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M E Williams

Publications and source records attributed to M E Williams.

At least 91 records · Page 5Linked to original sources
PubMed1993

Chromosome 11Q13 amplification in head and neck squamous cell carcinoma.

OBJECTIVE: To establish the frequency and clinicopathologic correlates of 11q13 amplification in head and neck squamous cell carcinoma. DESIGN: Retrospective clinicopathologic analysis. SETTING: University and private cancer centers. PATIENTS: Eighty-five patients with pathologically confirmed head and neck squamous cell carcinoma. MEASUREMENTS: The degree of DNA amplification in each tumor was determined using chromosome 11q13 probes for the bcl-1 major translocation cluster, PRAD1/cyclin D1 (CCND1), the fibroblast growth factor gene HST1, EMS1, and glutathione S transferase, pi-1. The presence or absence of amplification was correlated with anatomic site, tumor stage, cytologic grade, histologic pattern, and mitotic activity. RESULTS: Thirty-one patients (36%) showed a twofold to 10-fold amplification of 11q13 loci compared with the chromosome 11q23 ETS1 control probe. Twenty-nine of these encompassed bcl-1 through EMS1 loci; one sample showed only bcl-1 and PRAD1/cyclin D1 plus HST1 amplification, with another amplified at HST1 and EMS1 with minimal or no bcl-1 and PRAD1/cyclin D1 amplification. Amplification was significantly correlated with high cytologic grade, a diffusely infiltrative growth pattern, and with a hypopharyngeal primary site. CONCLUSIONS: Chromosome 11q13 amplification in head and neck squamous cell carcinoma is correlated with an aggressive histologic appearance and hypopharyngeal primary site and should be assessed in prospective clinical trials to determine its utility for treatment stratification and prognosis. Although PRAD1/cyclin D1 and EMS1 have been implicated in the pathogenesis of neoplasms with 11q13 amplification, rare cases with more limited amplicon size suggest that another relevant gene or genes may exist between these loci.

Adult↗
PubMed1993

Fc epsilon receptor-positive cells are a major source of antigen-induced interleukin-4 in spleens of mice infected with Schistosoma mansoni.

When cultured in vitro with either mitogen or parasite antigens, spleen cells from mice infected with Schistosoma mansoni produce significantly higher levels of IL-4 than splenocytes from control animals. Previous studies suggested that this increase in IL-4 production occurs because of a selective expansion of T helper type 2 (Th2) cells in infected mice. However, these experiments employed unfractionated spleen populations rather than purified T lymphocytes. Here we demonstrate that T-depleted spleen cells from infected animals synthesize high levels of interleukin-4 (IL-4), but no IL-5 when stimulated with parasite antigen in vitro. Nevertheless, when purified by sorting, T cells and non-B, non-T (NBNT) populations produced similar amounts of IL-4 in response to parasite antigen. The IL-4 producing NBNT cells were found to belong to an Fc epsilon receptor (Fc epsilon R)-positive population which after sort purification produced high levels of IL-4 (between 1000 and 2000 U of per 5 x 10(3) cells). FACS analysis revealed that these Fc epsilon R+ cells make up 0.53% of splenic NBNT cells in control animals while in 8-9-week-infected animals they increase to 3.8% of that population. In contrast, in mice with 8-week unisexual worm infections these cells comprise only 1.71% of NBNT cells, indicating that eggs are a major stimulus of the response. The expansion of Fc epsilon R+ cells and their production of IL-4 could be an important factor regulating the selection and induction of different CD4+ subsets in schistosome-infected hosts.

Animals↗
PubMed1993

Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly.

Voltage-dependent calcium (Ca2+) channels, expressed in the CNS, appear to be multimeric complexes comprised of at least alpha 1, alpha 2 and beta subunits. Previously, we cloned and expressed human neuronal alpha 1, alpha 2 and beta subunits to study recombinant channel complexes that display properties of those expressed in vivo. The alpha 1B-mediated channel subtype binds omega-conotoxin (CgTx) GVIA with high affinity and exhibits properties of N-type voltage-dependent Ca2+ channels. Here we describe several alpha 2 and beta splice variants and report results on the expression of omega-CgTx GVIA binding sites, assembly of the subunit complex and biophysical function of alpha 1B-mediated channel complexes containing some of these splice variants. We optimized recombinant expression in human embryonic kidney (HEK) 293 cells of alpha 1B alpha 2b beta 1 subunit complexes by controlling the expression levels of subunit mRNAs and monitored cell surface expression by binding of omega-CgTx GVIA to the alpha 1B subunit. Co-expression of either alpha 2b or beta 1 subunits with an alpha 1B subunit increased expression of binding sites while the most efficient expression was achieved when both alpha 2b and beta 1 subunits were co-expressed with an alpha 1B subunit. The presence of alpha 2b affects the affinity of omega-CgTx GVIA binding and barium (Ba2+) current magnitudes, although it does not appear to alter kinetic properties of the Ba2+ current. This is the first evidence of an alpha 2 subunit modulating the binding affinity of a cell-surface Ca2+ channel ligand. Our results demonstrate that alpha 1, alpha 2 and beta subunits together contribute to the efficient assembly and functional expression of voltage-dependent Ca2+ channel complexes.

Amino Acid Sequence↗
PubMed1993

Growth fraction in centrocytic and follicular center cell lymphomas: assessment in paraffin sections with a proliferating cell nuclear antigen antibody and morphometric correlates.

Measurement of growth fraction is an important way to provide an objective assessment of non-Hodgkin's lymphomas; however, many of the techniques used require fresh tissue and/or special instrumentation. Recently, antibodies to the proliferating cell nuclear antigen (PCNA)/cyclin reactive in paraffin-embedded sections have become available. To investigate the utility of one such antibody in the study of follicular center cell (FCC) lymphomas and cleaved cell lymphomas of centrocytic type (CC), paraffin sections from 40 cases that had been characterized in two previous morphometric studies were stained with a PCNA antibody. Strong correlations were found between PCNA staining in formalin- and B5-fixed tissues, between the overall proportion of PCNA-positive cells and the proportion in the area of greatest staining, and between strong and total staining. Proliferating cell nuclear antigen staining was significantly stronger in the noncleaved FCC lymphomas than in the cleaved cell lymphomas. The FCC lymphomas showed moderate to strong correlations between PCNA staining and morphometric features of transformation, but only nuclear area correlated with PCNA staining in the CC group. Proliferating cell nuclear antigen staining was not significantly different between CC lymphomas with and without the characteristic bcl-1/PRAD 1 gene rearrangement. In summary, PCNA staining of either B5- or formalin-fixed, paraffin-embedded tissue sections is a simple aid in the objective categorization of FCC lymphomas and may offer additional potentially prognostic information in some FCC subsets and in CC lymphomas. The findings further support the distinction between CC and true FCC lymphomas.

Cell Nucleus↗
PubMed1993

Acute promyelocytic leukemia with the pseudo-Chediak-Higashi anomaly and molecular documentation of t(15;17) chromosomal translocation.

Two morphologic variants of acute promyelocytic leukemia (AML M3) are recognized--the hypergranular form, in which Auer rods are usually numerous; and the microgranular form. The case of AML M3 reported here lacked numerous Auer rods but was hypergranular and demonstrated prominent giant Chediak-Higashi-like granules in the leukemic cells. Although routine karyotypic studies were inconclusive, at t(15;17) translocation was documented using Southern blot genotypic analysis and probes for the retinoic acid receptor-alpha and pml genes. This is the first case of this unusual morphologic anomaly in which the granules are described in routine histologic sections and the first with evidence of a t(15;17) chromosomal translocation. It also illustrates the importance of Southern blot analysis in suspected cases of AML M3 with "negative" karyotypic studies.

Adolescent↗
PubMed1993

Short versions of the Timed Manual Performance Test. Development, reliability, and validity.

The Timed Manual Performance test is gaining wider use as a measure of functional status in research and clinical settings. It is a rather lengthy 27-item test, however, requiring the use of a large cumbersome panel of doors. The authors, therefore, studied 1,286 community-dwelling elderly subjects recruited through their primary care provider to: 1) reduce the number of items in the Timed Manual Performance (TMP) test and 2) assess the reliability and validity of the shorter versions of the TMP compared with the 27-item TMP. Using principal components analysis, we identified two shorter measures, TMP (Doors) consisting of five board tasks and TMP (Table) consisting of six table tasks. Timed Manual Performance (Doors) and TMP (Table) involve less equipment than the original TMP and have higher rates of completion. Furthermore, not only are these tests reliable (alpha = 0.79 and 0.82 for TMP [Doors] and TMP [Table], respectively), they appear to be better measures of manual performance compared with the 27-item TMP.

Activities of Daily Living↗
PubMed1993

Chromosome 11q13, c-erbB-2, and c-myc amplification in invasive breast carcinoma: clinicopathologic correlations.

To determine the frequency and clinicopathologic correlates of chromosome 11q13 amplification in breast carcinoma, DNA from 50 invasive tumors was analyzed by Southern blot hybridization using probes for the 11q13 loci bcl-1, PRAD1, hst1, EMS1, and GST-pi, as well as oncogenes c-erbB-2 and c-myc. Sixteen tumors (32%) were amplified for one or more loci. Seven tumors (14%) showed amplification of 11q13 loci; six of these were coamplified with either c-erbB-2 (three), c-myc (two), or both (one). Nine additional tumors (18%) were amplified for c-erbB-2, and three of these were coamplified with c-myc. None showed c-myc amplification alone. Tumors with 11q13 amplification showed equivalent degrees of bcl-1, PRAD1, hst1, and EMS1 amplification, delineating an approximately 800-kb amplicon. GST-pi was inconsistently amplified, evidence that it lies outside the amplicon defined by bcl-1 and EMS1. Amplification of 11q13 was unassociated with patient age, tumor size, axillary lymph node status, hormone receptors, DNA content, histologic grade, mitotic rate, nuclear pleomorphism, or tubule formation. c-myc amplification correlated with the lack of tubule formation (p = 0.04), whereas c-erbB-2 amplification correlated with axillary lymph node positivity (p = 0.04), high histologic grade (p = 0.003), increased nuclear pleomorphism (p = 0.008), and a high mitotic rate (p = 0.02). The frequency of coamplification of 11q13 loci, c-myc, and c-erbB-2 contradicts previous proposals that amplification of these genes occurs in independent subsets of breast carcinoma. Extended clinical followup will be necessary to determine whether 11q13 amplification has prognostic utility in invasive breast cancer.

Adult↗
PubMed1993

Chromosome t(11;14)(q13;q32) breakpoints in centrocytic lymphoma are highly localized at the bcl-1 major translocation cluster.

Chromosome 11q13 translocation breakpoints have been found dispersed over more than 100 kb of genomic DNA in centrocytic lymphoma and lymphocytic lymphoma of intermediate differentiation (mantle cell lymphoma). Approximately one-half of these translocations occur at the bcl-1 major translocation cluster (MTC) and appear tightly clustered by Southern blot restriction mapping. In order to specifically characterize these t(11;14)(q13;q32) translocations, six cases of centrocytic lymphoma with MTC rearrangements on Southern blot were studied. Genomic DNA was amplified by PCR (polymerase chain reaction) using a consensus immunoglobulin heavy-chain joining gene (JH) primer and two separate MTC primers. Sequencing of the PCR products revealed the MTC breakpoints in all six cases to be clustered within a 61 basepair span, very similar to those previously reported in t(11;14)-containing human B-cell lines. No two breakpoints were identical. JH breakpoints involved JH4 in five cases and JH6 in the other. Tight clustering of the MTC breakpoints thus permits PCR detection of the t(11;14) in many cases of centrocytic lymphoma, which may be of value in classifying this subtype of non-Hodgkin's lymphoma.

Base Sequence↗
PubMed1993

Bcl-2 protein in centrocytic lymphoma; a paraffin section study.

Bcl-2 is an inner mitochondrial membrane protein which blocks apoptosis. Although present in many B cells, the vast majority of follicular center cells do not have detectable bcl-2 protein. The bcl-2 gene is translocated in most conventional small cleaved follicular center cell (SCFCC) lymphomas (centroblastic/centrocytic) but not in centrocytic lymphomas (CC). The translocated gene in the SCFCC lymphomas leads to 'aberrant' bcl-2 expression by the neoplastic follicular center cells. The frequency with which the normal non-translocated gene is expressed in CC lymphomas is, however, not well documented. Paraffin sections from 22 cases of centrocytic lymphoma were therefore stained with an anti-bcl-2 antibody. Genotypic studies in 14 cases demonstrated bcl-1/PRAD1 (cyclin D1; CCND1) rearrangements in ten and bcl-2 rearrangements in none. All centrocytic lymphomas demonstrated bcl-2 protein expression in the majority of neoplastic cells. Negative staining residual follicular centers were identified in four cases emphasizing the mantle zone growth pattern of a subset of CC lymphomas. Expression of bcl-2 protein in the absence of bcl-2 gene rearrangement is a feature shared by centrocytic lymphomas and mantle zone cells. However, because this type of bcl-2 expression is not specific for B-cells of the mantle zone, it does not further elucidate the true cell of origin for the centrocytic lymphomas.

Gene Rearrangement↗
PubMed1993

Centrocytic lymphoma: a morphometric study with comparison to other small cleaved follicular center cell lymphomas and genotypic correlates.

Centrocytic lymphoma (ML,CC) is distinguished from other cleaved follicular center cell (FCC) lymphomas in the Kiel classification by the lack of noncleaved FCC and not by morphological differences between the centrocytes (cleaved cells). Immunophenotypic and genotypic studies, however, have shown that the centrocytes in ML,CC are distinct from those of other small cleaved FCC lymphomas (ML,FCC,SC). To morphologically compare the cells of ML,CC with nine previously studied ML,FCC,SC and to relate the findings in ML,CC to the varied descriptions of lymphomas of intermediate differentiation, a morphometric analysis of 22 ML,CC was performed. Nuclei in ML,CC were, on average, significantly larger, rounder, and had less frequent nucleoli than those in ML,FCC,SC; however, the proportion of small round lymphocytes did not differ. Among the ML,CC, the only apparent immunophenotypic/genotypic correlate that was identified was greater nuclear ellipticity for the biopsies lacking chromosome 11q13 bcl-1 or PRAD1 rearrangement. Repeat biopsies in four patients with ML,CC showed an increase in nuclear size. These data demonstrate that a lack of transformed cells is not the only morphological difference between ML,CC and ML,FCC,SC. The morphological distinction, however, is not based on the proportion of small round lymphocytes present. In addition, the morphometric parameters illustrate the nuclear variability among ML,CC and demonstrate how the disease may evolve over time.

Cell Nucleus↗
PubMed1993

Chromosome 11 translocation breakpoints at the PRAD1/cyclin D1 gene locus in centrocytic lymphoma.

Centrocytic lymphoma is a CD5-positive B-cell neoplasm. Rearrangements at the chromosome 11q13 bcl-1 breakpoint loci are present in the majority of these lymphomas, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain joining genes. Recently, a gene lying approximately 110 kb telomeric of the bcl-1 major translocation cluster breakpoint locus, designated PRAD1, was proposed as a candidate bcl-1 oncogene. Accumulated evidence now indicates that this gene is the postulated bcl-1 oncogene. It encodes a protein with homology to cyclin family proteins designated cyclin D1 (CCND1). In order to determine whether 11q13 translocation breakpoints were present near the PRAD1 coding region in addition to the previously defined bcl-1 sites, we analyzed 27 centrocytic lymphomas by Southern blot using genomic and cDNA probes flanking the first exon of PRAD1. Five samples showed rearrangement at PRAD1 sites. In four of these, the breakpoints could be mapped from approximately one to 25 kb upstream of the first PRAD1 exon; each showed comigration of rearranged PRAD1 and immunoglobulin heavy-chain joining gene bands consistent with the t(11;14)(q13;q32). The fifth case was rearranged with PRAD1 probes only on BamHI-digested DNA, indicating either a point mutation or a polymorphism at this site. This sample also had rearrangement on multiple enzyme digests with the bcl-1 p94PS probe. None of 80 non-centrocytic B-cell neoplasms showed PRAD1 rearrangement. Thus, rearrangement at both bcl-1 and PRAD1 loci is strongly associated with centrocytic lymphoma, and provides a useful molecular marker for classifying this subtype of lymphoma. Furthermore, translocation-induced aberrant expression of the PRAD1 cyclin may lead to deregulated cell cycle control and play an important role in the pathogenesis of centrocytic lymphoma.

Chromosomes, Human, Pair 11↗
PubMed1992

Characterization of chromosome 11 translocation breakpoints at the bcl-1 and PRAD1 loci in centrocytic lymphoma.

The chromosome 11q13 bcl-1 locus is rearranged in the majority of centrocytic lymphomas, a CD5-positive B-cell non-Hodgkins lymphoma, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain genes. Although several 11q13 bcl-1 breakpoint sites have been characterized, a postulated bcl-1 oncogene was not identified. Recently, however, a gene encoding cyclin D1, designated PRAD1, was proposed as a candidate bcl-1 oncogene; accumulated evidence now indicates this gene is bcl-1. To further characterize 11q13 breakpoints in B-cell neoplasms, we analyzed 26 centrocytic lymphomas and 68 other B-cell cancers by Southern blot using a panel of breakpoint probes spanning 110 kilobases of the bcl-1 and PRAD1 loci. Nineteen centrocytic cases (73%) showed rearrangement, 15 at bcl-1 breakpoint sites and 5 at PRAD1 sites. One case was rearranged at both bcl-1 and PRAD1 loci. All but the latter case showed comigration of rearranged bcl-1 or PRAD1 bands and immunoglobulin heavy chain joining gene bands, consistent with the t(11;14). bcl-1 rearrangement was present in only one of 68 noncentrocytic B-cell neoplasms; none showed PRAD1 rearrangement. Thus, bcl-1 and PRAD1 rearrangement is strongly associated with centrocytic lymphoma, providing a useful molecular marker for classifying this subtype of lymphoma and suggesting an important role for PRAD1 cyclin D1 in the pathogenesis of this neoplasm.

Chromosomes, Human, Pair 11↗
PubMed1992

Antigen receptor-mediated anergy in resting T lymphocytes and T cell clones. Correlation with lymphokine secretion patterns.

The goal of these studies was to define the stimuli and factors that control the induction of anergy in unimmunized resting T lymphocytes. Initial experiments, aimed at establishing the system, showed that exposure of Th1 but not Th2 clones to immobilized anti-CD3 leads to a block in autocrine growth factor production and proliferation upon subsequent restimulation with Ag+APC. Anergy is not prevented by accessory cells, suggesting that this model of T cell tolerance may be due to receptor-mediated inhibitory signals, independent of costimulatory molecules. Culture of small (resting) unimmunized T lymphocytes with anti-CD3 +/- IL-2 induces unresponsiveness to restimulation with anti-CD3, but culture with anti-CD3+IL-4, which stimulates the differentiation of resting cells into IL-4 producers, does not induce anergy. Thus, IL-4-producing clones and bulk populations of IL-4-producing T cells are resistant to Ag receptor-mediated inhibitory stimuli. These results provide experimental models for studying the mechanisms of anergy in normal, unselected, mature T cells, and demonstrate fundamental similarities between cloned cell lines and unimmunized T lymphocytes in the induction of anergy.

Animals↗
PubMed1992

Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel.

N-type calcium channels are omega-conotoxin (omega-CgTx)-sensitive, voltage-dependent ion channels involved in the control of neurotransmitter release from neurons. Multiple subtypes of voltage-dependent calcium channel complexes exist, and it is the alpha 1 subunit of the complex that forms the pore through which calcium enters the cell. The primary structures of human neuronal calcium channel alpha 1B subunits were deduced by the characterization of overlapping complementary DNAs. Two forms (alpha 1B-1 and alpha 1B-2) were identified in human neuroblastoma (IMR32) cells and in the central nervous system, but not in skeletal muscle or aorta tissues. The alpha 1B-1 subunit directs the recombinant expression of N-type calcium channel activity when it is transiently co-expressed with human neuronal beta 2 and alpha 2b subunits in mammalian HEK293 cells. The recombinant channel was irreversibly blocked by omega-CgTx but was insensitive to dihydropyridines. The alpha 1B-1 alpha 2b beta 2-transfected cells displayed a single class of saturable, high-affinity (dissociation constant = 55 pM) omega-CgTx binding sites. Co-expression of the beta 2 subunit was necessary for N-type channel activity, whereas the alpha 2b subunit appeared to modulate the expression of the channel. The heterogeneity of alpha 1B subunits, along with the heterogeneity of alpha 2 and beta subunits, is consistent with multiple, biophysically distinct N-type calcium channels.

Amino Acid Sequence↗
PubMed1992

Combined kidney and pancreas transplantation. A 3-year experience.

Between May 1988 and September 1991, we performed 26 simultaneous kidney and pancreas transplants and one pancreas transplant after a kidney transplant. All transplants consisted of bladder drainage via a duodenal segment. Actuarial patient, kidney, and pancreas graft survival rates at 12 months were 96%, 88%, and 85%, respectively, and at 24 months were 96%, 88%, and 81%, respectively, and were not significantly different from those of diabetic recipients of cadaver kidney transplants alone. Excellent long-term glycemic control was obtained as monitored by fasting blood glucose and glycosylated hemoglobin levels and by oral glucose tolerance tests. The mean period of hospitalization and number of hospital admissions in the first year posttransplant were significantly greater for patients who received combined kidney and pancreas transplants than for those who received cadaver kidney transplants alone. Combined kidney and pancreas transplants can be performed with patient and graft survival comparable to those of kidney transplants alone, with excellent long-term glycemic control, but result in increased morbidity in the first postoperative year.

Adult↗