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Biomedical subjects

E Solomon

Publications and source records attributed to E Solomon.

At least 55 records · Page 3Linked to original sources
PubMed1996

Spinal bupivacaine in ambulatory surgery: the effect of saline dilution.

The safety of lidocaine spinal anesthesia has recently been called into question by reports of both permanent and transient neurologic toxicity. This study explored the possibility of adapting the longer acting spinal bupivacaine to ambulatory surgery. Sixty patients presenting for ambulatory arthroscopy were randomized to four groups receiving the following spinal anesthetics: Group I (15 mg bupivacaine), 3 mL of 0.5% spinal bupivacaine in 8% dextrose; Group II (10 mg bupivacaine), 2 mL of the 0.5% spinal bupivacaine+1 mL saline; Group III (7.5 mg bupivacaine), 1.5 mL of the 0.5% spinal bupivacaine%1.5 mL saline; Group IV (5 mg bupivacaine), 1 mL of the 0.5% spinal bupivacaine+2 mL saline. Maximum block height was T-5 in Group I versus T-8 in the other groups. Onset times to peak block were similar in all groups and averaged 14 min. Time to two-segment regression, complete regression, micturition, and discharge were significantly reduced from Group I to Group II and from Group II to Group III. Reductions in times between Groups III and IV did not achieve statistical significance. Times from placement of the spinal block until discharge were 471 +/- 35, 260 +/- 15,202 +/- 14, and 181 +/- 8 min, respectively, for the four groups. The intensity of motor block decreased significantly from group to group, such that 13 of the 15 patients in Group IV failed to achieve Bromage level 2 or 3. The intensity of sensory block also decreased from group to group with four patients in Group IV having pain intraoperatively that required further treatment. Therefore, Group III provided the optimum combination of adequate depth of anesthesia and rapid recovery. The results of this study indicate that spinal anesthesia with 7.5 mg of 0.5% bupivacaine in 8% dextrose diluted with an equal volume of saline provides an acceptable spinal anesthetic for ambulatory arthroscopy with a recovery profile appropriate to the ambulatory setting.

Adult↗
PubMed1996

Ordering of 66 STSs along the entire short arm of human chromosome 17 and chromosome assignment of a transcribed sequence (FMR1L2) homologous to FMR1.

Sixty-four PCR-markers previously assigned to the short arm of chromosome 17 and two newly established STSs were localized on a hybrid cell-YAC clone panel. The 66 STSs fell into 23 unique retention patterns, providing a map converting the entire short arm of human chromosome 17 with an average resolution of approximately 1.2 Mb. The combination of radiation-reduced hybrids, somatic cell hybrids and selected YAC clones enabled the precise localization of break-points in two cell hybrids. Since polymorphic STSs from the CEPH as well as the UTAH genetic map were used in this study, a physical link has been generated between these two high resolution genetic maps. FMR1L2, a second FMR1 autosomal homologue has been identified and assigned to a genomic interval between D17S796 and D17S799.

Animals↗
PubMed1996

Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse.

RT-PCR assays used to detect acute promyelocytic leukemia (APL) are generally considered less sensitive than those for other hematological malignancies, such as CGL. Most patients with APL express del(17q)-derived RAR alpha-PML transcripts as well as the putative leukemogenic PML-RAR alpha associated with add(15q). We have found that a nested RT-PCR for RAR alpha-PML affords greater sensitivity than that for PML-RAR alpha, particularly in patients with the commonest breakpoint pattern. Therefore, we have evaluated both assays in parallel to monitor a group of 12 de novo APL patients who relapsed despite treatment with both all-trans retinoic acid (ATRA) and chemotherapy. 5' (bcr 3) breakpoints in PML were over represented among the group and three patients had complex cytogenetic abnormalities suggesting both factors may increase the risk of relapse. The RAR alpha-PML assay changed the PCR status of two patients in morphological remission; in both cases disease contamination of bone marrow harvest specimens was detected. Although parallel assessment of PML-RAR alpha and RAR alpha-PML can enhance minimal residual disease detection in APL, this study demonstrates that treatment strategies involving determination of PCR status post-consolidation, even using RAR alpha-PML in addition to the more conventional PML-RAR alpha assay will fail to identify all patients at risk of relapse. Whether the duration of PCR positivity is a helpful prognostic indicator in those patients who ultimately become PCR negative is being addressed by

Adolescent↗
PubMed1996

Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.

Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.

Alleles↗
PubMed1996

Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q.

Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. HMPS appears to be inherited in an autosomal dominant manner. Genetic linkage analysis has been performed on a large family with HMPS. Data did not support linkage to the APC locus or to any of the loci for hereditary nonpolyposis colorectal cancer. Evidence that the HMPS locus lies on chromosome 6q was, however, provided by significant two-point LOD scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants and multipoint linkage analysis suggested that the HMPS locus lies in a 4-cM interval containing the D6S283 locus and flanked by markers D6S468 and D6S301.

Adenoma↗
PubMed1996

Establishing the presence of the t(15;17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial. M.R.C. Adult Leukaemia Working Party.

Detection of the t(15;17) or its molecular consequence, the PML-RAR alpha rearrangement, is critical for meaningful analysis of clinical trials involving patients with suspected acute promyelocytic leukaemia (APL). Its presence remains the best predictor of a favourable response to retinoids, such as ATRA, which in combination with chemotherapy confer significant improvements in disease-free survival. We have evaluated the relative efficacy of RT-PCR, cytogenetics and PML immunofluorescence staining to identify the existence of the translocation in 100 patients entered into the Medical Research Council (M.R.C.) ATRA trial. RT-PCR successfully identified PML-RAR alpha rearrangements in 93/100 patients, including 65 where only peripheral blood or post-induction marrow samples were available for analysis and in 12 patients in whom cytogenetic assessment failed to demonstrate t(15;17) due to poor-quality metaphases (10/12) or as a reflection of cryptic PML-RAR alpha rearrangements (2/12). Parallel employment of the RAR alpha-PML assay confirmed expression of del(17q)-derived transcripts in 81% and permitted determination of the PML breakpoint (a potential independent prognostic variable) in all 93 cases. Sequencing of RT-PCR products derived from 50 patients with 3' PML breakpoints revealed five bcr 2 cases, including a novel exon 5 breakpoint. 35/81 (43%) patients with cytogenetic evidence of t(15;17) possessed additional karyotypic abnormalities. In four patients with available buffy coat smears, lack of cytogenetic or molecular evidence of the t(15;17) was confirmed by a wild-type PML immunofluorescence nuclear staining pattern, in contrast to the characteristic microparticulate distribution detected in 14 patients with RT-PCR evidence of the rearrangement. However, although PML immunofluorescence staining is suitable for rapid determination of patients likely to benefit from ATRA, this approach does not obviate the need for cytogenetic and RT-PCR analysis of all patients entered into APL clinical trials, because both techniques provide additional information which may prove to be of independent prognostic significance.

Adolescent↗
PubMed1995

Localization of the human RNA polymerase I transcription factor gene (UBTF) to the D17S183 locus on chromosome 17q21 and construction of a long-range restriction map of the region.

Human upstream binding factor (hUBF) is a sequence-specific DNA-binding protein that is essential for the activation of human 18s and 28s rRNA gene transcription. We have isolated and localized the gene (UBTF) encoding hUBF to the D17S183 locus on chromosome 17q21 by analyzing a cosmid from the region and carrying out Southern analysis on a previously constructed chromosome 17 somatic cell hybrid mapping panel using a probe from the hUBF cDNA. Confirmation of its location at this region was obtained from the results of pulsed-field gel electrophoresis analysis of genomic DNA using the hUBF cDNA and other probes from the region. These data also enabled the construction of a long-range restriction map of the region.

Cell Line↗
PubMed1995

Physical mapping, cloning, and identification of genes within a 500-kb region containing BRCA1.

BRCA1 is a breast/ovarian cancer susceptibility gene on human chromosome 17q21. We describe a complete and detailed physical map of a 500-kb region of genomic DNA containing the BRCA1 gene and the partial cloning in phage P1 artificial chromosomes. Approximately 70 exons were isolated from this region, 11 of which were components of the BRCA1 gene. Analysis of the other exons revealed a rho-related G protein and the interferon-induced leucine-zipper protein IFP-35.

Amino Acid Sequence↗
PubMed1995

The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML.

Acute promyelocytic leukaemia (APL) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and the retinoic acid receptor alpha. PML is normally a component of a nuclear multiprotein complex (termed ND10, Kr bodies, nuclear bodies, PML oncogenic domains or PODs) which is disrupted in the APL disease state. PML contains a number of characterized motifs including a Zn2+ binding domain called the RING or C3HC4 finger. Here we describe the solution structure of the PML RING finger as solved by 1H NMR methods at physiological pH with r.m.s. deviations for backbone atoms of 0.88 and 1.39 A for all atoms. Additional biophysical studies including CD and optical spectroscopy, show that the PML RING finger requires Zn2+ for autonomous folding and that cysteines are used in metal ligation. A comparison of the structure with the previously solved equine herpes virus IE110 RING finger, shows significant differences suggesting that the RING motif is structurally diverse. The role of the RING domain in PML nuclear body formation was tested in vivo, by using site-directed mutagenesis and immunofluorescence on transiently transfected NIH 3T3 cells. Independently mutating two pairs of cysteines in each of the Zn2+ binding sites prevents PML nuclear body formation, suggesting that a fully folded RING domain is necessary for this process. These results suggest that the PML RING domain is probably involved in protein-protein interactions, a feature which may be common to other RING finger domains.

Amino Acid Sequence↗
PubMed1995

Cloning of the murine homolog of the leukemia-associated PML gene.

PML, a Ring-finger protein, participates in the disruption of normal myeloid differentiation when fused to the retinoic acid receptor alpha (RAR alpha) by the translocation between chromosomes (Chrs) 15 and 17 in acute promyelocytic leukemia (APL). As an initial step in the characterization of PML in species other than human, a murine cDNA clone of the PML gene was isolated and sequenced, and the intron/exon organization of the murine locus determined. The predicted amino acid sequence of the mouse PML protein shows 80% similarity to that of its human homolog. However, the mouse and human proteins show greater than 90% similarity in the proposed functional domains of the proteins. Despite its role in the etiology of APL, PML expression is not detectably altered during granulocytic differentiation in a murine in vitro system. Chromosomal localization of the Pml locus by somatic cell hybrids and by linkage analysis indicates that the gene maps to a region of mouse Chr 9 with known linkage homology to the region on human Chr 15q to which PML has been localized.

3T3 Cells↗
PubMed1995

Distinct transcription start sites generate two forms of BRCA1 mRNA.

Using primer extension and 5' RACE, we have mapped the 5' end of the BRCA1 gene and identified a new 5' exon. Two distinct BRCA1 transcripts differing by the first exons were found; these transcripts were generated by the alternative use of dual promoters and alternative splicing. The expression of the distinct transcripts was examined in four primary tissues (placenta, mammary gland, testis and thymus), six normal or cancer cell lines, four primary breast tumor tissues and four primary ovary tumour tissues. Both transcripts were detected in all the samples studied, with the exon 1a transcript being the major expressed form in mammary gland and the exon 1b transcript in placenta. This suggests that the two transcripts may be expressed in a tissue-specific fashion. The 5' flanking regions of both BRCA1 transcripts were analysed, neither contains a TATA box. Initiator elements, which have been proposed to mediate transcription in TATA-less promoters, were found at the transcription initiation sites. Transcription factor binding sites such as Sp1, PEA3, C/EBP, CREB, E4F1 and Pu boxes were identified in the 5' flanking regions of the exon 1a transcript, and Sp1, NF-kB and PEA3 binding sites in the 5' flanking region of the exon 1b transcript. The interactions of these DNA elements with trans-acting factors are likely to modulate the alternative use of the distinct transcription start sites and the expression of the BRCA1 gene.

Alternative Splicing↗
PubMed1995

Molecular genetics of sporadic and familial breast cancer.

Molecular genetic analysis of breast cancers indicates that the mechanisms underlying tumorigenesis are complicated. Many oncogenes and tumour suppressor genes have been implicated, encoding proteins that are important at many levels of cell regulation, from cell surface molecules responding to external signals (eg ERBB2) to nuclear factors controlling gene transcription (eg TP53, MYC). Several correlations have been found between certain genetic events and clinical outcome and have therefore proved useful prognostic indicators. The mapping and cloning of genes important in familial breast cancers (eg BRCA1) have provided the essential tools for pinpointing the genes that may be critical in early stage breast cancer as well as for developing genetic tests for predicting carrier status in breast cancer families. Clarification of the molecular consequences of mutation in breast cancer associated genes is beginning to address the factors that drive a normal breast cell to change into a breast cancer cell. However, these studies are still in their infancy, and considerable research will be required to complete the picture.

Ataxia Telangiectasia↗
PubMed1994

A case of acute monocytic leukemia with t(11;17) involving a rearrangement of MLL-1 and a region proximal to the RARA gene.

A case of acute monocytic leukemia with t(11;17)(123;q11-21) arising in a 4-month-old boy is described. The breakpoint on chromosome 11 could be mapped to an 8-kb BamHI fragment within the MLL-1 gene, as seen in the majority of infant leukemias. In situ hybridization with cosmid probes allowed us to map the breakpoint on 17q proximal to the RARA gene, while Southern and Northern analyses showed that the gene was not disrupted by the translocation.

Chromosomes, Human, Pair 11↗
PubMed1994

Towards cloning the familial breast-ovarian cancer gene on chromosome 17.

The past year has seen a great deal of excitement in the field of breast cancer genetics. Since linkage of the familial breast-ovarian cancer gene (BRCA1) to chromosome 17, the critical region has been narrowed to 1.0-1.5 Mb by recombination studies, a detailed physical map has been constructed and much of the region has been cloned in yeast artificial chromosome, bacteriophage P1 and cosmid vectors. The focus now lies on identifying the genes housed within the BRCA1 region and scanning them for oncogenic mutations.

Breast Neoplasms↗