxicities or treatment-related severe adverse events. Increasing doses of NESP corresponded with increased efficacy. The percentage (95% confidence interval) of patients responding ranged from 61% (42%, 77%) in the 1.0 mcg kg(-1)wk(-1)group to 83% (65%, 94%) in the 4.5 mcg kg(-1)wk(-1)group.

Adult↗
PubMed2001

Inhibition of cervical ripening by local application of cyclooxygenase 2 inhibitor.

OBJECTIVE: Our goal was to test the hypothesis that the previously demonstrated progesterone-independent prolongation of pregnancy in rats treated with cervical application of the cyclooxygenase 2 inhibitor nimesulide is the result of inhibition of cervical ripening. STUDY DESIGN: Timed-pregnant Sprague-Dawley rats were randomly allocated to treatment with 50 mg nimesulide or vehicle, applied daily on the cervix for 5 days (days 14-18). On day 19 the animals were humanely killed and the cervices were removed. In the first series of experiments the cervices of animals treated with nimesulide (n = 10) or vehicle (n = 10) were examined with a cervimeter, which stretches the cervical tissues in incremental steps of 0.2 mm at 1-minute intervals. A steeper slope through the linear portion of the resulting force-versus-displacement curve indicates more resistance to stretch. In the second series of experiments the cervices of animals treated with nimesulide (n = 11) or vehicle (n = 11) were examined with the Collascope optical device. The cervical content of cross-linked collagen was measured with light-induced fluorescence. The fluorescence spectrum at 390 nm (peak wavelength of the collagen spectrum) was determined. For standardization, the ratio of counts of collagen peak over reference counts was used in the final analyses as an indicator of cross-linked collagen content. RESULTS: Animals treated with cervical application of nimesulide had significantly higher resistance to stretch than controls (slope: 0.2564 +/- 0.1213 vs 0.1387 +/- 0.0652; P =.019). The cervical content of cross-linked collagen was not significantly different between nimesulide-treated animals and controls (light-induced fluorescence ratios: 3.2134 +/- 0.7390 vs 2.7892 +/- 0.8518; P =.227). CONCLUSIONS: Treatment with cervical application of the cyclooxygenase 2 inhibitor nimesulide prevents the physiologic process of cervical ripening in late pregnancy. The inhibition is not the result of changes in cross-linked collagen content. Inhibition of cervical ripening with locally administered cyclooxygenase 2 inhibitor may be a potentially valuable treatment for patients at risk for preterm delivery.

Administration, Topical↗
PubMed2001

Impairment of growth in fetuses destined to deliver preterm.

OBJECTIVE: The objective of this study was to test the hypothesis that fetuses destined to deliver preterm do not reach their individual growth potential. STUDY DESIGN: In a case control design, data on 44 preterm deliveries at < or =34 weeks were compared with data on a control group of next consecutive term deliveries. Criteria for inclusion were dating by ultrasonography at <20 weeks and no medical or obstetric complications. For each fetus, GROW v.2 software was used to generate an individual optimal growth curve and to calculate the percentile of achieved growth potential for birth weight based on 6 independent factors (maternal weight, height, parity, ethnicity, fetal sex, and gestational age) identified as determining fetal weight from multivariate logistic regression analysis of 40,000 uncomplicated term pregnancies. Birth weight percentiles based on standard norms were also calculated for each fetus. RESULTS: The number of fetuses with birth weight below the 5th, 10th, and 25th percentile of their growth potential was significantly higher in the preterm group (10, 13, and 18) compared with that in the control group (2, 2, and 6; P <.008, P <.001, and P <.008, respectively). There were no significant differences in variables defining growth potential between the case and control groups. The number of fetuses below the 5th and 10th percentile based on standard birth weight norms was not significantly different between preterm and term pregnancies (3 vs 1 and 5 vs 2; P =.37 and P =.27). Among preterm deliveries, those preceded by preterm premature rupture of the membranes had significantly fewer fetuses >75th percentile of their growth potential (2 vs 8; P =.025). Fetuses with lower gestational ages at preterm delivery achieved lower median percentiles of their growth potential. CONCLUSION: A significant proportion of fetuses destined to deliver preterm do not reach their individual growth potential compared with those delivered at term. This finding challenges our concept of preterm delivery and management strategy aimed at tocolysis.

Birth Weight↗
PubMed2001

The effects of cervical application of inhibitors of inducible nitric oxide synthase, cyclooxygenase-1, and cyclooxygenase-2 on delivery in rats.

OBJECTIVE: To investigate the effect of cervical application of nonselective and selective inhibitors of nitric oxide synthases--N-nitro-L-arginine methyl ester, L-N-iminoethyl-lysine, and aminoguanidine--as well as inhibitors of cyclooxygenases--indomethacin, and nimesulide--on timing of delivery and fetal death and disease in pregnant rats. STUDY DESIGN: In a series of experimental protocols, timed-pregnant Sprague-Dawley rats (length of pregnancy, 22 days) were randomly allocated to daily cervical applications of (1) 0.04 mg (n = 6), 0.4 mg (n = 6), 4 mg (n = 6), or 40 mg (n = 6) L-N-iminoethyl-lysine or vehicle (n = 12) on days 19 to 22 of pregnancy; (2) 50 mg aminoguanidine (n = 6), 150 mg aminoguanidine (n = 6), or vehicle (n = 10) on days 19 to 22 of pregnancy; (3) 3 mg indomethacin (n = 6) or vehicle (n = 6) on days 19 to 22 of pregnancy; (4) 12.5 mg/kg nimesulide (n = 8), 25 mg/kg nimesulide (n = 8), 50 mg/kg nimesulide (n = 12), or vehicle (n = 12) on days 19 to 22 of pregnancy and 50 mg/kg nimesulide (n = 23) or vehicle (n = 23) on days 14 to 22 of pregnancy; (5) 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine plus 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine (n = 10), or vehicle (n = 10) on days 14 to 22 of pregnancy. The following variables were evaluated: proportion of animals that were delivered on day 23, time to delivery of the first pup (midnight on day 22 was considered to be 0 hour), number of stillborn pups, and average pup weight of each litter. RESULTS: Unlike L-N-iminoethyl-lysine, aminoguanidine, and indomethacin, 50 mg/kg nimesulide applied on the cervix daily for 8 days significantly increased the proportion of animals that were delivered on day 23 (18 of 23 versus 7 of 23; P =.003) and the time to delivery of the first pup by a mean of 10.8 hours (P <.001). Shorter treatment with nimesulide for 4 days increased only the time to delivery of the first pup at the 25-mg/kg dosage (P =.008). Simultaneous application of aminoguanidine and nimesulide significantly (P =.008) prolonged pregnancy to a degree similar to nimesulide alone. The experiment with N-nitro-L-arginine methyl ester was aborted because of severe maternal side effects. Unlike pups in the L-N-iminoethyl-lysine, aminoguanidine, and nimesulide groups, significantly more pups in the indomethacin group died in utero compared with the control group (36.1% versus 3.1%; P <.001), and the surviving pups had lower birth weights (P <.001). CONCLUSIONS: In an animal model, nimesulide was effective in delaying the onset of labor, was well tolerated during pregnancy, and affected cervical ripening directly independent of progesterone withdrawal. Conversely, cervical application of nitric oxide synthase and nonselective cyclooxygenase inhibitors do not extend the duration of pregnancy in the dosages studied, and some are associated with significant adverse effects in the mothers and fetuses.

Administration, Topical↗
PubMed2001

The T cell death knell: immune-mediated tumor death in renal cell carcinoma.

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The conformation of the T-antigen disaccharide bound to Maclura pomifera agglutinin in aqueous solution.

The complex of Maclura pomifera agglutinin with the T-antigen disaccharide (beta-d-Gal-(1-->3)-alpha-d-GalNAc-(1-->O)-Me) was investigated by NMR spectroscopy in aqueous solution. Intramolecular transferred nuclear Overhauser enhancement (NOE) effects between the monosaccharide moieties were used to derive the ligand conformation in the lectin-bound state. Ligand protons in contact with the protein were identified by saturation transfer difference experiments and intermolecular transferred NOE effects. It is demonstrated that structural differences exist for the ligand-lectin complex in aqueous solution as compared with the previously published crystal structure (Lee, X., Thompson, A., Zhiming, Z., Ton-that, H., Biesterfeldt, J., Ogata, C., Xu, L., Johnston, R. A. Z. , and Young, N. M. (1998) J. Biol. Chem. 273, 6312-6318). In order to accommodate the O-methyl group of the disaccharide, the amino acid side chain of Tyr-122 has to rotate from its position in the crystal. The NMR data are in accord with two conformational families at the beta-(1-->3)glycosidic linkage in the solution complex with interglycosidic angles phi/psi = 45/-65 degrees and -65/-18 degrees. These differ from the bound conformation of the ligand in the crystal (phi/psi = 39/-8 degrees ) and are not highly populated by the ligand in the free state. The reason for the structural differences at the beta-(1-->3)glycosidic linkage are hydrogen bonds that stabilize the relative orientation of the monosaccharide units in the crystal. Our results demonstrate that the crystallization of a protein-carbohydrate complex can interfere with the delicate process of carbohydrate recognition in solution.

Antigens, Neoplasm↗
PubMed2000

Water pair and three-body potential of spectroscopic quality from Ab initio calculations

We present the first pair plus three-body potential of water from ab initio calculations that quantitatively reproduces the experimental far-infrared spectra of the water dimer and trimer. The dimer spectrum was obtained from the pair potential through rigorous six-dimensional quantum calculations of the vibration-rotation-tunneling levels. The three-body interactions, together with the pair potential, produce an accurate representation of the hydrogen bond torsional levels of the water trimer.

Journal Article↗
PubMed2000

Hydrops fetalis.

Although most NIH fetuses have poor prognosis, it is imperative to attempt to identify the underlying cause to present parents with the best estimate for prognosis and future outcomes. Identification of a disorder with a good prognosis may prevent unnecessary termination of pregnancy and give a chance for therapy. Identification of a disorder with poor prognosis may still provide information that may be unavailable after delivery regarding this and future pregnancies.

Counseling↗