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D A Berry

Publications and source records attributed to D A Berry.

At least 19 recordsLinked to original sources

Empirical Eigenfunctions and medial surface dynamics of a human vocal fold.

OBJECTIVES: The purpose of this investigation was to use an excised human larynx to substantiate physical mechanisms of sustained vocal fold oscillation over a variety of phonatory conditions. During sustained, flow-induced oscillation, dynamical data was collected from the medial surface of the vocal fold. The method of Empirical Eigenfunctions was used to analyze the data and to probe physical mechanisms of sustained oscillation. METHODS: Thirty microsutures were mounted on the medial margin of a human vocal fold. Across five distinct phonatory conditions, the vocal fold was set into oscillation and imaged with a high-speed digital imaging system. The position coordinates of the sutures were extracted from the images and converted into physical coordinates. Empirical Eigenfunctions were computed from the time-varying physical coordinates, and mechanisms of sustained oscillation were explored. RESULTS: Using the method of Empirical Eigenfunctions, physical mechanisms of sustained vocal fold oscillation were substantiated. In particular, the essential dynamics of vocal fold vibration were captured by two dominant Empirical Eigenfunctions. The largest Eigenfunction primarily captured the alternating convergent/divergent shape of the medial surface of the vocal fold, while the second largest Eigenfunction primarily captured the lateral vibrations of the vocal fold. CONCLUSIONS: The hemi-larynx setup yielded a view of the medial surface of the vocal folds, revealing the tissue vibrations which produced sound. Through the use of Empirical Eigenfunctions, the underlying modes of vibration were computed, disclosing physical mechanisms of sustained vocal fold oscillation. The investigation substantiated previous theoretical analyses and yielded significant data to help evaluate and refine computational models of vocal fold vibration.

Aged, 80 and over↗

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Aged↗

Actin binding proteins: regulation of cytoskeletal microfilaments.

The actin cytoskeleton is a complex structure that performs a wide range of cellular functions. In 2001, significant advances were made to our understanding of the structure and function of actin monomers. Many of these are likely to help us understand and distinguish between the structural models of actin microfilaments. In particular, 1) the structure of actin was resolved from crystals in the absence of cocrystallized actin binding proteins (ABPs), 2) the prokaryotic ancestral gene of actin was crystallized and its function as a bacterial cytoskeleton was revealed, and 3) the structure of the Arp2/3 complex was described for the first time. In this review we selected several ABPs (ADF/cofilin, profilin, gelsolin, thymosin beta4, DNase I, CapZ, tropomodulin, and Arp2/3) that regulate actin-driven assembly, i.e., movement that is independent of motor proteins. They were chosen because 1) they represent a family of related proteins, 2) they are widely distributed in nature, 3) an atomic structure (or at least a plausible model) is available for each of them, and 4) each is expressed in significant quantities in cells. These ABPs perform the following cellular functions: 1) they maintain the population of unassembled but assembly-ready actin monomers (profilin), 2) they regulate the state of polymerization of filaments (ADF/cofilin, profilin), 3) they bind to and block the growing ends of actin filaments (gelsolin), 4) they nucleate actin assembly (gelsolin, Arp2/3, cofilin), 5) they sever actin filaments (gelsolin, ADF/cofilin), 6) they bind to the sides of actin filaments (gelsolin, Arp2/3), and 7) they cross-link actin filaments (Arp2/3). Some of these ABPs are essential, whereas others may form regulatory ternary complexes. Some play crucial roles in human disorders, and for all of them, there are good reasons why investigations into their structures and functions should continue.

Actins↗

Comparison of methods of measuring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy.

PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer. PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P =.045 and P =.0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC-only 22% of patients with HER-2 in the primary tumor shed ECD into the serum. CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2-positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.

Adult↗

Nuclear membrane proteins in failing human dilated cardiomyopathy.

Emerin (34 kDa) is a 254 amino acid protein located on the cytoplasmic surface of the inner nuclear membrane in cardiac muscle. It interacts with nuclear lamins and nuclear actin. Emerin is usually completely absent in Emery-Dreifuss muscular dystrophy, a condition that also manifests in the heart. Nuclear lamins are specialized nuclear proteins that line the inner nuclear membrane. Two isoforms, lamin A and C, differ in their C-terminal amino acids. Both are important in apoptosis and are degraded by caspase enzymes. Mutations in the rod domain of the lamin A/C gene are known to cause dilated cardiomyopathy (DCM) (Fatkin et al. New Engl. J. Med. 1999, 351, 1715-1724). We have used Western blots to detect emerin and lamin A/C in left ventricles from both nondiseased and failing DCM samples. The lamins form dimers, however it is not known if they are homodimers and / or heterodimers. In this report we compare and quantify expression levels of emerin from samples of left ventricles from ten failing DCM patients and five nondiseased (donor) hearts. We observed three lamin bands that suggest the expression of the three isoforms of the A-type lamin gene, lamin A, lamin C and lamin C2 (Ye et al. Subcellular Biochem. 1998, 31, 587-610). Preliminary data show that both lamin isoforms and emerin are present.

Blotting, Western↗

A quantitative output-cost ratio in voice production.

A quantitative output-cost ratio (OCR) is proposed for objective use in voice production and is defined as the ratio of the acoustic output intensity to the collision intensity of the vocal folds. Measurement of the OCR is demonstrated in a laboratory experiment using 5 excised larynges and a transducer designed for use on human subjects. Data were gathered at constant fundamental frequency (150 Hz). Subglottal pressure was varied from 1.0 to 1.6 kPa, and glottal width at the vocal processes was varied from a pressed condition to a 2-mm gap. The OCR was plotted as a function of glottal width. With no vocal tract, the excised larynx experiments yielded a broad maxima in the OCR curves, across all subglottal pressure conditions, at about 0.6 mm. Computer simulations indicate that sharper maxima may occur when the influence of the vocal tract is taken into account. The potential clinical utility of the OCR is discussed for treatment of a wide range of voice disorders, including those involving both hyper- and hypoadduction.

Acoustics↗

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

Aspirin↗

High-speed digital imaging of the medial surface of the vocal folds.

High-speed digital imaging of the medial surface of the vocal folds was performed in excised canine larynx experiments. Building on the excised larynx investigations of Baer [Ph.D. dissertation, MIT, Boston, MA (1975)] and hemilarynx investigations of Jiang and Titze [Laryngoscope 103, 872-882 (1993)], nine vocal fold fleshpoints were tracked simultaneously along the medial surface of one coronal plane of the left vocal fold using a Kodak EktaPro 4540 high-speed digital imaging system. By imaging from two distinct views, 3D reconstructions of fleshpoint trajectories were performed with a sampling frequency of 4.5 kHz and a spatial resolution of approximately 0.08 mm. Quantitative results were derived from a typical example of periodic chestlike vibrations. Furthermore, these data were decomposed into empirical eigenfunctions, the building blocks of vocal fold vibration, illuminating basic mechanisms of self-sustained oscillation. Previously, such mechanisms have only been explored theoretically using computer models of vocal fold vibration [Berry et al., J. Acoust. Soc. Am. 95, 3595-3604 (1994)]. Similar to the theoretical studies, two eigenfunctions captured 98% of the variance of the data. Because this investigation utilized high-speed technology, the methodology may also be used to examine complex, aperiodic vibrations. Thus, this technique allows mechanisms of regular and irregular vocal fold vibration to be explored using direct observations of vibrating tissues in the laboratory.

Animals↗

Characterization of the medial surface of the vocal folds.

A method is developed for the quantification of the medial surface of the vocal folds in excised larynges. Lead molds were constructed from the glottal airway of a canine larynx for 3 distinct glottal configurations corresponding to "pressed" folds, just barely adducted folds, and 1-mm-abducted folds as measured between the vocal processes. With a high-resolution laser striping system, the 3-dimensional molds were digitally scanned. Low-order polynomials were fitted to the data, and goodness-of-fit statistics were reported. For all glottal configurations, a linear variation (flat surface) approximated the data with a coefficient of determination of 90%. This coefficient increased to roughly 95% when a quadratic variation (curvature) was included along the vertical dimension. If more than the top 5 mm or so of the folds was included (the portion usually corresponding to vibration), a cubic variation along the vertical dimension was necessary to explain a change in concavity at the conus elasticus. These findings suggest the utility of a model based on a convergence coefficient and a bulging coefficient. For all glottal configurations, the convergence coefficients and bulging coefficients can be computed. Because pre-phonatory conditions have a profound influence on vocal fold vibration and on the quality of phonation, such shaping parameters are highly significant. With the viability of this method substantiated, it is envisioned that future studies will characterize greater quantities of glottal shapes, including those of human vocal folds.

Animals↗

Cancer genomics: promises and complexities.

The impending final deciphering of the complete human genome, coupled with the advancement of high-throughput technologies, is positioned to bring about a fundamental transformation in cancer research. The era of molecular biology is transforming into the era of genomic biology, with an unprecedented promise of understanding multifactorial diseases and of identifying specific targets that can be used to develop patient-tailored therapies. Although the genomic approach is in an early phase of its development and its tools need to be honed, the application of genomic technologies to cancer research has already generated exciting results both in target identification and in disease classification. In this article, we review some of the developments pertinent to cancer research, discuss potentially problematic areas associated with them, and comment on future trends and issues.

DNA, Neoplasm↗

Circulating HER-2/erbB-2/c-neu (HER-2) extracellular domain as a prognostic factor in patients with metastatic breast cancer: Cancer and Leukemia Group B Study 8662.

PURPOSE: The HER-2/erbB-2/c-neu (HER-2) proto-oncogene is a M(r) 185,000 transmembrane tyrosine kinase that is amplified and/or overexpressed by 20-40% of breast cancers. HER-2 has been associated with worse prognosis and resistance or sensitivity to specific treatment. We evaluated circulating levels of extracellular domain of HER-2 (ECD/HER-2) in metastatic breast cancer patients and investigated the prognostic and predictive significance of circulating HER-2 levels regarding endocrine therapy or chemotherapy. EXPERIMENTAL DESIGN: Plasma samples from 242 patients were assayed for circulating ECD/HER-2 levels, using a sandwich enzyme immunoassay. ECD/HER-2 was correlated with clinical data gathered from these patients while they were participating in prospective Cancer and Leukemia Group B (CALGB) therapeutic protocols for metastatic breast cancer. RESULTS: Eighty-nine (37%) of 242 patients had elevated ECD/HER-2 levels (> or =10.5 ng/ml). ECD/HER-2 was significantly associated with tumor burden, progesterone receptor levels, and presence of visceral metastases. Patients with elevated pretreatment levels had a significantly shorter OS but not time-to-progression than did those with ECD/HER-2 levels <10.5 ng/ml in univariate analysis. In univariate but not multivariate subset analyses, among patients treated with endocrine therapy (megestrol acetate), elevated initial ECD/HER-2 was associated with worse OS compared with nonelevated patients. However, among patients treated with chemotherapy (mainly anthracycline-containing regimens), OS did not differ significantly. Rates of response to either endocrine therapy or chemotherapy were similar for patients with elevated and nonelevated ECD/HER-2 levels. CONCLUSIONS: ECD/HER-2 levels are elevated in 35-40% of patients with metastatic breast cancer. Elevated ECD/HER-2 levels are associated with a poorer prognosis in these patients. However, no predictive role for ECD/HER-2 was identified, either for endocrine therapy or for anthracycline-based chemotherapy in the metastatic setting.

Adult↗

HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer.

PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)-positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized-physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen. PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen-HER-2/neu status interactions and tamoxifen-p53 status interactions. RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen-HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome. CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.

Antineoplastic Agents, Hormonal↗

The oxidative DNA lesion 8,5'-(S)-cyclo-2'-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells.

Xeroderma pigmentosum (XP) patients with inherited defects in nucleotide excision repair (NER) are unable to excise from their DNA bulky photoproducts induced by UV radiation and therefore develop accelerated actinic damage, including cancer, on sun-exposed tissue. Some XP patients also develop a characteristic neurodegeneration believed to result from their inability to repair neuronal DNA damaged by endogenous metabolites since the harmful UV radiation in sunlight does not reach neurons. Free radicals, which are abundant in neurons, induce DNA lesions that, if unrepaired, might cause the XP neurodegeneration. Searching for such a lesion, we developed a synthesis for 8,5'-(S)-cyclo-2'-deoxyadenosine (cyclo-dA), a free radical-induced bulky lesion, and incorporated it into DNA to test its repair in mammalian cell extracts and living cells. Using extracts of normal and mutant Chinese hamster ovary (CHO) cells to test for NER and adult rat brain extracts to test for base excision repair, we found that cyclo-dA is repaired by NER and not by base excision repair. We measured host cell reactivation, which reflects a cell's capacity for NER, by transfecting CHO and XP cells with DNA constructs containing a single cyclo-dA or a cyclobutane thymine dimer at a specific site on the transcribed strand of a luciferase reporter gene. We found that, like the cyclobutane thymine dimer, cyclo-dA is a strong block to gene expression in CHO and human cells. Cyclo-dA was repaired extremely poorly in NER-deficient CHO cells and in cells from patients in XP complementation group A with neurodegeneration. Based on these findings, we propose that cyclo-dA is a candidate for an endogenous DNA lesion that might contribute to neurodegeneration in XP.

Adult↗

Association of angiogenesis in lymph node metastases with outcome of breast cancer.

BACKGROUND: Microvessel density (MVD) is a measure of the extent of new blood vessel growth or angiogenesis, which is required for tumor progression. Increased MVD in primary breast cancers appears to adversely affect disease-free survival and overall survival in patients with breast cancer. However, the clinical implications of angiogenesis in breast cancer metastases have not been well studied. The purpose of this study was to compare intratumoral MVD in primary breast cancer tissues with MVD in axillary lymph node metastases and to evaluate the relationships among primary- and metastatic-tumor MVD, disease-free survival, and overall survival in patients with lymph node-positive, stage II breast cancer who were treated with adjuvant chemotherapy in Cancer and Leukemia Group B Protocol 8082. METHODS: Immunostaining for factor VIII-related antigen was performed on tissue sections from 47 primary tumors and 91 axillary lymph nodes containing metastases from 110 patients with lymph node-positive breast cancer. Sections were examined for the presence or absence of focal areas of relatively intense neovascularization (vascular hot spots), and a quantitative assessment of intratumoral MVD was performed. RESULTS: The presence of vascular hot spots in axillary lymph node metastases, but not primary breast cancers, was associated with statistically significantly decreased disease-free survival (P =.006) and overall survival (P =.004) by univariate analysis. Similarly, increased MVD in metastases, but not in primary tumors, was statistically significantly associated with diminished overall survival in these patients (P =.02). In multivariate analysis, the number of positive axillary lymph nodes and the presence of vascular hot spots in axillary lymph node metastases predicted decreased disease-free survival (P =.0001 and.02, respectively) and overall survival (P =.0001 and.007, respectively). All P values were two-sided. CONCLUSION: This pilot study suggests that assessing neovascularization in axillary lymph node metastases may provide clinically useful information regarding survival in patients with primary breast cancer.

Antineoplastic Agents↗

Determination of P2X1alpha-sarcoglycan (adhalin) expression levels in failing human dilated cardiomyopathic left ventricles.

This study is concerned with the molecular basis of human idiopathic dilated cardiomyopathy (DCM). This disorder affects the entire heart including both atria and ventricles. It is characterized by a progressive dilatation of the ventricles and loss of contractile power that results in an impaired cardiac output. Changes in cellular levels of dystrophin have been reported in patients with muscular dystrophies (Beckers and Duchenne) which manifest as DCM. However, previous studies using Western blots dos Remedios et al., Electrophoresis 1996, 17, 235-238) of samples of left ventricles from DCM patients showed no abnormalities in dystrophin content. P2X receptors are ATP-gated cation channels located in the sarcolemma. They are upregulated by a factor of about two in the atria of DCM patients compared with nondiseased control samples. A dystrophin-associated protein, alpha-sarcoglycan, has recently been shown to be an ecto-ATPase (an extracellular ATPase) capable of regulating ATP concentrations in the space between the cardiomyocytes. In this report we examine the relationship between changes in P2X1 receptors in left ventricle samples from DCM patients and the concentration of alpha-sarcoglycan. We found no evidence for upregulation of P2X1 receptors nor was the expression of alpha-sarcoglycan significantly altered.

Cardiomyopathy, Dilated↗

A finite-element model of vocal-fold vibration.

A finite-element model of the vocal fold is developed from basic laws of continuum mechanics to obtain the oscillatory characteristics of the vocal folds. The model is capable of accommodating inhomogeneous, anisotropic material properties and irregular geometry of the boundaries. It has provisions for asymmetry across the midplane, both from the geometric and tension point of view, which enables one to simulate certain kinds of voice disorders due to vocal-fold paralysis. It employs the measured viscoelastic properties of the vocal-fold tissues. The detailed construction of the matrix differential equations of motion is presented followed by the solution scheme. Finally, typical results are presented and validated using an eigenvalue method and a commercial finite-element package (ABAQUS).

Computer Simulation↗

Increase in expression of P2X1 receptors in the atria of patients suffering from dilated cardiomyopathy.

P2X1 receptors are ATP-sensitive ligand-gated cation-selective channels abundant in smooth muscle tissues such as bladder and vas deferens. They have also been detected in the central and peripheral nervous system and in heart tissue. We have earlier reported distinct changes in the expression of the PX1 subtype of P2X receptors in hearts of patients suffering from dilated cardiomyopathy (DCM). The study was, however, based on Western blots from only five DCM samples and three control hearts. Moreover, the antibody was directed against a peptide derived from the sequence of rat P2X1. In the present project we have examined larger groups of both DCM and control hearts (n = 14 and 11, respectively). Furthermore, the antibody used in this paper differs significantly from the one used in our previous report. The present antibody was raised against an 18-residue peptide sequence (Lys 68-84 Val) derived from the human P2X1 sequence. Most of the label in the Western blots was concentrated over a triplet of bands migrating with an apparent Mr of about 45,000. Quantitative densitometry indicated that this band was more strongly expressed (by approximately 80%) in DCM hearts compared with the controls.

Adolescent↗