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F Al-Mulla

Publications and source records attributed to F Al-Mulla.

12 recordsLinked to original sources
PubMed2006

Metastatic recurrence of early-stage colorectal cancer is linked to loss of heterozygosity on chromosomes 4 and 14q.

OBJECTIVE: To investigate the prognostic value for loss of heterozygosity (LOH) of chromosomes 4 and 14q in early-stage colorectal cancer (CRC). METHODS: A total of 70, largely microsatellite stable, tumours and their corresponding normal mucosa were subjected to microdissection and analysed for LOH at chromosomes 4 and 14q by using 13 highly polymorphic microsatellite markers. LOH was correlated with the survival of the patients, using univariate, multivariate and Kaplan-Meier's survival curves. RESULT: LOH at D4S2935, D4S1579 and D4S1595 on chromosome 4 was significantly associated with metastatic recurrence of early-stage CRC. For chromosome arm 14q, two minimal regions of deletion were associated with metastatic recurrence and mapped to neighbouring markers D14S275/D14S49 at 14q12-13 and D14S65/D14S250 at 14q32. High-level loss (loss of five to eight of the informative microsatellite markers) on both chromosomes 4 and 14q, to be an independent prognostic indicator in early-stage CRC was shown by multivariate analysis. CONCLUSION: Determining the LOH of chromosomes 4 and 14q and their extent in primary tumours of patients with early-stage CRC may constitute a molecular signature of metastatic recurrence. This may be achieved if new finding sheds light on the treatment of this subgroup of patients that have been largely ignored.

Aged↗
PubMed2004

Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats.

Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.

Animals↗
PubMed2003

Expressive genomic hybridisation: gene expression profiling at the cytogenetic level.

AIMS: To describe a cytogenetic technique suitable for the rapid assessment of global gene expression that is based on comparative genomic hybridisation (CGH), and to use it to understand the relation between genetic amplifications and gene expression. METHODS: Whereas traditional CGH uses DNA as test and reference in hybridisations, expressive genomic hybridisation (EGH) uses globally amplified mRNA as test and normal DNA as reference. EGH is a rapid and powerful tool for localising and studying global gene expression profiles and correlating them with loci of genetic amplifications using traditional CGH. RESULTS: EGH was used to correlate genetic amplifications detected by CGH with the expression profile of two independent cell lines-Colo320 and T47D. Although many amplifications resulted in overexpression, other amplifications were partially or completely silenced at the cytogenetic level. CONCLUSION: This technique will assist in the analysis of overexpressed genes within amplicons and could resolve a controversial issue in cancer cytogenetics; namely, the relation between genetic amplifications and overexpression.

Cell Line↗
PubMed2001

Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer.

We have recently reported a novel function for carbonyl reductase (CR), namely, its ability to modulate the metastatic potential of malignant mouse cells. Because there are currently no data addressing a similar function for CR in human cancers, the aim of this study was to assess a correlation between survival and metastasis, and CR level in epithelial ovarian cancer. Using anti-CR antibody, immunohistochemical staining was performed on 73 epithelial ovarian cancers, 13 borderline malignant tumours, and 25 benign ovarian tumours for a total of 111 specimens. The combined rate for strongly and weakly positive reactions for CR was 32.0% for benign tumours, 38.5% for borderline malignant tumours, and 61.6% for ovarian cancers. The CR-positive rate was 35.7% (weakly positive alone) for ovarian cancers with retroperitoneal lymph node (RLN) metastasis and 67.8% for those without RLN metastasis (P< 0.05). The 5-year survival rate was 62.7% for the patients with CR-negative cancer and 86.1% for those with CR-positive cancer (P< 0.05). The present results indicate that decreased CR expression in epithelial ovarian cancer is associated with RLN metastasis and poor survival.

Adult↗
PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗
PubMed2001

Differences in in vitro invasive capacity induced by differences in Ki-Ras protein mutations.

The p21 proteins encoded by N-, Ki-, and H-ras are small guanine nucleotide-binding proteins that act as switches in several signal transduction pathways. Recently, evidence has been accumulating to suggest that valine-12 mutation in the Ki-Ras protein is associated with lung and colorectal tumours that are more aggressive than those carrying aspartate-12 mutation. The purpose of this study was to determine whether cells transfected with different Ki-ras codon-12 mutants have different biological behaviours in vitro that could reflect the differences in behaviour in vivo. For that reason, Rat-1 fibroblasts transfected with the valine-12 or aspartate-12 mutant or the wild-type Ki-ras gene were assessed in terms of in vitro invasion, transformation, and VEGF production. Both mutants demonstrated equal abilities to transform Rat-1 cells and induce VEGF production, while cells transfected with wild-type Ki-Ras failed to do so. Most significantly, the valine-12 mutants demonstrated a greater ability to invade Matrigel than cells expressing the aspartate-12 mutant or wild-type Ki-Ras proteins. This study complements previous experimental data that specific Ras mutations differ in their effects in vivo and shows, for the first time, a significant difference in Matrigel invasion in vitro. The precise mechanisms behind these biological differences in vivo and in vitro should now be investigated.

Aspartic Acid↗
PubMed2000

Carbonyl reductase: a novel metastasis-modulating function.

To explore reasons for differences in the malignancy of tumors, we have compared two cell lines derived from a mouse lung adenocarcinoma cell line that differ 10-fold in their capacity to form lung metastases from s.c. primary tumors or after i.v. injection. One mRNA encoding carbonyl reductase was identified at a relatively high abundance in the subline with low metastatic capacity but was not detectable in the highly metastatic subline. Transfection of the former subline with a plasmid construct expressing antisense carbonyl reductase rendered the cells highly metastatic. Conversely, the capacity of the highly metastatic cells to metastasize was markedly reduced after transfection with a construct expressing carbonyl reductase. We also found that human prostate cancers show loss of carbonyl reductase expression compared with normal prostate epithelia. These data suggest that carbonyl reductase has an important function in modifying the metastatic behavior of malignant tumors.

Adenocarcinoma↗
PubMed1999

Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression.

Recent evidence associates the codon 12 valine-for-glycine (G12V) mutant Ki-Ras protein with higher stage and increased lethality of colorectal carcinomas, while the codon 12 aspartate-for-glycine (G12D) Ras mutation shows no such association. Several observations may be relevant to this phenomenon. First, GTPase activity of G12V Ras is one-quarter that of G12D Ras and one-tenth that of wild-type (WT) Ras. Second, binding of the GTP analogue GppNp to G12D Ras is 8-fold weaker than its binding to G12V or WT Ras and crystal structures indicate that electrostatic repulsion between the carboxylate group of the G12D Asp-12 side-chain and the gamma phosphate of the bound nucleotide may make GTP binding to G12D Ras weaker even than that of GppNp. It is proposed that this lowering of affinity for GTP allows G12D Ras an escape from the oncogenic GTP-bound state, whereas GTP tightly bound to G12V mutant Ras generates a more persistent, potentially oncogenic, signal. Structural comparisons also suggest that differences between the Switch I (effector) region of G12D and G12V Ras could modify interactions with downstream signalling molecules such as Raf-1, neurofibromin, and phosphatidylinositol 3-hydroxy-kinase. Other differences between the G12D and G12V mutant Ras proteins include a lower affinity of the GTPase activating protein GAP for G12V than for G12D or WT Ras; but, as both G12D and G12V Ras are refractory to GTPase activation by GAP binding, this may be less significant. These studies complement experimental data showing that such Ras mutations differ in their effects in vitro and in vivo and, with recent data indicating heterogeneity of ras mutation in colorectal carcinomas and other tumours, make it plausible that codon 12 Ras mutations differ in carcinogenic potential and prognostic significance.

Aspartic Acid↗
PubMed1999

Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases.

We have analyzed 26 tumors from 12 patients with metastatic colorectal adenocarcinoma by comparative genomic hybridization (CGH). Primary tumors and their lymph node metastases from five Dukes' C patients as well as primary tumors and their liver metastases from seven Dukes' D patients were used to assess the extent of genetic differences between primary and secondary colorectal carcinomas from the same patients, to calculate the degree of clonal divergence and genetic heterogeneity in metastatic colorectal cancer, and to determine the differences in genetic imbalances between Dukes' C and D stage tumors. We show that the same genetic aberrations were frequently found in the primary tumors and their metastases. However, metastases often contained genetic aberrations not found in the corresponding primary tumors. The comparison of Dukes' stages C and D revealed genetic aberrations common to both. However, reduced copy number of chromosome arm 17p (5/5 vs. 0/7; P = 0.001) was significantly associated with Dukes' stage C and lymph node metastases, while increased copy number of chromosome arms 6p (6/7 vs. 0/5; P = 0.007) and 17q (5/7 vs. 0/5; P = 0.027) was associated more with Dukes' stage D and liver metastases. Our results established a repertoire of chromosomal alterations associated with metastatic colorectal cancer and suggest that Dukes' C (lymph node metastasis) tumors are not always simply an earlier stage of Dukes' D (liver metastasis) tumors and, thus, in some instances at least, they are distinct forms of the disease.

Carcinoma↗
PubMed1998

Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality.

The point mutations occurring in codons 12 and 13 of Ki-ras in 78 patients with colorectal carcinoma (31 Dukes' A and B, 21 Dukes' C, and 26 Dukes' D) have been determined by allele-specific oligonucleotide hybridization and sequencing. Duplicate samples of invasive primary carcinoma, adjacent normal tissue, and available lymph node and liver metastases from the same patients were microdissected from paraffin sections. There were no differences in the mutation rate between primary carcinomas and secondary deposits: 26 of 78 (33 per cent) primary carcinomas, 10 of 32 (31 per cent) lymph node metastases, and 10 of 26 (38 per cent) liver metastases. Multiple sampling revealed frequent heterogeneity within carcinomas: 9 of 26 primaries with Ki-ras mutations also contained areas of carcinoma with only the wild-type gene, implying that Ki-ras mutation, even when present in a colonic carcinoma, may not have been necessary for establishing the malignant phenotype. Also, 2 of 26 (8 per cent) Dukes' D patients had a mutation in their primary carcinoma but none in liver metastases and 6 of 47 (13 per cent) Dukes' C and D patients had mutations in liver or lymph node metastases but none in the primary carcinoma. Such heterogeneity may modify the effectiveness of novel therapies targeting mutant Ki-ras function, such as farnesyltransferase inhibition. Mutation of codon 12 from GGT (glycine) to GTT (valine) was more prevalent in primary and metastatic deposits of Dukes' C/D carcinomas (P = 0.01) than in primary carcinomas from Dukes' A/B patients. Mutations of codon 12 to GAT, AGT, GCT and codon 13 GGC to GAC were also found, but no correlation with carcinoma aggressiveness was apparent. Follow-up of 71/78 patients (up to 12 years) revealed decreased overall survival (P = 0.001) in patients with the GGT to GTT transversion in codon 12, even when the analysis was restricted to Dukes' D cases, supporting the suggestion that this mutation may confer a more aggressive phenotype in colorectal carcinoma.

Adenocarcinoma↗
PubMedDate not supplied

BRCA1 gene expression in breast cancer in Kuwait: correlation with prognostic parameters.

OBJECTIVES: This study assessed the BRCA1 gene expression in breast cancer in Kuwait, and compared it with other known prognostic factors for the disease. MATERIALS AND METHODS: Forty-eight random samples of archival paraffin-embedded breast cancer tissues were studied for BRCA1 gene expression. Immunohistochemical method utilizing antibodies against different epitopes on the BRCA1 protein was used to study BRCA1 protein expression. In addition, for 29 patients, reverse transcription-polymerase chain reaction was used to detect BRCA1 mRNA expression. BRCA1 expression was correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor status, and C-erbB-2 expression. RESULTS: No demonstrable BRCA1 mRNA and protein expression was found in 79 and 83% of the breast cancer tissues, respectively. A positive relationship was demonstrated between lack of BRCA1 (mRNA and protein) expression and high histological grade, negative estrogen and progesterone receptor status, and overexpression of C-erbB-2 in the breast cancer tissues. CONCLUSIONS: The study demonstrated lack of BRCA1 gene expression (mRNA and protein) in the majority of breast cancers in Kuwait and confirmed the inverse relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer.

Adult↗