Radio-pathologic conferences of the Massachusetts General Hospital. Posttransplantation non-Hodgkin's lymphoma of the adrenal gland.
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Adrenal Gland Neoplasms↗
Biomedical subjects
S Chao
Publications and source records attributed to S Chao.
Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity.
Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.
3T3 Cells↗
Preoperative dobutamine stress echocardiography versus cardiac arteriography for risk assessment prior to renal transplantation.
Because coronary artery disease is the leading cause of death in patients with end-stage renal disease, we prospectively studied the prognostic value of dobutamine stress echocardiography (DSE) compared to coronary angiography (CA) as an evaluative tool. Thirty-three patients at high risk for coronary artery disease were selected from a cohort of 133 renal transplant candidates and underwent both DSE and CA. In this study, the value of DSE was found to exist in its strong negative predictive value (92%). A negative DSE coupled with a negative clinical cardiac evaluation was found to practicably exclude the necessity for CA. DSE can thus serve as a non-invasive, low cost screening test.
Adrenergic beta-Agonists↗
Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides.
A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Oral d,l sotalol reduces the incidence of postoperative atrial fibrillation in coronary artery bypass surgery patients: a randomized, double-blind, placebo-controlled study.
OBJECTIVES: The purpose of this prospective, randomized, double-blind, placebo-controlled study was to assess the efficacy of preoperatively and postoperatively administered oral d,l sotalol in preventing the occurrence of postoperative atrial fibrillation (AF). BACKGROUND: Atrial fibrillation is the most common arrhythmia following coronary artery bypass surgery (CABG). Its etiology, prevention and treatment remain highly controversial. Furthermore, its associated morbidity results in a prolongation of the length of hospital stay post-CABG. METHODS: A total of 85 patients, of which 73 were to undergo CABG and 12 CABG plus valvular surgery (ejection fraction > or = 28% and absence of clinical heart failure), were randomized to receive either sotalol (40 patients; mean dose = 190 +/- 43 mg/day) started 24 to 48 h before open heart surgery and continued for four days postoperatively, or placebo (45 patients, mean dose = 176 +/- 32 mg/day). RESULTS: Atrial fibrillation occurred in a total of 22/85 (26%) patients. The incidence of postoperative AF was significantly (p = 0.008) lower in patients on sotalol (12.5%) as compared with placebo (38%). Significant bradycardia/hypotension, necessitating drug withdrawal, occurred in 2 of 40 (5%) patients on sotalol and none in the placebo group (p = 0.2). None of the patients on sotalol developed Torsade de pointes or sustained ventricular arrhythmias. Postoperative mortality was not significantly different in sotalol versus placebo (0% vs. 2%, p = 1.0). Patients in the sotalol group had a nonsignificantly shorter length of hospital stay as compared with placebo (7 +/- 2 days vs. 8 +/- 4 days; p = 0.24). CONCLUSIONS: The administration of sotalol, in dosages ranging from 80 to 120 mg, was associated with a significant decrease (67%) in postoperative AF in patients undergoing CABG without appreciable side effects. Sotalol should be considered for the prevention of postoperative AF in patients undergoing CABG in the absence of heart failure and significant left ventricular dysfunction.
Administration, Oral↗
Induction of apoptosis in the germline and follicle layer of Drosophila egg chambers.
The reaper and head involution defective genes can induce apoptotic death in several Drosophila cell types, including portions of the embryo and eye. By a combination of FLP recombinase and the yeast Gal4/UAS transcription activation system, we expressed both cell death genes in discrete clones in the adult ovarian follicle cell layer. The expression of either reaper or head involution defective induced follicle cell apoptosis during all oogenic stages. Unexpectedly, the disruption of the follicle layer led to the induced degeneration of the nurse cells in an apoptotic manner, demonstrating a germline-somatic interaction required for germ cell viability. The germline apoptosis initiates at a specific time in oogenesis, coinciding with the beginning of vitellogenesis. This observation is intriguing given previous suggestions of a process to eliminate defective egg chambers at these same oogenic stages. The induce germline degeneration initiates with the transient formation of a network of filamentous actin around the nurse cell nucleus, in close association with a product of the adducin-related hu-li tai shao gene. This was immediately followed by nuclear condensation and DNA fragmentation, both characteristics diagnostic of apoptosis. Occurring concomitantly with the nuclear phenotypes were the disorganization of ring canals, and the degradation of Armadillo protein (a beta-catenin homolog) and filamentous actin. Germ cells degenerating as a normal consequence of oogenesis displayed a similar set of phenotypes, suggesting that a common apoptotic mechanism may underlie these different germline death phenomena.
Actins↗
A maize map standard with sequenced core markers, grass genome reference points and 932 expressed sequence tagged sites (ESTs) in a 1736-locus map.
We have constructed a 1736-locus maize genome map containing1156 loci probed by cDNAs, 545 probed by random genomic clones, 16 by simple sequence repeats (SSRs), 14 by isozymes, and 5 by anonymous clones. Sequence information is available for 56% of the loci with 66% of the sequenced loci assigned functions. A total of 596 new ESTs were mapped from a B73 library of 5-wk-old shoots. The map contains 237 loci probed by barley, oat, wheat, rice, or tripsacum clones, which serve as grass genome reference points in comparisons between maize and other grass maps. Ninety core markers selected for low copy number, high polymorphism, and even spacing along the chromosome delineate the 100 bins on the map. The average bin size is 17 cM. Use of bin assignments enables comparison among different maize mapping populations and experiments including those involving cytogenetic stocks, mutants, or quantitative trait loci. Integration of nonmaize markers in the map extends the resources available for gene discovery beyond the boundaries of maize mapping information into the expanse of map, sequence, and phenotype information from other grass species. This map provides a foundation for numerous basic and applied investigations including studies of gene organization, gene and genome evolution, targeted cloning, and dissection of complex traits.
Chromosome Mapping↗
[A single strand comformation polymorphism of vacuolating cytotoxin gene in H. pylori].
OBJECTIVE: To use PCR/SSCP analysis of the vacuolating cytotoxin gene (vacA) of H. pylori for differentiation of various strains of H. pylori. METHODS: PCR was performed using the primers amplifing vacA gene of the bacteria embeded in the gastric mucosa of 159 patients with various gastric duodenal diseases. The products of PCR were further processed for SSCP analysis and southern blot hybridization. In the meantime, vacA genes of three different SSCP-patterns from three patients with duodenal ulcers were sequenced. RESULTS: The rate of detection of H. pylori with the method was 100%. vacA1 and vacA2, the two subtypes of vacA, were 76.5% (114/149) and 23.5%(35/149), respectively. Eight different SSCP-patterns were distributed in various gastroduodenal diseases, and that 80% of duodenal ulcers was predominated with B pattern. Sequencing of DNA indicated a diversity of vacA gene structure. CONCLUSION: PCR/SSCP can be used in the differentiation of different strains of H. pylori in epidemology, and in the follow up study after H. pylori eradication, especially in the differentiation between H. pylori recrudescence and reinfection.
Adult↗
[The significance of detection of Helicobacter pylori in saliva].
OBJECTIVE: To explore noninvasive and effective method to detect Helicobacter pylori (Hp) in saliva. METHODS: DNAs of saliva and gastric mucosa from 138 and 159 patients of various gastro-duodenal diseases were detected with PCR by use of primers amplifying vacA gene. The products were further processed for SSCP and Southern blot hybridization. RESULTS: The rate of detection of Hp in saliva and gastric mucosa was 71.7% and 100% respectively. vacA(1) and vacA(2), being the two subtypes of vacA, were recognized in Hp. PCR/SSCP analysis showed a 98% identity of the strains of Hp in the saliva and gastric mucosa. CONCLUSION: Hp could be colonized in saliva and probably transmitted orally. The new method may provide noninvasive approach for detection of Hp and could be used in the investigation of family aggregation of Hp infection.
Adult↗
Late complications in patients with pectoral defibrillator implants with transvenous defibrillator lead systems: high incidence of insulation breakdown.
As the majority of ICDs with transvenous leads are now implanted in the pectoral region, complications associated with the technique are being identified. To determine the incidence of lead complications in patients with transvenous defibrillator leads and ICDs implanted in the pectoral region, 132 unselected consecutive patients with transvenous defibrillator leads had ICDs implanted in the pectoral region. Three lead systems were used: (1) lead system 1 (45 patients) consisted of a transvenous pacing sensing lead and a superior vena cava coil with a submuscular patch used for defibrillation; (2) lead system 2 (36 patients) utilized a CPI Endotak lead system; and (3) lead system 3 (51 patients) utilized a Medtronic Transvene lead system. Patients were followed for 3-54 months (cumulative 2,269, mean 18 months). The average duration of follow-up with the three systems was 32, 12 and 11 months, respectively. At 30 months follow-up, all three lead systems had a low incidence of complications. However, there was a 13% overall incidence (45% actuarial incidence) of erosion of the insulation of the pacing sensing lead of system 1 at 50 months of follow-up. All lead complications were seen in patients with ICDs whose weights were > 195 g and volumes > 115 cc. The erosion was probably a consequence of the pressure by the large ICD against the lead in the pectoral pocket. Follow-up with lead systems 2 and 3 is relatively short (average 12 months) but no lead erosions were seen. Pectoral implantation of ICDs with long transvenous leads and large generators is associated with a moderate risk of late complications in the form of insulation breaks caused by pressure of the generator against the leads. The use of less redundant leads coupled with smaller ICDs will probably eliminate this complication.
Defibrillators, Implantable↗
Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Use of a two-hybrid system to investigate molecular interactions of GAP-43.
We used the 'interaction trap' (two-hybrid system) to identify polypeptides that interact with the neuronal phosphoprotein, GAP-43, in an intracellular environment. GAP-43 (neuromodulin, B-50, F1), a protein kinase C (PKC) substrate important for the growth and plasticity of neuronal connections, has been implicated in vitro in several signal transduction pathways. In the yeast-based cloning system, the only strong interaction that was detected between GAP-43 and the calcium effector protein, calmodulin (CaM). PKC phosphorylates GAP-43 on serine 41. When we changed this serine to an aspartate residue to mimic constitutive phosphorylation, the interaction with CaM was blocked. Surprisingly, the N-terminal third of GAP-43 alone bound CaM more strongly than did intact GAP-43, suggesting that the protein's C-terminus may play a role in modulating the interaction with CaM. These results, along with other recent findings, suggest a novel role for the interaction between GAP-43 and CaM.
Calmodulin↗
Physical and genetic mapping of chromosome 9S in maize using mutations with terminal deficiencies.
Deletion mapping was employed to determine the physical order of five morphological variants, pyd1, yg2, wd1, v28 and u31, with respect to restriction fragment length polymorphism (RFLP) markers located at the distal end of chromosome 9S in maize. The genetic materials used were a series of terminal-deficiency mutants, newly derived with McCLintock's original stocks developed in the 1940s, via breakage-fusion-bridge cycles. A combined physical map and genetic map has been constructed based on data gathered from both genetic complementation tests and RFLP analysis. The location of v31 in relation to RFLP markers was further determined by interval mapping. The physical distance between the healed telomeric end and the most distal RFLP marker in two terminal-deficiency lines was established by using pulsed field gel electrophoresis and verified by Bal31 digestion. The results from this study set a foundation for studies on the mechanism of healing of broken chromosome ends in higher plants.
Chromosome Mapping↗
Cloning maize telomeres by complementation in Saccharomyces cerevisiae.
Maize telomeric restriction fragments were cloned by virtue of their ability to function as telomeres on a linear plasmid in Saccharomyces cerevisiae. Nine maize telomeric YAC transformants (MTYs) were selected by hybridization to the Arabidopsis telomere repeat (CCCTAAA) from a pool of 1537 primary transformants. Bal31 digestion of MTY3 and MTY9 DNA indicated that the telomere hybridizing tracts are located at the terminus of the linear chromosome and therefore function as telomeres in yeast. Subclones generated for pMTY7 (pMTY7SC1) and pMTY9 (pMTY9ER) hybridized to Bal31 sensitive restriction fragments in maize DNA, indicating that maize telomeric restriction fragments had been cloned. Both pMTY7SC and pMTY9ER detected telomeric RFLPs, allowing the endpoints of seven chromosome arms to be determined. Additionally, pMTY7ER mapped to the centromeric regions of chromosomes 2 and 3, suggesting a relationship between centromeric and telomeric sequences. DNA sequencing of pMTY7SC and pMTY9ER revealed that both subclones contained CA-rich regions with sporadic occurrences of the telomere repeat and its degenerate repeats.
Base Sequence↗
Relationship between chromosome 9 of maize and wheat homeologous group 7 chromosomes.
Comparison of the genetic map of maize chromosome 9 with maps of wheat chromosomes has revealed a high degree of colinearity between maize chromosome 9 and the group 4 and 7 chromosomes of wheat. The order of DNA markers on the short arm and a proximal region of the long arm of the genetic map of maize chromosome 9 is highly conserved with the marker order on the short arm and proximal region of the long arm of the genetic map of the wheat homeologous group 7 chromosomes. A major part of the long arm of the genetic map of maize chromosome 9 is homeologous with a short segment in the proximal region of the long arm of the genetic map of the wheat group 4 chromosomes. Evidence is also presented that maize chromosome 9 has diverged from the wheat group 7 chromosomes by both a pericentric and a paracentric inversion. The paracentric inversion is probably unique to maize among the major cereal genomes.
Centromere↗
Serum-free medium for long-term growth, freezing, cloning and fusion of myelomas and hybridomas.
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Animals↗
Development of a core RFLP map in maize using an immortalized F2 population.
A map derived from restriction fragment length polymorphisms (RFLPs) in maize (Zea mays L.) is presented. The map was constructed in an immortalized Tx303 x CO159 F2 mapping population that allowed for an unlimited number of markers to be mapped and pooled F3 seed to be distributed to other laboratories. A total of 215 markers consisting of 159 genomic clones, 16 isozymes and 35 cloned genes of defined function have been placed on 10 chromosomes. An examination of segregation data has revealed several genomic regions with aberrant segregation ratios favoring either parent or the heterozygote. Mapping of cloned genes and isozymes that have been previously mapped by functional criteria has provided 29 points of alignment with the classical maize genetic map. Screening of all mapped RFLP probes against a collection of U.S. Corn Belt germplasm using EcoRI, HindIII and EcoRV has resulted in a set of 97 core markers being defined. The designation of a set of core markers allows the maize genome to be subdivided into a series of bins which serve as the backbone for maize genetic information and database boundaries. The merits and applications of core markers and bins are discussed.
Crosses, Genetic↗
Characterization of Arabidopsis thaliana telomeres isolated in yeast.
In an effort to learn more about the genomic organization of chromosomal termini in plants we employed a functional complementation strategy to isolate Arabidopsis thaliana telomeres in the yeast, Saccharomyces cerevisiae. Eight yeast episomes carrying A. thaliana telomeric sequences were obtained. The plant sequences carried on two episomes, YpAtT1 and YpAtT7, were characterized in detail. The telomeric origins of YpAtT1 and YpAtT7 insert DNAs were confirmed by demonstrating that corresponding genomic sequences are preferentially degraded during exonucleolytic digestion. The isolated telomeric restriction fragments contain G-rich repeat arrays characteristic of A. thaliana telomeres, as well as subterminal telomere-associated sequences (TASs). DNA sequence analysis revealed the presence of variant telomeric repeats at the centromere-proximal border of the terminal block of telomere repeats. The TAS flanking the telomeric G-rich repeat in YpAtT7 corresponds to a repetitive element present at other A. thaliana telomeres, while more proximal sequences are unique to one telomere. The YpAtT1 TAS is unique in the Landsberg strain of A. thaliana from which the clone originated; however, the Landsberg TAS cross-hybridizes weakly to a second telomere in the strain Columbia. Restriction analysis with cytosine methylation-sensitive endonucleases indicated that both TASs are highly methylated in the genome.
Base Sequence↗