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Biomedical subjects

R Maynard

Publications and source records attributed to R Maynard.

At least 19 recordsLinked to original sources
PubMed2000

Instabilities of waves in nonlinear disordered media

We develop a self-consistent theory of temporal fluctuations of a speckle pattern resulting from the multiple scattering of a coherent wave in a weakly nonlinear disordered medium. The speckle pattern is shown to become unstable if the nonlinearity exceeds a threshold value. The instability is due to a feedback provided by the multiple scattering and manifests itself in spontaneous fluctuations of the scattered intensity. The development of instability is independent of the sign of nonlinearity.

Journal Article↗
PubMed2000

Immunohistochemical p16INK4a analysis of archival tumors with deletion, hypermethylation, or mutation of the CDKN2/MTS1 gene. A comparison of four commercial antibodies.

The MTS1/CDKN2/p16 gene encoding the p16INK4a tumor-suppressor protein is commonly inactivated by homozygous deletion or hypermethylation of the promoter in a wide range of human malignancies. In select tumor types, including pancreatic adenocarcinomas, intragenic mutations are found in a significant percentage of cases. The immunoreactivity of mutant p16 proteins has not been comprehensively studied. Moreover, the immunohistochemical properties of commercially available antibodies have not been described in detail. We studied 35 pancreatic adenocarcinomas with a molecularly defined p16 status (16 homozygous deletions, 3 hypermethylated cases, and 16 tumors with an intragenic mutation in one allele associated with loss of the second allele). In addition, we studied nine cell lines (three homozygous deletions, three hypermethylated lines, and three intragenic mutations). Paraffin sections of the tumors and cell blocks were reacted with four different anti-p16 antibodies: polyclonal and monoclonal (clone G175-405) antibodies from PharMingen, monoclonal antibody DCS-50 from Oncogene Science, and monoclonal antibody ZJ11 from Neo-Markers. Optimal staining conditions were established for each antibody. The pancreatic carcinomas with homozygous p16 deletions were largely devoid of nuclear staining (admixed nonneoplastic cells served as internal positive controls); only one adenocarcinoma each reacted with DCS-50 and the polyclonal antibody, and five were positive with ZJ11, suggesting that nonspecific nuclear staining can occur under certain conditions. Antibody DCS-50 produced nuclear staining in all three hypermethylated carcinomas, whereas G175-405 stained none of them. Three of the four antibodies produced nuclear immunoreactivity in 7 to 14 of the 16 carcinomas carrying p16 mutations; G175-405 showed only weak reactivity in one case. Cytoplasmic staining was present in all carcinomas and cell lines and with all antibodies and therefore cannot be considered specific; it was strongest with G175-405. Thus, we found antibody G175-405 to be the most specific, and monoclonals DCS-50 and ZJ11 the least specific for wild-type p16. However, the former tends to give stronger cytoplasmic background staining. For tumor types in which p16 mutations are uncommon, the PharMingen polyclonal antibody may be a suitable alternative.

Antibodies↗
PubMed1999

Frequent loss of KAI1 expression in squamous and lymphoid neoplasms. An immunohistochemical study of archival tissues.

The metastasis suppressor gene KAI1 was identified by its ability to inhibit the formation of pulmonary metastases in experimental models for prostatic carcinoma. Down-regulation of this gene may be correlated with the invasive phenotype in melanomas and colon and bladder carcinomas and with the metastatic phenotype in carcinomas of the lung, breast, prostate, and pancreas. The goal of our study was to establish an immunohistochemical method to detect KAI1 expression in archival tissues. Using cell lines with known KAI1 levels and paraffin-embedded KAI1 positive tissues as controls, we observed strong membrane staining in lymphoid follicular centers and squamous epithelia. We then demonstrated the utility of our assay by studying KAI1 expression in 34 lymphoid and 57 squamous lesions. All eight reactive lymph nodes were KAI1 positive. In contrast, three of 13 follicular small cleaved and five of 13 diffuse large cell lymphomas were KAI1 negative. Seventy-nine percent (37 of 47) of invasive squamous cell carcinomas from the lung (n = 15), head and neck (n = 18), and cervix (n = 14) showed extensive KAI1 down-regulation. Loss of KAI1 expression was also found in a subset of 10 high-grade cervical dysplasias. Our data show that (i) immunohistochemistry is a suitable technique for evaluating KAI1 expression in archival tissues; (ii) KAI1 was not expressed in a subset of both low-grade and high-grade lymphomas; and (iii) there was extensive down-regulation of KAI1 in squamous cell carcinomas, suggestive of an important role of the gene in the suppression of invasion in these malignancies.

Animals↗
PubMed1999

Correlation of abnormal RB, p16ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers.

This study was performed to determine the frequency of inactivation and clinical correlates in non-small cell lung cancer (NSCLC) of three known tumor suppressor genes [TSGs; RB, MTS1/CDKN2 (p16), and p53] and various regions of 3p loss of heterozygosity (LOH) as other major potential TSG sites. Paraffin sections from 103 resected NSCLCs were analyzed for expression of pRB, p16, and p53 by immunohistochemistry, whereas DNA from tumor and normal tissue were tested for LOH at 3p25-26, 3p21, and 3p14. Previously published LOH data for 5q, 11p, 17q, and 18q were also available. Loss of pRB or p16 expression and overexpression of p53 were considered abnormal. The immunohistochemical and LOH data were correlated with a variety of clinical parameters including stage, age, sex, smoking history, and survival. With respect to pRB, p16, and p53, the tumors could be grouped into four categories: normal for all three proteins (21%); abnormal for pRB or p16 and normal for p53 (30%); normal for pRB and p16 and abnormal for p53 (20%); and abnormal in both pathways (28%). Aberrant expression of pRB, p16, p53, and 3p LOH, either individually or in combination, was not associated with survival differences or any other clinical parameters, with the exception that pRB/pl6 abnormalities were more common in older patients (P = 0.0005). pRB and p16 expression showed a strong inverse correlation (P = 0.002), whereas there was no correlation between expression of pRB, p16, and p53. Abnormal expression of any of the three genes inversely correlated with K-ras codon 12 mutations (P = 0.004), but not with 3p LOH or LOH at other TSG loci. We conclude that resectable NSCLCs show distinct patterns of TSG inactivation, but that no clear clinical correlates exist either alone or in combination for pRB, p16, p53, and 3p abnormalities.

Adult↗
PubMed1998

Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression.

Pancreatic adenocarcinoma develops from histologically identifiable intraductal lesions that undergo a series of architectural, cytological, and genetic changes. Limited genetic evidence recently suggested that the p16 gene plays a role in the progression of these "duct lesions." Duct lesions were identified in pancreata from 33 pancreaticoduodenectomies performed for infiltrating adenocarcinoma. All of these infiltrating adenocarcinomas were previously shown to contain alterations in the p16 gene or its promoter. Monoclonal and polyclonal anti-p16 antibodies were used for histological immunodetection. One hundred twenty-six duct lesions were identified. Nine (30%) of 30 flat, 4 (27%) of 15 papillary, 37 (55%) of 67 papillary with atypia, and 10 (71%) of 14 carcinoma in situ duct lesions showed loss of p16 expression. These included 30% of the flat lesions versus 53% of the nonflat lesions and 29% of the nonatypical lesions versus 58% of the atypical lesions. For both comparisons, the differences were statistically significant (P = 0.036 and P = 0.003, respectively). Loss of p16 expression occurs more frequently, but not exclusively, in higher-grade duct lesions. These data support the hypothesis that pancreatic duct lesions are neoplastic and that they represent the precursors of infiltrating adenocarcinoma. Immunohistochemical detection of p16 provides a new technology to study the genetic alterations in and stages of progression of large numbers of morphologically defined pancreatic duct lesions.

Adenocarcinoma↗
PubMed1997

Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.

The Rb/p16 tumor-suppressive pathway is abrogated frequently in human tumors, either through inactivation of the Rb or p16INK4a/CDKN2/MTS1 tumor-suppressor proteins, or through alteration or overexpression of the cyclin D1 or cyclin-dependent kinase 4 oncoproteins. We reported previously that the p16 gene was genetically inactivated in 82% of pancreatic carcinomas. Nearly half of these inactivations were by intragenic mutation of p16, and the remainder were by homozygous deletion of the gene. Here, we analyzed pancreatic carcinomas for additional mechanisms by which the Rb/p16 pathway might be inactivated. Transcriptional silencing of the p16 gene in association with methylation of its 5'-CpG island was examined by methylation-specific PCR in 18 pancreatic carcinomas. Nine of these were known to harbor an intragenic mutation in p16, and nine had a wild-type p16 coding sequence. Seven of the 18 tumors were hypermethylated, and all 7 were p16 wild-type (P = 0.001). Complete silencing of transcription from methylated wild-type gene sequences was demonstrated. Immunohistochemical analysis revealed normal expression levels of the Rb protein in all carcinomas studied. None of the carcinomas had genomic amplification of the cyclin D1 or CDK4 genes, and none had mutation of the p16-binding domain of CDK4. An additional p16 mutation was identified. In total, the Rb/p16 pathway was abrogated in 49 of the 50 carcinomas (98%) studied, all through inactivation of the p16 gene. Similar results were obtained in an independently analyzed series of 19 pancreatic carcinomas. These data demonstrate the central role of the Rb/p16 pathway in the development of pancreatic carcinoma.

Carrier Proteins↗
PubMed1993

Cerebral hemodynamics during cardiopulmonary bypass in children using near-infrared spectroscopy.

We describe a new noninvasive method using near-infrared spectroscopy for monitoring cerebral hemodynamics during cardiopulmonary bypass in children. All patients were undergoing open heart operations for repair of congenital heart defects. Standardized anesthesia, an alpha-stat method of blood gas management, and nonpulsatile flow were used in all cases. All measurements during bypass were made after steady-state conditions had been reached. Cerebral blood flow was measured on 13 occasions in 4 children, aged between 4 and 10 months (median, 5 months). Values of 15.9 to 53.5 mL x 100 g-1 x min-1 were obtained. Cerebral blood volume was measured in 1 patient, aged 4 months. Volumes of 4.3 to 8.0 mL x 100 g-1 were obtained on bypass at full pump flow (2.4 L.min-1 x m-2). On bypass at half flow, the volume increased to 14.7 mL x 100 g-1. Change in cerebral blood volume with changing carbon dioxide tension (CBVR) was measured in 13 patients aged from 1 to 90 months (median, 13.5 months). Preoperatively, CBVR was 0.12 +/- 0.07 mL x 100 g-1 x kPa-1 and was independent of mean arterial pressure, which remained between 40 and 80 mm Hg in all cases. During hypothermic bypass (25 degrees C), CBVR was significantly reduced to 0.05 +/- 0.02 mL x 100 g-1 x kPa-1. In addition, there were three values at mean arterial pressure of lower than 40 mm Hg in which CBVR was negative (-0.04 +/- 0.01 mL x 100 g-1 x kPa-1). We conclude that near-infrared spectroscopy is useful for the noninvasive investigation of cerebral hemodynamics during cardiopulmonary bypass.

Carbon Dioxide↗
PubMed1992

Effect of rapid thoracic compression on the cerebral blood flow-velocity patterns of small infants.

We measured the middle cerebral artery (MCA) flow-velocities of 12 small infants (mean weight, 2,882 +/- 602 g) before, during, and after the rapid thoracic compression (RTC) maneuvers of partial forced expiratory flow-volume studies. Cerebral flow-velocities were measured using transcranial Doppler ultrasonography. RTC increased MCA end diastolic flow-velocities and Pourcelot indices of all infants (P less than 0.001). These values returned to baseline immediately after the release of chest compression. We also measured the MCA flow-velocities of several preterm infants during their normal daily activities. The changes in flow-velocity patterns observed during normal daily life were similar to those observed during RTC. These findings demonstrate that RTC produces real, but likely not pathologic, changes in cerebral blood flow-velocities.

Blood Flow Velocity↗