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Biomedical subjects

S Ali

Publications and source records attributed to S Ali.

At least 73 records · Page 4Linked to original sources
PubMed2001

Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance.

Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression.

Animals↗
PubMed2001

Detection of Y chromosome-specific DNA in the plasma and urine of pregnant women using nested polymerase chain reaction.

The present study was undertaken to evaluate a nested polymerase chain reaction (PCR) for detection of Y chromosome-specific fetal DNA in maternal plasma and urine of pregnant women during different gestational stages. DNA isolated from plasma and urine samples of 80 pregnant women (between 7 and 40 weeks' gestation) underwent amplification for Y chromosome-specific 198 bp DNA by nested PCR. The postpartum analysis of fetal gender showed that 55 women carried male and 25 female fetuses. Among the 55 women bearing male fetuses, Y chromosome-specific signals were detected in 53 (96%) plasma and 21 (38%) urine samples. Moreover, out of 25 women bearing female fetuses, 3 (12%) and 1 (4%) women had Y chromosome-specific signal in plasma and urine, respectively. Analysis of results with respect to gestational age revealed that there was no significant difference in the detection of Y chromosome-specific DNA between different trimesters in maternal plasma of women bearing male fetuses. These results showed that fetus-specific DNA was detected with high sensitivity (96%) and specificity (88%) in the maternal plasma by nested PCR, and therefore the method could be useful as a non-invasive procedure for fetal sex determination and prenatal diagnosis.

Adult↗
PubMed2001

Allele loss on chromosome 1p36 in epithelial ovarian cancers.

OBJECTIVES: Prior studies have shown that allelic loss on chromosome 1p36 occurs frequently in ovarian as well as several other types of cancer. This suggests that inactivation of gene(s) in this region may play a role in the pathogenesis of these cancers. The aim of this study was to further delineate the region of loss on chromosome 1p36 in ovarian cancers and to identify associated patient or tumor characteristics. METHODS: Paired normal/cancer DNA samples from 75 ovarian cancers (21 early stage I/II and 54 advanced stage III/IV) were analyzed using microsatellite markers. RESULTS: Forty-nine of 75 (65%) ovarian cancers had loss of at least one marker. The marker demonstrating the most frequent loss was D1S1597, which was lost in 29/57 (51%) informative cases. Allele loss on 1p36 was significantly more common in poorly differentiated ovarian cancers (73%) relative to well or moderately differentiated cases (48%) (P = 0.03). Evidence was obtained for two common regions of deletion: one flanked by D1S1646/D1S244 and another more proximally by D1S244/D1S228. CONCLUSION: These findings further delineate regions on chromosome 1p36 proposed to contain tumor suppressor gene(s) that may play a role in the development and/or progression of epithelial ovarian carcinoma. Allele loss on 1p36 is associated with poor histologic grade.

Alleles↗
PubMed2001

Minisatellite associated sequence amplification (MASA) of the hypervariable repeat marker 33.15 reveals a male specific band in humans.

The 16-nt (5' CACCTCTCCACCTGCC 3') consensus sequence of the hypervariable repeat marker 33.15 was used as primer to conduct minisatellite associated sequence amplification (MASA) of human genomic DNA. MASA detected a 513-bp Y chromosome specific band in males as well as a number of variable bands ranging from 260-2700 bp in both the sexes. Overall polymorphism of the variable alleles was low with the band sharing probability of identity being 1.04x10(-4). Cloning and sequence analysis of the male specific band (GenBank accession no. AF134482) showed a high level (60-80%) of sequence homology with several human Y chromosome derived clones. Similar analysis of Indian rhinoceros (Rhinoceros unicornis) genomic DNA showed male specific isomorphic band though of different size. This assay may provide a useful method for the detection of Y chromosome related heterochromatic sequences in human and other vertebrates.

Animals↗
PubMed2001

Use of markers of bone turnover for monitoring bone metastases and the response to therapy.

Metastatic bone disease is a frequent complication of breast and other cancers, resulting in skeletal complications that are a significant cause of morbidity and mortality. Bone metastases can be difficult to diagnose radiologically and it can also be difficult to evaluate patients' response to treatment by using the methods that are currently available (radiography, bone scans, and computed axial tomography scans). These are relatively insensitive procedures, thus, there is a requirement for new methods for assessing bone response to ensure patients benefit from the optimum type and duration of treatment. Biochemical markers of bone turnover, such as N-telopeptide and the pyridinium cross-links pyridinoline and deoxypyridinoline, may provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in cancer patients who have documented evidence of metastatic bone disease. Increased levels are also observed in some patients without clinical evidence of bone metastases, when compared with normal subjects. Rises in such markers may be the first indication of bone involvement and therefore may potentially be useful in early diagnosis of progression. Preliminary data suggest bone marker level correlates with the extent of metastatic disease and the number of skeletal sites involved. Markers of bone turnover may be helpful in identifying those patients likely to respond to bisphosphonate treatment. Such markers are also potentially useful in monitoring the effectiveness of bisphosphonate therapy in the management of bone metastases, in both patients with metastatic breast disease and multiple myeloma.

Amino Acids↗
PubMed2001

Estimation of radon concentrations in coal mines using a hybrid technique calibration curve.

The results of epidemiological studies in various countries show that radon and its progeny cause carcinogenic effects on mine workers. Therefore, it becomes of paramount importance to monitor radon concentrations and consequently determine the radon dose rates in coal mines for the protection of coal miners. A new calibration curve was obtained for radon concentration estimation using hybrid techniques. A calibration curve was generated using 226Ra activity concentration measured by a HPGe detector-based gamma-ray spectrometer versus alpha-track-density rate due to radon and its progeny on CR-39 track detector. Using the slope of the experimentally determined curve in the units of Becqueral per kilogram (Bq kg-1) per unit alpha-track-density per hour (cm-2 h-1), radon concentrations (Bq m-3) were estimated using coal samples from various coal mines in two provinces of Pakistan, Punjab and Balochistan. Consequently, radon dose rates were computed in the simulated environment of the coal mines. Results of these computations may be considered with a caveat that the method developed in this paper provides only a screening method to indicate the radon dose in coal mines. It has been shown that the actual measurements of radon concentrations in the coal mines are in agreement with the estimated radon concentrations using the hybrid-technique calibration curve.

Calibration↗
PubMed2001

Assessment of a two-generation reproductive and fertility study of mercuric chloride in rats.

Effects of mercuric chloride (MC) on the reproductive performance of two successive generations of rats was evaluated. F(0) rats were exposed to 0.0:0.0 (males:females), 0.50:0.75 (males:females), 1.00:1.50 (males:females) and 1.50:2.50 (males:females) mg/kg/day MC. Selected parental F(1) males and females were exposed to the same doses received by their parents (F(0)). Significant differences resulting from exposure of the F(0) generation to MC were found in implantation efficiency, fertility, live births and day 4 survival indices, litter size, and the body weight of F(1) pups. However, the continued exposure of the F(1) generation to MC did not affect fertility index or litter size, but did significantly affect implantation efficiency, live births and day 4 survival indices. In F(0) males, body weight and weights of the kidneys, testes, epididymides, prostate and seminal vesicles were significantly different, while in F(1) males, body weight, kidney weight, brain weight, liver weight and the weights of the testes, prostate and seminal vesicles were significantly different. In F(0) females, body weight and the weights of the kidneys, brain and liver were significantly different, while in F(1,) females, body weight, as well as the weights of the kidneys, liver, adrenals, uterus and ovaries were significantly different. These data showed that exposure to MC resulted in more adverse reproductive effects in the first generation and that these effects moderated in the second generation.

Animals↗
PubMed2001

Prospective association of lipoprotein(a) concentrations and apo(a) size with coronary heart disease among men in the Multiple Risk Factor Intervention Trial.

In this nested case-control study, lipoprotein (a) [Lp(a)] concentrations and apo(a) isoform size were measured in serum samples obtained from men participating in the prospective Multiple Risk Factor Intervention Trial (MRFIT). Serum from men aged 35 to 57 years and stored for up to 20 years were analyzed for Lp(a) levels (n=736) and isoform size (n=487), respectively. Cases involved nonfatal myocardial infarctions (MI; n=98), documented during the active phase of the study that ended on February 28, 1982 and coronary heart disease (CHD) deaths (n=148) monitored through 1990. Median Lp(a) levels did not differ between cases and controls and mean apo(a) size did not vary between cases and controls in the entire study population. When adjusted for age and Lp(a) concentration, logistic regression analysis indicated that small apo(a) isoforms were associated with CHD deaths among smokers (OR 3.31; 95% CI 1.07-10.28).

Adult↗
PubMed2001

Retroviral infection of the FGF2 gene into MCF-7 cells induces branching morphogenesis, retards cell growth and suppresses tumorigenicity in nude mice.

FGF2 (basic fibroblast growth factor) is a multifunctional growth factor and exhibits diverse function in different cell types. In breast, loss of FGF2 expression is associated with malignant progression. In order to understand the role of FGF2 in maintenance of normal breast structures and control of cell growth, we restored FGF2 expression in the breast cancer cell line MCF-7. The FGF2 retrovirally infected MCF-7 cells (MCF-7.F2.5) not only expressed FGF2 in cytoplasm and nuclei, but also released FGF2 into culture medium both on plastic and in Matrigel conditions. The MCF-7.F2.5 cells formed branches in Matrigel and this effect was abolished by the addition of a neutralising anti-FGF2 antibody or function blocking antibodies to alpha2, alpha3 and beta1 integrins. Furthermore, MCF-7.F2.5 cells lost their ability for anchorage-independent growth in soft agar. When MCF-7 and MCF-7.F2.5 cells were injected into nude mice, there was a 1.6- to 3.2-fold reduction of tumour volume with MCF-7.F2.5 cells in comparison with the parental MCF-7 cells. MCF-7.F2.5 cells also demonstrated a reduction in oestrogen receptor-alpha (ERalpha) both in vitro and in vivo. Our results suggest that introduction of the FGF2 gene into MCF-7 cells altered the malignant tumour cells towards a more benign phenotype in vitro and in vivo.

Animals↗
PubMed2001

The 3' non-coding region of a C4 photosynthesis gene increases transgene expression when combined with heterologous promoters.

The Me1 gene of the dicot Flaveria bidentis encodes NADP malic enzyme, which catalyses the decarboxylation reaction of C4 photosynthesis in bundle sheath cells. We have previously shown that the 3' non-coding region (Me1 3') controls quantitative expression of the gene. We wondered whether Me1 3' can increase expression when combined with heterologous promoters. We tested a highly expressed, constitutive promoter, the S4 promoter from subterranean clover stunt virus, and a highly expressed, leaf-specific promoter, the light-harvesting chlorophyll a/b-binding protein gene 3 (Lhcb3) promoter of Arabidopsis thaliana. Promoter-3'-end combinations were tested in transgenic C4 Flaveria plants and C3 tobacco. We found that Me1 3' increased expression of the gusA reporter gene several-fold in leaves of both species in combination with either of the promoters. In both cases Me1 3' does not alter the expression pattern for either promoter. We conclude that Me1 3' can be used as a transcription terminator to increase transgene expression in C3 dicot plants.

3' Untranslated Regions↗
PubMed2001

Quantitative regulation of the Flaveria Me1 gene is controlled by the 3'-untranslated region and sequences near the amino terminus.

The Me1 gene of Flaveria bidentis codes for the C4 isoform of NADP malic enzyme, which accumulates to a high-level only in bundle sheath cells. Previous experiments demonstrated that sequences at the 5' end of the gene control cell specificity whereas sequences at the 3' end are necessary for high-level expression. To localize quantitative regulator sequences, we have analysed a series of Me1 3' deletion constructs fused to the gusA reporter gene. We show that sequences within the 3'-untranslated region (3'-UTR) control quantitative levels of expression. Analysis of 5' promoter fusions demonstrated that high-level expression also requires sequences within the N-terminal coding region of the gene, suggesting possible interactions between the 3'-UTR and 5' coding regions. Cell-specific regulatory sequences are located in a different part of the 5' end of the gene, between 1023 bp upstream of the transcription start and the start of translation.

3' Untranslated Regions↗
PubMed2001

C-type natriuretic peptide (CNP) regulates cocaine-induced dopamine increase and immediate early gene expression in rat brain.

The neuropeptide C-type natriuretic peptide (CNP) is the primary biologically active natriuretic peptide in brain. Using in situ hybridization, the present report demonstrates that CNP regulates egr-1, c-fos and junB immediate early gene expression in rat brain. In the frontal cortex, CNP induced immediate early gene expression whereas it inhibited dose-dependently the cocaine-induced early gene expression in the dopaminergic projection fields nucleus accumbens and caudate-putamen. CNP may produce its effect directly on dopaminergic neurons because we found that its receptor, guanylyl cyclase GC-B, was expressed in the mesencephalon where dopaminergic neurons originate, as well as in their projection fields. The inhibition by CNP of the early gene expression elicited by cocaine in the caudate-putamen is correlated with a CNP-evoked decrease in cocaine-induced rise in extracellular dopamine, measured by in vivo microdialysis experiments. The significance of the inhibition of cocaine-induced dopamine release and early gene induction by the endogenous peptide CNP is demonstrated by data indicating that CNP reduced the cocaine-induced spontaneous locomotor activation. By inhibiting dopaminergic neuronal activity, CNP represents a potential negative regulator of related behavioural effects of cocaine.

Animals↗
PubMed2001

Accelerating the induction of Fas-mediated T cell apoptosis: a strategy for transplant tolerance?

Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction of specific tolerance after organ transplantation.

Apoptosis↗
PubMed2001

Proteinuria in obstructive sleep apnea.

BACKGROUND: Previous studies have reported an association between obstructive sleep apnea (OSA) and proteinuria, but are limited in their ability to assess proteinuria accurately, to adjust for confounders such as obesity, or to exclude confidently underlying renal disease in patients with OSA and nephrotic-range proteinuria. METHODS: The spot urine protein/creatinine ratio was measured in a prospective consecutive series of 148 patients referred for polysomnography who were not diabetic and had not been treated previously for OSA. The urine protein/creatinine ratio was compared across four levels of OSA severity, based on the frequency of apneas and hypopneas per hour: <5 (absent), 5 to 14.9 (mild), 15 to 29.9 (moderate), and > or =30 (severe). RESULTS: The median level of urine protein/creatinine ratio in all categories of OSA was <0.2 (range 0.03 to 0.69; median 0.06 in patients with normal apnea hypopnea index, 0.06, 0.07, 0.07 in patients with mild, moderate, and severe OSA, respectively). Eight subjects had a urine protein/creatinine ratio greater than 0.2. Univariate analysis showed a significant association between urine protein/creatinine ratio and older age (P < 0.0001), hypertension (P < 0.0001), coronary artery disease (P = 0.003), and arousal index (P = 0.003). Body mass index (P = 0.16), estimated creatinine clearance (P = 0.17), and apnea hypopnea index (P = 0.13) were not associated with the urine protein/creatinine ratio. In multiple regression analysis, only age and hypertension were independent positive predictors of the urine protein/creatinine ratio (P < 0.0001, R2 = 0.17). CONCLUSION: Clinically significant proteinuria is uncommon in sleep apnea. Nephrotic range proteinuria should not be ascribed to sleep apnea and deserves a thorough renal evaluation.

Adult↗
PubMed2001

Treatment of psoriasis. Part 1. Topical therapy and phototherapy.

UNLABELLED: New developments in the topical therapy and phototherapy of psoriasis have greatly improved our ability to safely and effectively treat this debilitating disease. Topical corticosteroids remain the most commonly prescribed agents for psoriasis, but they are frequently prescribed with other agents. Investigations of corticosteroids claiming an improved benefit/risk ratio have yielded promising results, but more work is needed. Use of anthralin and tar has declined with the availability of the noncorticosteroids calcipotriene and tazarotene. Other experimental topical therapies are in various stages of development. Broadband ultraviolet B (UVB) remains the most commonly used phototherapy light source, but many patients are being treated with a new form of ultraviolet light, narrowband UVB. Although PUVA remains one of the most effective psoriasis treatments, its use is declining because of its association with cutaneous malignancies. New radiation sources such as lasers have been added to our armamentarium of available therapies and even newer light source-based treatments are being examined. LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be familiar with the varying topical treatments for psoriasis as well as the different modalities of phototherapy. Participants should also have a better understanding of side effects associated with each treatment, which should help in determining options for therapy.

Administration, Topical↗
PubMed2001

Treatment of psoriasis. Part 2. Systemic therapies.

The array of systemic medications used in the treatment of psoriasis is rapidly expanding. In the United States, methotrexate, retinoids, and cyclosporine are the only systemic drugs approved by the Food and Drug Administration for the treatment of psoriasis. Monitoring and dosage recommendations for these medications are reviewed. Other drugs that are currently available include tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, and sulfasalazine. Experience with these drugs is summarized, and dosage and monitoring recommendations in published literature are presented. Combinations of different treatments are addressed and investigational therapies that are in development are reviewed.

Cyclosporine↗
PubMed2001

Satellite-tagged transcribing sequences in Bubalus bubalis genome undergo programmed modulation in meiocytes: possible implications for transcriptional inactivation.

We cloned and sequenced a 1378 bp BamHI satellite DNA fraction from the water buffalo Bubalus bubalis and have studied its expression in different tissues. The GC-rich sequences of the resultant contig pDS5 crosshybridize only with bovid DNA and are not conserved evolutionarily. Typing of buffalo genomic DNA using pDS5 with several restriction enzymes revealed multilocus monomorphic bands. Similar typing of cattle, buffalo, goat, sheep, and gaur genomic DNA revealed variations in copy number and allele length giving rise to species-specific band patterns. Expression study of pDS5 in bubaline samples by RNA slot-blot, Northern blot, and RT-PCR showed various levels of signal in all the somatic tissues and germline cells except heart. A GenBank database search revealed homology of pDS5 sequences in the 5' region from nt 1-1261 with collagen gene. An AluI typing analysis of DNA from bubaline semen samples showed consistent loss of two bands. The presence of corresponding bands in somatic tissues suggests a sequence modulation within the pDS5 array in meiocytes during spermatogenesis, which is restored in the somatic cells after fertilization. Modulation of the satellite-tagged transcribing sequence in the meiocytes may be a mechanism of its inactivation.

Animals↗