Bcr-Abl inhibition as a modality of CML therapeutics.
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Animals↗
Biomedical subjects
A Matter
Publications and source records attributed to A Matter.
Strong coherence between solar variability and the monsoon in Oman between 9 and 6 kyr ago.
Variations in the amount of solar radiation reaching the Earth are thought to influence climate, but the extent of this influence on timescales of millennia to decades is unclear. A number of climate records show correlations between solar cycles and climate, but the absolute changes in solar intensity over the range of decades to millennia are small and the influence of solar flux on climate is not well established. The formation of stalagmites in northern Oman has recorded past northward shifts of the intertropical convergence zone, whose northward migration stops near the southern shoreline of Arabia in the present climate. Here we present a high-resolution record of oxygen isotope variations, for the period from 9.6 to 6.1 kyr before present, in a Th-U-dated stalagmite from Oman. The delta18O record from the stalagmite, which serves as a proxy for variations in the tropical circulation and monsoon rainfall, allows us to make a direct comparison of the delta18O record with the Delta14C record from tree rings, which largely reflects changes in solar activity. The excellent correlation between the two records suggests that one of the primary controls on centennial- to decadal-scale changes in tropical rainfall and monsoon intensity during this time are variations in solar radiation.
Journal Article↗
Cool glacial temperatures and changes in moisture source recorded in oman groundwaters
Concentrations of atmospheric noble gases (neon, argon, krypton, and xenon) dissolved in groundwaters from northern Oman indicate that the average ground temperature during the Late Pleistocene (15,000 to 24,000 years before present) was 6.5 degrees +/- 0.6 degrees C lower than that of today. Stable oxygen and hydrogen isotopic groundwater data show that the origin of atmospheric water vapor changed from a primarily southern, Indian Ocean source during the Late Pleistocene to a dominantly northern, Mediterranean source today. The reduced northern water vapor source is consistent with a drier Last Glacial Maximum through much of northern Africa and Arabia.
Journal Article↗
Interactive image-guided surgical resection of intracranial arteriovenous malformations.
Surgical excision is the only treatment method that immediately prevents increased morbidity or mortality as a result of hemorrhage from arteriovenous malformations (AVMs). For those lesions located deep within the cerebral hemispheres or near eloquent areas, conventional surgical resection may be associated with an unacceptable degree of morbidity and mortality. Herein we report our experience in the resection of these lesions using interactive image guidance. There were five women and five men in the patient group. Their age ranged from 16 to 73 years (mean = 41). Clinical presentation included hemorrhage (n = 7), headaches (n = 2), and seizures (n = 1). All lesions were classified using the Spetzler-Martin grading system as follows: grade I (n = 4), grade II (n = 5), and grade III (n = 1). The locations of the lesions were supratentorial (9) and infratentorial (1). Surgical planning was carried out using the Neurological Surgery Planning System software developed at Wayne State University. An infrared-based system was used to locate and define the lesion intraoperatively. For those lesions located near or within eloquent areas, an awake craniotomy with functional mapping was carried out. Clinical follow-up ranged from 3 to 62 months (mean = 34). Complete surgical excision was achieved in all patients, which was demonstrated postoperatively by digital substraction angiography. The preoperative neurological status remained unchanged in seven patients and improved in three. There was no associated morbidity and mortality with this technique. Image-guided surgical resection of arteriovenous malformations represents a valuable technique, especially in small deep-seated lesions and in those near eloquent areas.
Adolescent↗
Permanent I-125 brain stem implants in children.
Between 1988 and 1997, 28 children have had iodine-125 implants for CNS tumors performed in our institution. Ten had stereotactic implantation in the brain stem region, and nine had the diagnosis of brain stem glioma (8 diffuse pontine, 1 midbrain tumor). Their ages ranged from 1.8 to 12 years. All patients had histological confirmation of malignancy (7 high-grade glioma, 2 low-grade glioma, 1 PNET). Diffuse pontine glioma patients received external beam radiation (50 Gy) followed by a fractionated stereotactic boost of 3 Gyx4 fractions. After 4-6 weeks, patients were reevaluated for stereotactic interstitial I-125 therapy. The planned implant dose was 82.9 Gy to the enhancing tumor (4 cGy per h). Preliminary results indicated that no surgical complications were associated with the catheter placement. Four patients have died (7-9 months from diagnosis) and four patients remain alive (5-38 months from diagnosis, median 10 months). Two autopsies confirmed the presence of progressive glioblastoma multiforme and intralesional necrosis. In one patient who received an implant alone for midbrain LGA, necrosis without tumor was found on biopsy after 36 months. He was successfully treated with hyperbaric oxygen therapy. The implementation of permanent I-125 implants appears to have a role in the management of pediatric CNS malignancy. This study confirms the results of previous reports regarding the safety of stereotactic interstitial brachytherapy in the brain stem. Tumor control for patients with high-grade brain stem glioma remains poor even with high focal radiation doses.
Brachytherapy↗
Interactive image guided surgery of the pineal region.
A wide variety of lesions occur in the pineal region. Of these, only 25% may benefit from surgical resection, being benign or radioresistant in nature. In the remaining 75% (malignant or radiosensitive), a conservative approach is preferred. Surgical resection of lesions arising from the pineal region has been associated with high morbidity and mortality, due to the complex microanatomy of this area. Recently computer-assisted surgery has emerged as an ideal method to safely approach many intracranial lesions. In the present study we discuss our experience in interactive image-guided surgical management of pineal mass lesions, in terms of patient selection, methodology, and surgical morbidity and mortality. From July 1992 to December 1996, 15 patients underwent interactive image guided surgical procedures. There were eight men and seven women. Age ranged from 5 to 79 years (mean 30). Preoperatively all patients underwent neuroimaging studies that included computed tomography and magnetic resonance imaging under stereotactic conditions. Surgical planning was carried out using the Neurological Surgical Planning System software developed at Wayne State University. In patients with a preoperative diagnosis of a malignant or radiosensitive lesion (n = 10), an interactive image-guided stereotactic biopsy was considered, whereas for those with benign or radioresistant lesions (n = 5) surgical excision using an infrared based system was carried out. Histological diagnosis was obtained in all patients. There was no morbidity and mortality associated with computer-assisted procedures for biopsies the diagnostic yield was 100%. For patients that underwent interactive image-guided surgery, gross total removal was accomplished in 3 and in 1 patient a subtotal resection greater than 90% was achieved. Interactive image-guided biopsy represents a safe and accurate method in the diagnosis of malignant and/or radiosensitive pineal lesions. Using this technique surgeons can simulate preoperatively the surgical trajectory, thus avoiding damage to critical and vascular structures. For patients with benign or radioresistant lesions, computer-assisted surgical excision is recommended.
Adolescent↗
Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients.
PURPOSE: To compare the prognostic impact of tumor angiogenesis factors (vascular endothelial growth factor [VEGF], angiogenin, and basic fibroblast growth factor [bFGF]), tumor proteolysis factors (urokinase-type plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]), and conventional tumor markers (stage, grade, and steroid receptors) in early breast cancer. PATIENTS AND METHODS: In the primary clinical study, tumor angiogenesis and other factors were detected in frozen biopsies from 305 primary breast tumors. VEGF expression was assessed by chemiluminescence immunosorbent assay (ICMA); angiogenin, bFGF, uPA, and PAI-1 by enzyme-linked immunosorbent assay (ELISA); and steroid receptors (estrogen receptor [ER] and progesterone receptor [PgR]) by enzyme immunoassay (EIA). In the validating clinical study, another set of 190 node-negative primary breast tumor samples were collected at a separate institution. RESULTS: Univariate analysis of the primary study showed that VEGF levels were positively correlated with recurrence (P < .001). Angiogenin levels were positively correlated with disease relapse (P < .005) for the overall collective group, but not within the node-negative subset. No significant correlations were found between tumor bFGF levels and patient survival. In multivariate regression analysis, the only independent predictors of relapse-free survival (RFS) were VEGF, uPA, and lymph node status. In the validation set, the distribution of VEGF and uPA values were similar to those in the primary study; low expression of both VEGF and uPA identified patients with a < or = 20% likelihood of recurrence within 7 years. CONCLUSION: Separate primary and validating clinical studies concur that tumor VEGF level is the most important prognostic parameter among several markers of tumor angiogenesis and proteolysis.
Adult↗
Interactive image-guided resection of cerebral cavernous malformations.
Between July 1992, and February 1997, 15 patients with cavernous malformations underwent interactive image-guided resection of their lesions. There were eight women and seven men in the group, ranging in age from 6 years to 62 years (mean 34 years). Clinical presentations included seizures (n = 7), headache (n = 4), and hemorrhage (n = 4). Prior conventional subtotal resection had been performed in one patient, and a history of prior hemorrhage was found for two patients. Diagnosis was made using magnetic resonance imaging and digital substraction angiography. Locations of the lesions were temporal (n = 9), frontal (n = 3), thalamus (n = 1), basal ganglia (n = 1), and pons (n = 1). Size ranged from 9 to 20 mm (mean 12 mm). For those lesions located near or within eloquent areas (n = 7), an awake craniotomy with functional cortical and subcortical mapping was performed. An infrared system was used intraoperatively to confirm the location and the extent of the resection of these lesions in real time. In 1996 we started using a robotic microscope to aid in localization and resection. Clinical follow-up ranged from 2 to 54 months (mean 27 months). In all 15 patients, complete surgical resection was achieved as demonstrated by postoperative magnetic resonance imaging studies. Two patients had postoperative transient neurological deficits (13.3%) that cleared over a 6-month period. One of them had a lesion in the pons, with multiple cranial nerve deficits postoperatively that gradually improved. There was no associated mortality. Histological diagnosis was consistent with cavernous angioma in all cases. Clinical follow-up revealed that 13 patients experienced complete recovery from preoperative symptoms and two patients with seizures showed marked improvement. We conclude that interactive image-guided surgery for deep-seated cavernous malformations represents a very accurate and safe approach.
Adolescent↗
Radiosurgical treatment of meningiomas.
From January 1992 to November 1996, 17 patients with the diagnosis of intracranial meningioma underwent radiosurgical treatment. Of these, 7 patients were treated using a Linac-based system (group 1), and 10 using the Leksell Gamma Knife unit (group 2). The follow-up ranged between 12 and 48 (median 33) months for group 1 and between 1 and 11 (median 5) months for group 2, consisting of clinical and MRI assessments every 3 months during the first year, and every 6 months thereafter. There were 14 women and 3 men. The mean age was 42 years. Prior to radiosurgery, 15 patients underwent surgical procedures. Histological diagnosis was consistent with benign meningioma, except in 2 patients (malignant meningioma). In 15 patients with benign meningiomas there was no evidence of tumor growth as demonstrated by clinical and radiological evaluation, in 2 patients with a malignant histological type there was tumor progression.
Adult↗
Cellular and in vivo characterization of the MCR rat mammary tumor model.
The slowly growing, transplantable MCR-83 rat mammary tumor is estrogen-dependent and non-metastasizing. A rapidly growing, estrogen-independent, metastasizing subline (MCR-86) was subsequently isolated in vivo. We have established and characterized cell lines from both MCR rat mammary tumors. MCR cell lines and tumors were studied in vivo and in vitro. Analysis of DNA from tumors and cell lines showed that mutations had not occurred in codons 12, 13 and 61 of the Ha-ras and Ki-ras genes. Additionally, dominant transforming activity could not be detected by DNA transfection using NIH 3T3 focus-forming assay. No gene amplification was detected for either the EGF-receptor or c-erbB-2 genes. Differences in the tyrosine phosphorylation patterns were found between the 2 MCR cell lines. Addition of serum to starved cells resulted in the tyrosine phosphorylation of a 120-kDa protein, which was elevated in the MCR-86. The lack of ras activation in the MCR tumors differentiates this model from the widely studied, chemically induced rodent mammary tumors. In addition, the differences in the cellular phosphotyrosine patterns between MCR-83 and MCR-86 suggests the occurrence of alterations in signalling pathways that involve tyrosine protein kinases.
3T3 Cells↗
New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity.
Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.
Adenosylmethionine Decarboxylase↗
Hepatitis B virus polymerase gene: expression of the long open reading frame using the baculovirus expression system.
A recombinant baculovirus was constructed containing a copy of the hepatitis B virus (HBV) genome which was inserted to produce an in-frame fusion of the precore (pre-C) coding region with the first 11 amino acids of the polyhedrin gene. The recombinant baculovirus expressed the 25K pre-C protein and two novel proteins, of approximately 93K and 72K. Both the 93K and 72K proteins are recognized by an anti-polymerase monoclonal antibody. Northern blot analysis of the mRNA produced during infection of Spodoptera frugiperda cells by the HBV recombinant baculovirus detected only one HBV mRNA species, suggesting that the three HBV-specific proteins expressed are translated from the same mRNA. No larger fusion proteins cross-reacting with either anti-core or polymerase antibodies were detected. These findings suggest that the two proteins encoded within the HBV polymerase gene are not produced via a core-polymerase fusion intermediate but by internal binding of ribosomes. These results are the first clear demonstration of efficient expression of two bona fide unprocessed polymerase proteins in a 1:1 ratio from an unspliced pre-C mRNA-like transcript. With the successful expression of the polymerase gene in insect cells it is now possible to produce large amounts of these proteins, allowing a more detailed structural and functional analysis of these proteins.
Baculoviridae↗
Cytogenetics of breast cancer.
Chromosome counts were performed on 1,100 cells from 17 malignant breast carcinomas and on 168 cells of four normal tissue samples after amethopterin treatment and G-banding. Karyotypes were established from 216 cells of 11 tumor-derived cultures and from 47 cells of four nonmalignant tissue-derived cultures. Karyotypes of cells from nonmalignant samples showed a normal diploid chromosomal constitution with no consistent loss or gain of a specific chromosome. Structural chromosomal abnormalities were not observed. Tumor-derived cultures could be distinguished from normal cultures on the basis of a significantly increased incidence of numerical changes and structural chromosomal aberrations. In nine of 11 tumor-derived cultures, numerically normal cells were shown to be pseudodiploid, with frequencies ranging to 43% (mean, 13.2%) of the diploid cells. In agreement with previous reports, cytogenetic analyses showed predominantly diploid cells. Clonal numerical changes of chromosomes 17, 18, 20, and 21 could be detected in three tumor samples. Clonal structural abnormalities could be observed in two of 11 analyzed tumours. A t(6;12)(p21;p13) and an enlarged chromosome 7 (7q+) were found in a patient with invasive ductal carcinoma. An inversion of chromosome 7 [inv(7)(q11.2q32)] was observed in one case, also diagnosed as invasive ductal carcinoma. The significance of these findings in relation to clinical data is discussed.
Adult↗
An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase.
A bacterial expression vector containing a segment of the v-abl gene from Abelson murine leukemia virus (A-MuLV) was constructed such that the gag region of v-abl was replaced by a sequence encoding the IgG-binding domain of the S. aureus protein A. pabl HP, a fusion protein encoded by this vector was rapidly purified to near homogeneity by affinity chromatography on IgG-Affigel and Mono Q FPLC. The Km of the pabl HP kinase for ATP varied with [Val5]-angiotensin II concentration and was 21.2 microM at saturating concentrations of [Val5]-angiotensin II. The Km for [Val5]-angiotensin II at saturating concentrations of ATP was 3.8 mM. The turnover number, at 20 degrees C, was 62 mumol min-1 mumol-1. Initial rate studies support a ternary complex kinetic mechanism for phosphoryl transferase. The substrate specificity of the pabl HP kinase was further characterized using synthetic peptides. This expression system, which enables the rapid purification of recombinant v-abl kinase is suitable for the comparative enzymological study of mutant v-abl enzymes generated by site-directed mutagenesis.
Abelson murine leukemia virus↗
A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.
Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.
Alkaloids↗
Ribosomal protein S6 kinase and PKC in human mammary tumor cells.
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Alkaloids↗
CGP 6809, a sugar-containing nitrosourea derivative: pharmacological and physicochemical properties.
CGP 6809 is a water-soluble nitrosourea derivative with quite distinct chemical and biological properties as compared with the well-known representatives of this class of compounds. It is related to the antibiotic streptozotocin, from which it is distinguished in the structure of the sugar moiety and the position of the methylnitrosourea residue. CGP 6809 possesses practically the same alkylating potential as streptozotocin; however, its carbamoylating activity is comparable with that of CCNU. In contrast to other nitrosourea derivatives, CGP 6809 showed relatively little activity in murine leukemias but was markedly active in solid transplantable melanomas (Harding-Passay, B16), in the 11095 prostate carcinoma, and in a substrain of Yoshida hepatoma (AH 7974) resistant to BCNU and CCNU. In the Ehrlich and Yoshida ascitic tumors complete responses were seen with no toxic death. Dose-dependent activity was found in the human lung carcinoma MBA 9812 and almost complete growth inhibition was achieved in the human melanoma WM 47 by both the oral and parenteral routes of administration. However, mammary tumor lines (Ca 755, 2661/61, R-3230AC), the Guerin-T8 uterus epithelioma, and the Rous sarcoma/S-R proved to be relatively refractory to this drug. This was also the case for the Lewis lung carcinoma implanted i.m. or s.c. However, development of lung metastases was markedly inhibited. Combination therapy using CGP 6809 with cyclophosphamide, 5-fluorouracil, or chlorambucil in the same model led to partial responses of the primary tumor as well as almost total eradication of lung metastases.
Alkylation↗