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Biomedical subjects

K Patel

Publications and source records attributed to K Patel.

At least 181 records · Page 10Linked to original sources
PubMed1994

Cervical metastases of occult origin: the impact of combined modality therapy.

BACKGROUND: We have updated our experience with metastatic carcinoma to the neck of occult origin to assess whether increasing use of adjunctive radiation therapy has had a significant impact. METHODS: This retrospective review of 115 patients treated between 1977 and 1990 includes 73 (63%) with squamous cell carcinoma. These 73 patients were analyzed for survival, control of disease in the neck, and incidence of subsequent primary tumors. RESULTS: There has been no change in the proportion of patients with advanced neck disease (N2/N3 = 52; 71%) when compared to our last report. Surgery included comprehensive neck dissection in 59 (81%) and adjunctive radiotherapy was employed in 54 (83% of surgically treated patients). Primary carcinomas within the head and neck were identified subsequently in 9 (12%) patients, including 4 of 11 (36%) who did not have adjunctive radiotherapy and 5 of 54 (9%) who did (P = 0.038). Control of the treated neck (54/73; 74%) has improved significantly (P = 0.005) when compared to our earlier experience (37/74; 50%), and this was most apparent in those with extensive neck disease. However, cumulative survival at 5 years (45%) was not significantly different from that previously reported. CONCLUSION: Our data support the increased use of adjunctive radiation therapy for metastatic squamous cell carcinoma in the neck of occult origin. Control of neck disease has improved and the likelihood that a primary will be identified has been reduced, but there has been no improvement in survival when compared to historical controls.

Adult↗
PubMed1994

The effects of chemotherapy on morphology, cellular proliferation, apoptosis and oncoprotein expression in primary breast carcinoma.

The use of chemotherapy as a form of primary treatment for breast cancer is increasing and, as a result, more resection specimens contain tumours which have been exposed to cytotoxic drugs. We have studied the effects of chemotherapy on the tumour morphology and various biological features of breast carcinoma in a group of 35 patients. These were a group who responded to treatment in a clinical study of the use of primary chemotherapy designed to reduce tumour bulk prior to surgery. Characteristic morphological changes, temporally related to the administration of cytotoxic agents, are seen. The malignant cells become enlarged with vacuolated cytoplasm and vesicular nuclei containing prominent nuclei; occasionally the nuclei were angular and hyperchromatic. These features are interpreted as degenerative in nature. In 15 cases sufficient material was present in the pretreatment biopsies to compare the grade of the tumours before and after chemotherapy: changes were found in six tumours. Cytotoxic drugs do not induce a consistent pattern of change in the proliferation and apoptotic indices of individual tumours, but there is a tendency to reduce proliferative activity over all the tumours as a group. It was also found that chemotherapy is capable of modifying the expression of the oncoproteins c-erbB-2 and p53 in a minority of cases of breast cancer, usually resulting in an acquisition of immunoreactive oncoprotein. It is important to be aware of these effects when studying breast carcinomas removed after chemotherapy.

Adult↗
PubMed1994

Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17.

Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.

Alleles↗
PubMed1994

Olfactory receptor gene cluster on human chromosome 17: possible duplication of an ancestral receptor repertoire.

A gene superfamily of olfactory receptors (ORs) has recently been identified in a number of species. These receptors share a seven transmembrane domain structure with many neurotransmitter and hormone receptors, and are likely to underlie the recognition and G-protein-mediated transduction of odorant signals. Previously, OR genes cloned in different species were from random locations in the respective genomes. We report here the cloning of 16 human OR genes, all from chromosome 17 (17p13.3). The intronless coding regions are physically mapped (on 35 cosmids) in one 0.35Mb long contiguous cluster, with an average intergenic separation of 15kb. The human OR genes in the cluster belong to four different gene subfamilies, displaying as much sequence variability as any randomly selected group of ORs. This suggests that the cluster identified may be one of several copies of an ancestral OR gene repertoire whose existence may predate the divergence of mammals. The latter may have duplicated in some species to form the present mammalian OR gene repertoire, with several hundred genes. The human chromosome 17 OR gene cluster may thus be a good model for understanding human olfaction, as well as the ontogeny and phylogeny of the OR gene superfamily.

Amino Acid Sequence↗
PubMed1994

Down-regulation of integrin alpha 1/beta 1 expression and association with cell rounding in human cytomegalovirus-infected fibroblasts.

Human cytomegalovirus (HCMV) causes a c.p.e. characterized by rounding of the infected cell. Since interactions with the extracellular matrix may be involved in the cell rounding, we have analysed the expression of integrins, which are the main cell surface receptors involved in cell-substrate adhesion and spreading. By FACS analysis, a selective decrease in cell surface expression of alpha 1/beta 1 integrin was observed in HCMV-infected fibroblasts. This decrease coincides with cell rounding. Immunoprecipitation studies and FACS analysis of permeabilized cells have further demonstrated that total levels of this integrin are decreased in infected cells, suggesting that the reduction in cell surface alpha 1/beta 1 integrin is not due to a defect in transport to the surface. Furthermore, we have ruled out the possibility that the observed decrease in alpha 1/beta 1 expression is caused by a cytokine released from the infected cells by showing that the reduction is abolished by inactivating the HCMV with u.v. irradiation, and that conditioned medium from HCMV-infected cells has no effect on expression of alpha 1/beta 1 integrin in uninfected cells. Concomitant with the reduction in alpha 1/beta 1 levels, the HCMV-infected fibroblasts show a reduced ability to adhere to laminin and collagen IV. Taken together the data indicate that de novo synthesis of HCMV protein(s) causes a decreased assembly/expression of alpha 1/beta 1 integrin, coincident with the well characterized morphological alterations of the infected cell.

Cell Line↗
PubMed1994

p53 expression in cultured cells following radioisotope labelling.

p53 inhibits division following cellular damage. Cultured cells were found to express p53 protein following pulse labelling with radioisotopes, even at low doses normally used for growth and metabolic labelling studies. Some stem cells are exquisitely sensitive to radiation and thus p53 may have evolved as a major regulator of stem cell function. Therefore any genetic damage may be able to induce p53 expression, which in turn will affect the biochemical outcome of many experiments by both cell cycle arrest and other mechanisms. In some cases the use of radioisotopes may directly change the results of the experiment. This will require a careful re-evaluation of the current literature and experimental protocols utilising radioisotopes.

Cell Cycle↗
PubMed1994

The kinetic organization of the ulcer-associated cell lineage (UACL): delineation of a novel putative stem-cell region.

We have examined the proliferative organization of the ulcer-associated cell lineage (UACL), in a series of human ileal tissues involved by Crohn's disease, using antibodies to trefoil peptides and Ki-67. The UACL arises in conjunction with endodermal damage and is likely to play a role in subsequent tissue repair. Our study supports the view that the UACL initially forms through extrusion from the base of a parent intestinal crypt without indigenous mitotic activity. Eventually a duct forms extending to the gut surface and within this duct a proliferative zone develops. We also confirm that the trefoil peptides pS2 and hSP, which play a major role in the repair process, are spatially segregated within the UACL with a zone of overlap in the duct. Using triple antibody labelling techniques we have demonstrated that the zone of overlap of these peptides coincides with the proliferative region and provides evidence for a novel stem cell zone.

Cell Division↗
PubMed1994

Does nasal septal deviation influence adult posterior choanal size?

Despite the development of modern imaging techniques, no study has been carried out to establish the normal size (particularly the area) of the adult posterior choanae. In this study we present our findings of the normal anatomical sizes of the adult posterior choanae and its relationship to septal deviation, by analysing MRI images of 70 patients. Coronal sections through the sphenoid rostrum and axial sections through the nasal septum were used. There were 32 males and 38 female patients. The age ranged between 18 and 73 years (mean 35.6). Our results show that the posterior choanal dimensions were as follows: right area: 1.35-6.1 cm2 (mean 2.7 cm2); left area: 1.4-5.9 cm2 (mean 2.7 cm2); right width: 0.9-2.1 cm (mean 1.5 cm); left width: 0.9-2.2 cm (mean 1.5 cm); right height: 2.5-4.0 cm (mean 2.6 cm); and left height: 1.5-4.0 cm (mean 2.5 cm). Chi-square analysis showed no statistically significant differences between left- and right-sided measurements. Twenty-three patients had a deviated septum towards the left side, 22 patients towards the right side, and 25 patients had no septal deviation. Chi-square analysis showed no statistical correlation between deviation of the nasal septum and any of the three dimensions of the posterior choanae studied.

Adult↗
PubMed1993

Antibodies chaperone circulating IL-6. Paradoxical effects of anti-IL-6 "neutralizing" antibodies in vivo.

In the baboon or the mouse, a stimulus such as LPS, TNF, or IL-1 typically led to a rapid induction of circulating IL-6, the levels peaked by 2 to 3 h and then declined to near-baseline values by 6 to 8 h. Administration to baboons or mice of "neutralizing" anti-IL-6 mAb followed by an IL-6 inducer led to a marked and sustained increase in circulating IL-6 levels. IL-6 Ag, IL-6 biologic activity, neutralizing anti-IL-6 mAb, and IL-6/anti-IL-6-mAb complexes could all be observed for an extended period of time (beyond 8 h) in the circulation of such animals. Nevertheless, in mice, if the anti-IL-6 mAb had been administered before the IL-6 inducer, there was a reduction in the in vivo IL-6-induced stimulation of fibrinogen levels, indicating that most of the intravascular IL-6 was not readily available for eliciting hepatocyte effects under these experimental conditions. Intraperitoneal administration into mice of mixtures of murine rIL-6 or human rIL-6 together with their respective anti-IL-6 mAb led to a marked increase in the appearance and longevity in the peripheral circulation of the exogenously administered murine or human rIL-6 species in a biologically active form. Varying the ratio of human rIL-6 to anti-human IL-6 mAb indicated that a molar ratio of 1:1 was sufficient for the ability of mAb to chaperone IL-6 in the murine circulation. Human rIL-6 mixed with "neutralizing" mAb in the approximate ratio 1:1 elicited an enhanced fibrinogen response in vivo in the mouse; an IL-6:mAb ratio of 1:125 led to a reduction in the fibrinogen response even though the levels of circulating B9 bioactivity and of human rIL-6-Ag were maximal under these conditions. Gel-filtration chromatographic and Western blotting analyses of IL-6 present in vivo in the mAb-free baboon revealed that although the IL-6 Ag was largely present in high molecular mass complexes of size 400 kDa in association with soluble IL-6 receptor, the B9 bioactivity was largely of low molecular mass (20 kDa). In contrast, in the anti-IL-6 mAb-treated baboon or mouse, the IL-6 Ag and bioactivity were both largely in complexes of 200 kDa. Thus, the binding of IL-6 in the intravascular compartment to other proteins, anti-IL-6 mAb in the present studies, gives IL-6 unexpected biochemical and pharmacologic properties in vivo.

Animals↗
PubMed1993

Vase mini-exon usage by NCAM is not restricted to tumours of neuroectodermal origin.

The neural cell adhesion molecule (NCAM) plays an important role in normal development. Many variants of NCAM are generated through post-transcriptional and post-translational modifications. These variants are tissue-specific and their expression is developmentally regulated. NCAM is also re-expressed in a number of human tumours, including neuroblastoma, rhabdomyosarcoma, Wilms' tumour and Ewing's sarcoma. We have characterized the NCAM variants associated with rhabdomyosarcoma. Polysialylated NCAMs are present in this tumour and, after neuraminidase treatment, they resolve into 2 bands of 140 and 120 kDa. These data were corroborated by Northern-blot analysis where mRNA species of 6.7 and 5.5 kb are detected. These mRNA code for the 140- and 120-kDa NCAM proteins respectively. PCR analysis shows that the previously described VASE mini-exon is also present in NCAM found in rhabdomyosarcoma. The VASE mini-exon, spliced at exon 7-8 junctions, has previously been detected in neural and heart NCAM, as well as in NCAMs found in human small-cell lung carcinoma (SCLC). DNA sequencing confirmed that the VASE mini-exon in rhabdomyosarcoma is identical to that found in neuroblastoma and SCLC.

Alternative Splicing↗
PubMed1993

Mutation of p53 in primary biopsy material and cell lines from Hodgkin disease.

The p53 tumor-suppressor gene encodes a nuclear phosphoprotein that arrests cell cycle progress at G1. It may facilitate DNA damage repair and is frequently mutated in many human tumors. Hodgkin disease, a malignant condition of the lymphoid system, is characterized by the presence of Reed-Sternberg cells and mononuclear variants (Hodgkin cells), whose etiology remains unknown. The large multinucleated Reed-Sternberg cells often comprise < 1% of the total cell population within a biopsy specimen and are thought to be the neoplastic component in an admixture of reactive cells. It has been shown in the large majority of cases that up to 60% of these multinucleated cells react with CM-1, an anti-p53 antibody. However, whether this "overexpression" of p53 protein reflects abnormality at the DNA level can no longer be assumed by immunocytochemistry alone. p53 from six Hodgkin disease-derived cell lines was examined by immunoprecipitation, polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis, and sequencing. In one cell line, point mutations were identified in exons 5 and 8 of p53. Sequencing of cloned PCR products confirmed the mutations to be on different alleles. A strategy involving extraction of nuclei followed by enrichment by flow cytometry was used to determine whether p53 overexpression in the Reed-Sternberg cells from patient biopsy material was due to mutations in this gene. Single-strand conformation polymorphism revealed additional bands in the polyploid nuclear preparations, suggesting abnormalities, and sequence analysis confirmed the presence of point mutations.

Base Sequence↗
PubMed1993

The mechanism of iron uptake by transferrins: the structure of an 18 kDa NII-domain fragment from duck ovotransferrin at 2.3 A resolution.

The molecular structure of an iron-containing 18 kDa fragment of duck ovotransferrin, obtained by proteolysis of the intact protein, has been elucidated by protein crystallographic techniques at 2.3 A resolution. This structure supports a mechanism of iron uptake in the intact protein whereby the binding of the synergistic (bi)carbonate anion is followed by binding of the metal with the lobe in the open configuration. These stages are then followed by domain closure in which the aspartic acid residue plays a further key role, by forming an interdomain hydrogen-bond interaction in addition to serving as a ligand to the iron. This essential dual role is highlighted by model building studies on the C-terminal lobe of a known human variant. In this variant a mutation of a glycine by an arginine residue enables the aspartic acid to form an ion pair and reduce its effectiveness for both metal binding and domain closure. The X-ray structure of the 18 kDa fragment strongly suggests that the histidine residue present at the iron binding site of the intact protein and arising from the second interdomain connecting strand has been removed during the preparative proteolysis.

Journal Article↗
PubMed1993

Mapping on human and mouse chromosomes of the gene for the beta-galactoside-binding protein, an autocrine-negative growth factor.

The structural gene for beta-galactoside-binding protein (Lgals-1), a cell growth regulatory molecule and cystostatic factor, is assigned to the E-region of mouse chromosome 15 and to the region q12-q13.1 of human chromosome 22. The evolutionary conservation of these two regions has been previously suggested from comparative mapping of several loci. These include the murine SIS oncogene (Pdgfb) and its human homolog, the platelet-derived growth factor-beta polypeptide, PDGFB. The findings presented here extend the genetic homology of the two regions.

Animals↗
PubMed1993

Efficiency and specificity of gene isolation by exon amplification.

Exon amplification is an increasingly popular approach to the identification of transcribed sequences and will complement other strategies to isolate genes. We have used this system to amplify candidate exons from 32 cosmids, including 8 cosmids which span a well characterized 185-kb region of the human major histocompatibility class II region on Chromosome (Chr) 6. We have examined the efficiency, specificity, and reproducibility of the system in isolating exons from genes known to be present on particular cosmids and have determined the nature and frequency of artefact amplifications in routine cosmid screening. We were able to clone at least one exon from 88% (7/8) of all known genes tested (including exons which are differentially spliced) and obtained artefacts from 19% (6/32) of the cosmids tested. Such artefacts generally arise from the amplification of noncoding sequences flanked by regions with high homology to acceptor and donor splice junctions. We show that the exon amplification procedure can be used successfully with a wide variety of cosmids which have different numbers of genes and gene structures and describe several approaches to the characterization of novel exons cloned in this study.

Amino Acid Sequence↗
PubMed1993

Intra- and interobserver variability in interpretation of DMSA scans using a set of standardized criteria.

A set of criteria was developed to standardize assessment of DMSA renal scintigraphy which were performed to evaluate children for acute pyelonephritis and renal scarring. This study was undertaken to assess intra- and interobserver variability in the interpretation of DMSA renal scintigraphy using these criteria. Renal contours and parenchyma were assessed in three zones. Contours were assessed as normal or abnormal and parenchymal defects were evaluated in terms of character, shape and degree in three regions (upper and lower pole and midzone). Two nuclear medicine physicians blindly reviewed 57 DMSA scintigraphy on two occasions each. Disagreement of each observer's evaluation of the same scintigraphy on two different occasions was described as intraobserver variability, and the comparison between readings by each of the two observers was described as interobserver variability. High levels of intra- (95.9% and 90.6% respectively, p < 0.05) and interobserver agreement (84.4%, p < 0.05) were demonstrated. There were minor differences in inconsistencies between the two kidneys or different kidney zones. We conclude that standardization of criteria resulted in higher intra- and interobserver consistency in interpretation of DMSA scintigraphy.

Acute Disease↗
PubMed1993

"Junction trapping". A simple PCR-based method for the isolation of YAC-insert termini.

A new and potentially reliable method for the isolation of yeast artificial chromosome (YAC)-insert termini, termed junction trapping, is described. This method is based on simple partial digestions of the YAC-containing yeast strain, ligation to a plasmid vector, and selection of the termini by two rounds of polymerase chain reaction (PCR). To date, the method has generated both terminal sequences from each of nine YACs (100%) that have been examined.

Chromosome Mapping↗