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Biomedical subjects

R J Epstein

Publications and source records attributed to R J Epstein.

At least 19 recordsLinked to original sources
PubMed2006

Polarization and readout of coupled single spins in diamond.

We study the coupling of a single nitrogen-vacancy center in diamond to a nearby single nitrogen defect at room temperature. The magnetic dipolar coupling leads to a splitting in the electron spin resonance frequency of the nitrogen-vacancy center, allowing readout of the state of a single nitrogen electron spin. At magnetic fields where the spin splitting of the two centers is the same, we observe a strong polarization of the nitrogen electron spin. The amount of polarization can be controlled by the optical excitation power. We combine the polarization and the readout in time-resolved pump-probe measurements to determine the spin relaxation time of a single nitrogen electron spin. Finally, we discuss indications for hyperfine-induced polarization of the nitrogen nuclear spin.

Journal Article↗
PubMed2006

Microfabricated surface-electrode ion trap for scalable quantum information processing.

Individual laser-cooled 24Mg+ ions are confined in a linear Paul trap with a novel geometry where gold electrodes are located in a single plane and the ions are trapped 40 microm above this plane. The relatively simple trap design and fabrication procedure are important for large-scale quantum information processing (QIP) using ions. Measured ion motional frequencies are compared to simulations. Measurements of ion recooling after cooling is temporarily suspended yield a heating rate of approximately 5 motional quanta per millisecond for a trap frequency of 2.83 MHz, sufficiently low to be useful for QIP.

Journal Article↗
PubMed2003

Nonrandom intragenic variations in patterns of codon bias implicate a sequential interplay between transitional genetic drift and functional amino acid selection.

Although most codon third bases appear to be functionless, the synonymous codons so defined exhibit a strikingly nonrandom distribution (codon bias) within human and other genes. To examine this phenomenon further, we generated a database of DNA sequences encoding human transmembrane cell-surface receptor proteins. Using this database we show here that the guanine and cytosine content of codon third bases (GC3) varies intragenically with the nature of the specified receptor domains (transmembrane > extracellular > intracellular domains; p < 0.001), the phenotype of the encoded amino acids (hydrophobic > hydrophilic > neutral amino acids; p < 0.001), and the receptor affiliation of the transmembrane (G-protein-coupled receptors > receptor tyrosine kinases; p < 0.001). Within gene regions specifying transmembrane domains, GC3 declines as domain functionality becomes redundant with increasing hydrophobicity (p < 0.001). Codons containing the second-base cytosine (XCZ, which encodes neutral amino acids) are selectively depleted of third-base adenine content (A3: XCA codons) when encoding transmembrane domain residues, consistent with positive selection for transitional mutation of XCG to XTG (which encodes hydrophobic amino acids) rather than to the synonymous XCA. Supporting this XCG --> XTG mechanism of codon bias, the G3:A3 ratio of codons specifying the transmembrane amino acid glycine (GGZ) is intermediate between that of its functional homolog alanine (GCZ) and that of hydrophobic valine (GTZ), even though the C3:T3 ratios are similar. Conversely, nearest-neighbor analysis of third bases 5' to codons specifying valine and leucine (CTZ) confirms a significant difference in C3:T3 but not G3:A3 ratios (i.e., C3/G1 --> T3/G1 > C3/A1; p < 0.001), consistent with the functionally advantageous retention of hydrophobic residues. These data raise the possibility that patterns of intragenic codon bias reflect a balance between negative and positive selection, suggesting in turn that analysis of codon third-base usage may help to predict the functional significance of encoded products.

Amino Acids↗
PubMed2002

Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells.

We previously reported that the ErbB2 oncoprotein prolongs and amplifies growth factor signalling by impairing ligand-dependent downregulation of hetero-oligomerised epidermal growth factor receptors. Here we show that treatment of A431 cells with different epidermal growth factor receptor ligands can cause growth inhibition to an extent paralleling ErbB2 tyrosine phosphorylation. To determine whether such growth inhibition signifies an interaction between the cell cycle machinery and ErbB2-dependent alterations of cell signalling kinetics, we used MCF7 breast cancer cells (which express wild-type p53) to create transient and stable ErbB2 transfectants (MCF7-B2). Compared with parental cells, MCF7-B2 cells are characterised by upregulation of p53, p21(WAF) and Myc, downregulation of Bcl2, and apoptosis. In contrast, MCF7-B2 cells co-transfected with dominant negative p53 (MCF7-B2/Delta p53) exhibit reduced apoptosis and enhanced growth relative to both parental MCF7-B2 and control cells. These data imply that wild-type p53 limits survival of ErbB2-overexpressing breast cancer cells, and suggest that signals of varying length and/or intensity may evoke different cell outcomes depending upon the integrity of cell cycle control genes. We submit that acquisition of cell cycle control defects may play a permissive role in ErbB2 upregulation, and that the ErbB2 overexpression phenotype may in turn select for the survival of cells with p53 mutations or other tumour suppressor gene defects.

Apoptosis↗
PubMed2001

Association of ErbB2 Ser1113 phosphorylation with epidermal growth factor receptor co-expression and poor prognosis in human breast cancer.

The carboxyterminal domain of the epidermal growth factor receptor (EGFR)--a putative binding site for the ubiquitin ligase Cbl--is the site of serine phosphorylation events which are essential for ligand-dependent EGFR desensitization and degradation. Using a monoclonal antibody (aPS1113) which selectively recognizes the homologous phosphorylated domain in the ErbB2 oncoprotein, we show here that wild-type ErbB2 becomes Ser1113-phosphorylated following treatment of 3T3 cells with growth factors or tyrosine phosphatase inhibitors. In EGFR-overexpressing A431 cells, ligand-inducible aPS1113 immunoreactivity declines more rapidly than other detectable phosphorylation events and is followed by EGFR downregulation. Analysis of 65 ErbB2-expressing primary breast cancers reveals a highly significant relationship between Ser1113 phosphorylation and EGFR overexpression (p < 0.0001) as well as an association with poor prognosis (p = 0.005). We submit that ErbB2 Ser1113 phosphorylation status represents a novel and informative biomarker of cancer cell biology and tumor behavior.

Animals↗
PubMed2001

Multisite phosphotyping of the ErbB-2 oncoprotein in human breast cancer.

BACKGROUND: Overexpression of the ErbB-2 (HER2/neu) receptor tyrosine kinase is one of the most common molecular changes in human cancer, but the functional significance of this phenotype remains uncertain. METHODS AND RESULTS: Using phosphorylation-specific antibodies recognizing different ErbB-2 functional states, we assessed the phosphorylation status of ErbB-2 in 102 human breast cancer specimens. Quantitative ErbB-2 immunoblotting intensity correlated directly with that of immunohistochemistry (r = 0.84). Widely varying phosphorylation profiles were evident in 65 ErbB-2-positive carcinomas, suggesting different ErbB-2 functions in different tumors. In a subset of patients for whom clinical data were obtainable, mortality trends were strongly associated with the quantitative signal intensities of ErbB-2 phosphoantibodies (P < or =.02), but not with those of conventional antibodies to ErbB-2 (P = .147), epidermal growth factor receptor (P = .44), or phosphotyrosine (P = .94). CONCLUSION: Although requiring corroboration in larger prospective clinical studies, these findings suggest that immunophenotyping using phosphorylation-specific antibodies may enable more accurate prediction of cancer behavior than is currently obtainable using conventional reagents.

3T3 Cells↗
PubMed2000

A functional significance for codon third bases.

Most amino acids are specified by more than one trinucleotide codon. Here we show that amino acids of differing functional importance may be distinguished by the pattern of synonymous codon usage. GC-rich genes tend to be of a greater transcriptional (p<0.01) and mitogenic (p<0.0001) significance than AT-rich genes, consistent with GC-->AT mutational drift in methylated genomic regions. Third-base GC retention also identifies critical amino acids within individual proteins, as indicated by non-random patterns of codon variation between gene homologs and also by differential sequelae of site-directed mutagenesis. Sequence analysis of human receptor tyrosine kinase genes confirms that functionally important transmembrane hydrophobic amino acids are specified by codons containing GC third bases more often than are transmembrane neutral amino acids (chi(2)=134.2). Amino acids encoded by GC third bases thus appear more tightly linked to cell function and survival than are those encoded by AT third bases.

Amino Acids↗
PubMed2000

Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery.

OBJECTIVE: To determine the effectiveness of mitomycin-C (MMC), 0.02%, in preventing recurrence of corneal subepithelial fibrosis after debridement and/or keratectomy in patients who have undergone refractive corneal surgery. DESIGN: Noncomparative case series. PARTICIPANTS: Eight eyes of five patients with corneal subepithelial fibrosis who had previously undergone radial keratotomy (n = 4) or photorefractive keratectomy (n = 4). INTERVENTION: All eyes underwent epithelial debridement followed by a single intraoperative application of MMC (0.02%) for 2 minutes followed by saline irrigation. The eyes were then patched, or a bandage contact lens placed until epithelial healing was complete. MAIN OUTCOME MEASURES: Corneal clarity and best-corrected visual acuity (BCVA). RESULTS: In all cases, the cornea remained clear with no recurrence throughout the follow-up period (6-25 mos., mean, 13.8 mos). No adverse reactions were reported. BCVA improved in all cases. CONCLUSIONS: Subepithelial fibrosis can be a visually disabling condition after refractive corneal surgery. Topical application of MMC (0.02%) may be a successful method of preventing recurrence of subepithelial fibrosis after debridement.

Administration, Topical↗
PubMed2000

Delayed keratitis after laser in situ keratomileusis.

We report 2 cases of delayed keratitis that occurred after uneventful laser in situ keratomileusis (LASIK). The first patient presented with a peripheral corneal infiltrate 3 months after a LASIK enhancement procedure. The infiltrate progressed despite treatment with topical combination tobramycin-dexamethasone. The flap was then lifted and the interface was irrigated with fortified antibiotics. The keratitis promptly resolved, and the patient recovered a best corrected visual acuity (BCVA) of 20/20. The second patient presented with decreased vision, inflammation, and a sublamellar infiltrate 1 month after primary LASIK. The flap was promptly lifted and irrigated with antibiotics. Cultures were positive for Staphylococcus epidermidis. One week later, the infiltrate had resolved and BCVA had returned to 20/20. Delayed bacterial keratitis has been described as a rare occurrence after incisional refractive surgery. To the best of our knowledge, it has not yet been reported after LASIK. It is important to consider infectious keratitis in the differential diagnosis of a patient who presents with corneal inflammation, even months after having LASIK.

Adult↗
PubMed2000

Dual X-ray absorptiometry detects disease- and treatment-related alterations of bone density in prostate cancer patients.

Metastatic bone disease is an important clinical problem which has proven difficult to study because of a lack of noninvasive investigative modalities. Here we show that dual-energy X-ray absorptiometry (DXA) scanning provides clinically useful information about the status of metastatic bone lesions in cancer patients undergoing palliative treatment. In the study group of 21 patients, a significant increase in metastatic bone mineral density (BMD) was confirmed in prostate (n = 14) relative to breast (n = 7) cancer patients. With respect to the prostate cancer cohort, further increases in lesional BMD were evident in all evaluable patients in whom biochemical progression occurred; conversely, lesional BMD declined in patients who had a partial response to therapy. BMD of uninvolved bone decreased with all types of androgen-deprivation therapy regardless of whether patients responded or relapsed. We conclude that BMD changes in both lesional and uninvolved bone are readily detectable in metastatic prostate cancer, and propose that DXA scanning represents a promising new approach to monitoring the natural history and therapeutic course of this disease.

Absorptiometry, Photon↗