Biomedical subjects

M Ilyas

Publications and source records attributed to M Ilyas.

At least 19 recordsLinked to original sources

PubMed2005

A new chromone from Ficus lyrata.

A new chromone, named 5,6-dihydroxy-2-methylchromone (FL-2), along with seven known flavonoids, 5-hydroxy-7,3,3',4'-tetramethoxyflavone (FL-3), 5,4'-dihydroxy-6,7,8-trimethoxyflavone (FL-4), 5,4'-dihydroxy-7,8-dimethoxyflavone (FL-5), 4-methoxychalcone (FL-6), 7,4'-dimethoxyapigenin (FL-7), 5,7,4'-trihydroxy-2',3',6'-trimethoxyisoflavone (FL-8 a rare flavonoid), acacetin-7-O-glucoside (FL-9) and acacetin-7-O-neohesperidoside (FL-10), and beta-sitosterol-D-glucoside (FL-1) have been isolated from the leaves of Ficus lyrata. Their structures have been established on the basis of chemical and spectral evidence (IR, UV, 1H NMR, 13C NMR and mass spectra).

Chromones↗

PubMed2004

A new biflavonoid from leaves of Garcinia nervosa.

The isolation of a new biflavonoid, identified as I-3, II-3, I-5, II-5, I-7, II-7, I-4', II-4'-octahydroxy [I-2', II-2'] biflavone, from the leaves of Garcinia nervosa is reported. The structure was established by chemical and physical means (IR, UV, 1H-NMR, 13C-NMR data).

Biflavonoids↗

PubMed2001

Antibody targeting studies in a transgenic murine model of spontaneous colorectal tumors.

Monoclonal antibodies (mAbs) have been used to treat malignancies in humans with varying degrees of success. Progress has been hindered by the lack of suitable animal models, which would ideally consist of immunocompetent animals that are tolerant to tumor-associated antigens. Suitable models would allow the study and optimization of anti-tumor immunotherapy. We describe a murine model for the study of immunotherapy in colorectal cancers. Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein that is expressed on normal human intestinal epithelium and that is overexpressed in intestinal tumors. Mice that are transgenic for the human CEA gene (CEA.Tg) were crossed with multiple intestinal neoplasia (MIN) mice. MIN mice carry a germline APC mutation and are prone to the development of intestinal adenomas. The offspring from the MIN x CEA.Tg cross developed intestinal adenomas that were shown by immunohistochemistry to overexpress CEA. Pharmacokinetic studies by using (125)I-labeled anti-CEA mAb PR1A3 showed rapid localization of antibody to tissues expressing CEA, especially the gastrointestinal tract. Macroscopic and microscopic radioautographic analysis of the gastrointestinal tracts from MIN/CEA.Tg mice indicated that PR1A3 targeted and was retained in tumors at levels higher than in areas of normal gut. These results demonstrate the utility of the MIN/CEA.Tg mouse as a model for the study of anti-CEA immunotherapy and, furthermore, demonstrate the efficiency of tumor localization by PR1A3.

Animals↗

PubMed2001

Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer.

BACKGROUND: Ulcerative colitis associated colorectal cancer (UCACRC) has several distinctive clinicopathological and genetic features which differ from sporadic colorectal cancer (SCRC). Hypermethylation of the E-cadherin gene (CDH1) has not been described previously in colorectal cancer. AIMS: A panel of SCRC and UCACRC were investigated for mutations in CDH1, and for hypermethylation of the promoter region of CDH1. SUBJECTS AND METHODS: DNA was available from 14 patients with UCACRC and from 14 with SCRC. All exons of CDH1 were amplified with the polymerase chain reaction (PCR) and screened using single strand conformational polymorphism and direct sequencing. Hypermethylation of the CDH1 promoter region was determined by methylation specific PCR following bisulphite modification, and compared with E-cadherin protein expression from a previous immunohistochemistry study. RESULTS: Thirteen of 28 cancers (46%) were hypermethylated in the CDH1 promoter region-eight cancers (57%) in the UCACRC group and five cancers (36%) in the SCRC group (NS)-and this correlated with reduced E-cadherin expression (p<0.05). There was a trend for methylation to be associated with a more advanced stage of cancer although this did not reach statistical significance. There were no mutations in CDH1 in either group although there were several polymorphisms. CONCLUSION: We have demonstrated hypermethylation of the promoter region in CDH1 in 46% of colorectal cancers studied. There was no difference between the UCACRC and SCRC groups. Just as there are specific differences in the genetic changes between UCACRC and SCRC, there is also likely to be a large degree of overlap among the genetic pathways of these cancers.

Cadherins↗

PubMed2001

Molecular pathology of solid tumours: some practical suggestions for translating research into clinical practice.

"Molecular pathology" can be broadly defined as the use of genetic data, in addition to the standard pathological parameters, to optimise diagnosis and to indicate treatment and prognosis. The benefit to be gained from the exploitation of molecular techniques to provide additional information to aid patient management is potentially vast. Currently, molecular pathology is rarely used in clinical practice, although it is anticipated that it will eventually become a part of routine practice. However, incorporating molecular techniques into routine practice will not be straightforward because there are several issues to be resolved. Following on from a symposium held at the Royal College of Pathologists to discuss some of these issues, the establishment of a committee of molecular pathology is proposed to plan and coordinate the introduction of molecular pathology into routine clinical practice.

Congresses as Topic↗

PubMed2001

Ultrasonographic appearance of Ascaris lumbricoides in the small bowel.

Roundworm infestation, one of the most common helminthic diseases worldwide, is caused by Ascaris lumbricoides, one of the largest parasites that infests the human bowel. A lumbricoides is virtually universal at some stage of childhood in semitropical and tropical regions. This study describes our experience with the ultrasonographic appearance of intestinal ascariasis in 84 patients, 2.5 to 42 years of age, examined over 2 years beginning October 1997. The patients' conditions ranged from acute intestinal obstruction to no clinical features pertaining to obstruction. Ultrasonographic examination was performed with an Echocee power Doppler real-time unit with a variable-frequency 3.7-MHz convex, 7.5-MHz linear probe. In longitudinal section the Ascaris worm presented as a linear intraluminal mass with 3 or 4 linear echogenic interfaces; in the cross section, it was round, sometimes appearing as a "target" sign. Some worms also showed serpentine movements. Sonographic examination of the patients in the left lateral decubitus position after ingestion of water improved detection and visualization of the worms in some cases. It is concluded that A lumbricoides in the small bowel has a sonographic appearance that can be recognized by the wary observer.

Adolescent↗

PubMed2000

APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits".

Although APC mutations occur at a high frequency in colorectal cancers, few studies have performed a comprehensive analysis by screening the whole gene for mutations and assessing allelic loss. APC seems to act as a tumor-suppressor gene in a "nonclassical" fashion: data from familial adenomatous polyposis (FAP) show that the site of the germ-line mutation determines the type of "second hit" in FAP tumors, and simple protein inactivation is selected weakly, if at all. In this study, we screened the entire coding region of APC for mutations and assessed allelic loss in a set of 41 colorectal cancer cell lines. Of 41 cancers, 32 (83%) showed evidence of APC mutation and/or allelic loss. We identified several APC mutations and found a "hotspot" for somatic mutation in sporadic colorectal tumors at codon 1,554. Our results suggest that APC mutations occur in the great majority of colorectal cancers, the exceptions almost all being RER+ tumors, which may substitute for altered APC function by mutations in beta-catenin and/or at other loci. When combined with previously published data, our results show that there is interdependence of the "two hits" at APC in sporadic colorectal tumors as well as in FAP. APC mutations in the "mutation cluster region," especially those close to codon 1,300, are associated with allelic loss, whereas tumors with mutations outside this region tend to harbor truncating mutations. The causes of this phenomenon are probably selection for retained N-terminal and lost C-terminal APC functions, effects on beta-catenin levels, and APC protein stability.

Base Sequence↗

PubMed2000

APC mutations are sufficient for the growth of early colorectal adenomas.

It is not clear whether APC mutations are sufficient for early colorectal adenomas to grow or whether additional mutations at other loci are required. We previously have screened 210 early colorectal adenomas from familial adenomatous polyposis patients for mutations and allelic loss at APC. Here, we determined whether allelic loss at APC had any effect on the nearby alpha-catenin gene. However, loss on 5q in familial adenomatous polyposis adenomas rarely extended as far as alpha-catenin, and no differences in alpha-catenin protein expression were found in tumors that showed loss encompassing both APC and alpha-catenin. We then screened all 210 tumors for mutations at candidate loci other than APC (K-ras, beta-catenin, and allelic loss at 1p33-p35 and 1p36) and for microsatellite instability (MSI). Each of these loci has been implicated previously in early colorectal tumorigenesis. One tumor harbored a beta-catenin mutation and another MSI, but none showed K-ras mutation or allelic loss at 1p33-p35 or 1p36. These data support the following hypotheses derived from sporadic colorectal tumors: beta-catenin mutations are generally an alternative to mutations at APC, MSI is not usually an early phenomenon in colorectal tumorigenesis, and K-ras mutations are more typical of large- and moderate-sized adenomas. Contrary to some previous reports, chromosome 1p allelic loss is infrequent in very early adenomas. APC mutations are generally sufficient for colorectal tumors to grow to about 1-cm diameter, although chance mutations at other loci can provide these early colorectal adenomas with a selective advantage, and some colorectal tumors may develop along a pathway not involving APC.

Adenoma↗

PubMed2000

Adhesion molecule expression in breast cancer: the phoenix in tumour metastasis?

Adhesion molecules have a number of diverse roles, amongst which is the control of tissue architecture and the maintenance of tissue integrity. Most tumours have an abnormal architecture and loss of tissue integrity is thought to be an important step in the development of local invasion. Thus, alterations in adhesion molecules may have a role in both tumour development and tumour invasion. The role of these molecules in the establishment of tumour metastases is much less certain. The tumour cells in a metastatic deposit are in a different environment and are faced with a different set of selection pressures, which may drive tumour evolution in a new direction. Metastatic deposits often resemble the tumour of origin and not infrequently show better differentiation. Together with evidence from experimental maintenance systems which shows that maintenance of intercellular contact may prevent apoptosis, this implies a role for adhesion molecules in tumour metastasis.

Breast Neoplasms↗

PubMed2000

The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea.

INTRODUCTION: Germline mutations in E-cadherin (CDH1) have been reported in families with early onset, diffuse gastric cancer. More recently, mutations in CDH1 have been described in colorectal cancer cell lines. AIMS: We have investigated if germline mutations in CDH1 occur among different groups of Korean gastric and colorectal cancer patients, with and without a positive family history. METHODS: We studied 131 patients and 168 normal controls (88 Korean and 80 non-Korean). Patients were divided into five groups: group I, 20 gastric cancer patients with a family history; group II, 26 colorectal cancer patients with a family history of gastric cancer (those from familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindred were excluded); group III, 16 HNPCC patients without identified germline mutations in hMLH1 and hMSH2; group IV, 35 gastric cancer patients without a family history; and group V, 34 colorectal cancer patients without a family history. Polymerase chain reaction, single strand conformational polymorphism analysis, direct sequencing, and genotyping for identified variants were performed. RESULTS: Several germline changes in CDH1 were found. In addition to previously described polymorphisms, we found three novel changes, two of which were missense changes (T340A and L599V). T340A was present in one patient in group III and one in group V. L599V was present in one patient in group II, in two in group III, and in one in group IV. T340A was not found in normal controls while L599V was present in two of 88 Korean controls. Patients with these variants may appear to have a tendency to early onset cancer with a positive family history, although differences in frequencies did not reach statistical significance. Genotyping results suggest that these variants might have a common origin, particularly T340A. CONCLUSION: We have described two new missense germline variants in CDH1 in various groups of Korean gastrointestinal cancer patients. Further work is required to assess if these variants increase the risk of gastrointestinal cancer.

Adolescent↗

PubMed2000

Urinary tract infection guidelines questioned.

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Child, Preschool↗

PubMed1999

Transforming growth factor beta stimulation of colorectal cancer cell lines: type II receptor bypass and changes in adhesion molecule expression.

The type II transforming growth factor (TGF)-beta receptor gene (TGFBR2) is often mutated in nucleotide repeat sequences in colorectal cancers that are replication error positive (RER+). These mutations are thought to be selected for escape from growth inhibition by TGF-beta rather than representing bystander events because of an increased mutation rate. We investigated the role of TGFBR2 mutations in 12 colorectal cancer cell lines. Six of these were RER+, and these were shown to have homozygous TGFBR2 mutations. All cell lines then were tested for changes in proliferation in response to TGF-beta stimulation. Despite homozygous mutation of the type II TGF-beta receptor, two RER+ cell lines, Lovo and SW48, showed statistically significant growth inhibition when stimulated by TGF-beta1 in serum-free conditions. This shows that the type II TGF-beta receptor can be bypassed in certain cases to maintain growth inhibition. We next investigated whether there was any alternative mode through which TGFBR2 mutation may give a selective advantage, such as a change in adhesion molecule expression. All cell lines were stimulated with TGF-beta1 and adhesion molecules detected by ELISA. No consistent changes were identified between the RER+ and the RER- cell lines, although changes in E-cadherin, beta-catenin, and gamma-catenin were identified in individual cell lines. We conclude that (i) type II TGF-beta receptor activity can be bypassed and thus TGFBR2 mutations in RER+ cancers may, at least sometimes, be just "bystander" events and (ii) TGF-beta can affect adhesion molecule expression so that TGFBR2 mutation may give rise to a selective advantage through an effect other escape from growth inhibition.

Cell Adhesion↗

PubMed1999

Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells.

Epithelial (E)-cadherin and its associated cytoplasmic proteins (alpha-, beta-, and gamma-catenins) are important mediators of epithelial cell-cell adhesion and intracellular signaling. Much evidence exists suggesting a tumor/invasion suppressor role for E-cadherin, and loss of expression, as well as mutations, has been described in a number of epithelial cancers. To investigate whether E-cadherin gene (CDH1) mutations occur in colorectal cancer, we screened 49 human colon carcinoma cell lines from 43 patients by single-strand conformation polymorphism (SSCP) analysis and direct sequencing. In addition to silent changes, polymorphisms, and intronic variants in a number of the cell lines, we detected frameshift single-base deletions in repeat regions of exon 3 (codons 120 and 126) causing premature truncations at codon 216 in four replication-error-positive (RER+) cell lines (LS174T, HCT116, GP2d, and GP5d) derived from 3 patients. In LS174T such a mutation inevitably contributes to its lack of E-cadherin protein expression and function. Transfection of full-length E-cadherin cDNA into LS174T cells enhanced intercellular adhesion, induced differentiation, retarded proliferation, inhibited tumorigenicity, and restored responsiveness to the migratory effects induced by the motogenic trefoil factor 2 (human spasmolytic polypeptide). These results indicate that, although inactivating E-cadherin mutations occur relatively infrequently in colorectal cancer cell lines overall (3/43 = 7%), they are more common in cells with an RER+ phenotype (3/10 = 30%) and may contribute to the dysfunction of the E-cadherin-catenin-mediated adhesion/signaling system commonly seen in these tumors. These results also indicate that normal E-cadherin-mediated cell adhesion can restore the ability of colonic tumor cells to respond to trefoil factor 2.

Animals↗

PubMed1999

Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas.

Mutations in the adenomatous polyposis coli or beta-catenin gene lead to cytosolic accumulation of beta-catenin and, subsequently, to increased transcriptional activity of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by beta-catenin overexpression, we used colorectal cell lines for transfection with the beta-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by beta-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun and fra-1, and for the urokinase-type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in beta-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of beta-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of beta-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, beta-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.

Adenocarcinoma↗

PubMed1999

Changes in the expression of syndecan-1 in the colorectal adenoma-carcinoma sequence.

Syndecan-1, a transmembrane heparan sulphate proteoglycan (HSPG), functions as a matrix receptor on the basal surface of epithelial cells. It also co-localizes with E-cadherin at the lateral cell surface where its function is uncertain. Tumour development in the large bowel is associated with loss of normal epithelial adhesion and altered patterns of expression of cell adhesion molecules, possibly including syndecan-1. To evaluate changes in syndecan-1 expression during the development of colorectal neoplasia, 59 adenomas and 20 carcinomas arising from adenomas were investigated by immunohistochemistry. The staining intensity and distribution of syndecan-1 and E-cadherin in sequential sections was examined, semi-quantified and compared. Staining of syndecan-1 and E-cadherin was uniform in normal colorectal epithelial cells, and located at the basolateral surface. No significant change was seen in either molecule in mildly or moderately dysplastic adenomas. A significant reduction in expression of both syndecan-1 and E-cadherin was seen in severely dysplastic epithelium as compared to moderate dysplasia (P = 0.001 and P = 0.004 respectively). Similarly, there was a significant reduction of both molecules in carcinomas compared with associated adenomas (syndecan-1 P = 0.00003; E-cadherin P = 0.002). In both cases the loss of syndecan-1 expression was more striking than that of E-cadherin. Previous in vitro studies have shown that epithelial cells made deficient in syndecan-1 cease to express E-cadherin, suggesting a causal association. Our results support these findings and indicate that disruption of cell-matrix adhesion is critical in colorectal carcinogenesis, probably preceding changes in the purely homotypic cell-cell adhesion mediated by E-cadherin.

Adenoma↗

PubMed1999

Genetic pathways in colorectal and other cancers.

Cells from cancers show aberrant behaviour such as unrestrained growth, invasion into adjacent tissue and metastasis. All these features of cancer cell behaviour can be explained in terms of genetic changes and the functional impact of these changes. In this review, colorectal cancer (CRC) is examined as a classical example of multistep carcinogenesis. First there is an overview which shows that cancers develop by a process of somatic evolution. This gives rise to preferred genetic pathways of tumorigenesis. The factors which may influence the development and ultimate choice of genetic pathways are then examined. Next, CRC is studied as a specific disease and the putative genetic pathways are described. The mutations that comprise these pathways and the possible functional sequelae of these are explored. The review concludes with a look at those avenues which may further elucidate the natural history of CRC and lead to improved therapy.

Colorectal Neoplasms↗

PubMed1999

Genetic pathways in colorectal and other cancers.

Cell Transformation, Neoplastic↗

PubMed1999

Expression of syndecan-1 in inflammatory bowel disease and a possible mechanism of heparin therapy.

Heparin apparently aids healing in ulcerative colitis although its mechanism of action is unknown. The purpose of this study was to investigate the hypothesis that heparin functions as a coreceptor molecule for basic fibroblast growth factor, a role usually performed by heparan sulfate chains on syndecan-1. A marked reduction of syndecan-1 immunostaining was found in reparative epithelium from inflammatory bowel disease patients. Removal of heparan sulfate on gastrointestinal epithelial cells in vitro reduced the proliferative response to basic fibroblast growth factor. The response to basic fibroblast growth factor was completely restored by the addition of heparin. Loss of syndecan-1 expression occurs in the regenerative mucosa in inflammatory bowel disease. Although this may facilitate tissue motility, its loss probably adversely affects the ability of cells to bind basic fibroblast growth factor. The present data show that heparin may substitute the loss of functional activity of syndecan-1 in the binding of basic fibroblast growth factor.

Cells, Cultured↗