PubMed Health⌕ Search

Biomedical subjects

El-Nasir Lalani

Publications and source records attributed to El-Nasir Lalani.

At least 19 recordsLinked to original sources
PubMed2006

Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy.

Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers.

Administration, Cutaneous↗
PubMed2006

Changes in vascular flow after transdermal oestradiol therapy for prostate cancer: a mechanism for cardiovascular toxicity and benefit?

OBJECTIVE: To report the influence of transdermal oestradiol therapy on the vascular dynamics of men with advanced prostate cancer. PATIENTS AND METHODS: Twenty patients with newly diagnosed locally advanced or metastatic prostate cancer (10 each) were treated using transdermal oestradiol patches. The vascular flow was assessed 6-monthly before and during a year of therapy using arterial and venous Doppler and duplex ultrasonography, arterial and venous photoplethysmography and opto-electronic plethysmography. RESULTS: Arterial flow, as measured by the mean and peak systolic velocities and photoplethysmography, significantly increased over time. Arterial compliance initially decreased but had normalized after 12 months. The venous variables were unaffected. As a result, the total limb blood flow and the capillary filtration rate were significantly increased. CONCLUSION: Transdermal oestradiol therapy causes an increase in arterial but not venous flow, and an initial decrease in arterial compliance, which adapts to the physiological range with time. It is possible that these changes may account for the increase in cardiovascular toxicity seen in the early phase of oestrogen therapy, and the cardioprotective effect that accrues thereafter.

Administration, Cutaneous↗
PubMed2006

p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo.

To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.

Animals↗
PubMed2005

Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism.

PURPOSE: Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. MATERIALS AND METHODS: A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. RESULTS: Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. CONCLUSIONS: These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis.

Administration, Cutaneous↗
PubMed2005

Trefoil factor 2 (TFF2) deficiency in murine digestive tract influences the immune system.

BACKGROUND AND AIMS: The gastrointestinal trefoil factor family (TFF1, TFF2, TFF3) peptides are considered to play an important role in maintaining the integrity of the mucosa. The physiological role of TFF2 in the protection of the GI tract was investigated in TFF2 deficiency. METHODS: TFF2-/- mice were generated and differential expression of various genes was assessed by using a mouse expression microarray, quantitative real time PCR, Northern blots or immunohistochemistry. RESULTS: On an mRNA level we found 128 differentially expressed genes. We observed modulation of a number of crucial genes involved in innate and adaptive immunity in the TFF2-/- mice. Expression of proteasomal subunits genes (LMP2, LMP7 and PSMB5) involved in the MHC class I presentation pathway were modulated indicating the formation of immunoproteasomes improving antigen presentation. Expression of one subunit of a transporter (TAP1) responsible for importing degraded antigens into ER was increased, similarly to the BAG2 gene that modulates chaperone activity in ER helping proper loading on MHC class I molecules. Several mouse defensin (cryptdin) genes coding important intestinal microbicidal proteins were up-regulated as a consequence of TFF2 deficiency. Normally moderate expression of TFF3 was highly increased in stomach.

Animals↗
PubMed2005

Expression of hepatocyte growth factor and its receptor c-met, correlates with severity of pathological injury in experimental alcoholic liver disease.

Expression of hepatocyte growth factor (HGF) and its receptor, c-met is up-regulated in various forms of liver injury. This study evaluated the relationship between HGF and c-met expression and pathological changes in experimental alcoholic liver disease. Rats (5 per group) were fed ethanol and a diet containing saturated fat corn oil or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In a second set of experiments, Kupffer cells, endothelial cells and hepatocytes were isolated from rats in each group. Pathological evaluation and analysis of HGF and c-met expression were performed in liver and the different cell types. Increased expression of HGF and c-met expression was detected in the liver of rats showing necroinflammatory changes. The Kupffer and endothelial cells were primarily responsible for the increase in HGF, c-met expression was seen only in hepatocytes. Thus, up-regulation of HGF and c-met occurred in the presence of the necrosis and inflammation suggesting that HGF may be acting to protect against liver injury or accelerate the regenerative process.

Animals↗
PubMed2004

Transcriptional control of TFF3 (intestinal trefoil factor) via promoter binding sites for the nuclear factor kappaB and C/EBPbeta.

The acute phase response is strictly connected with modulation of gene expression. Transcriptional control of many genes is mediated by binding of diverse transcription factors to cis-acting DNA motifs in the respective promoter sequence. We now describe such regulatory elements for the TFF3 gene coding for a peptide involved in response to gut irritation. TNF-alpha stimulation, which induces NF-kappaB activation, evoked up to 10-fold reduction of TFF3 expression in the colon tumour cell line HT-29. Several consensus binding sites for members of the NF-kappaB transcription factor subunits are located in the 5'-flanking region of TFF3. Mutating these sites was aimed at discovering which one is responsible for NF-kappaB binding and thus regulation of TFF3 expression.

CCAAT-Enhancer-Binding Proteins↗
PubMed2004

TFF2 (trefoil family factor2) inhibits apoptosis in breast and colorectal cancer cell lines.

We have recently demonstrated that human TFF2 inhibits apoptosis in the non-TFF2 expressing breast adenocarcinoma cell line MCF-7. In this study we examined the impact of TFF2 and an anti-TFF2 antibody (hSP3) on the survival of other human adenocarcinoma cell lines; TFF2-positive (LS174T and SW480) and TFF2-negative (MCF-7 and T47D). Addition of TFF2 protected the (TFF2-) lines but had no effect on those constitutively expressing TFF2. Blocking with hSP3 significantly increased apoptosis in the (TFF2+) cell lines with minimal effect on the (TFF2-) cells. Our results show that the cytoprotective effect of TFF2 seen in MCF-7 cells is not cell line-specific and can be abrogated by inhibition of its expression.

Antibodies↗
PubMed2004

TFF1 is membrane-associated in breast carcinoma cell line MCF-7.

Trefoil factor family (TFF) domain peptides, products of mucin-secreting epithelial cells, are thought to influence mucosal integrity. Molecular studies revealed that mammalian TFFs lack transmembrane domains. Using immunocytochemistry and FACS analysis we demonstrated the association of TFF1 with the cell membrane in MCF-7 (a breast adenocarcinoma cell line), and tested the hypothesis that glycosylphosphatidylinositol (GPI) linkage is the mechanism for this association. Cleavage of GPI anchorage using phospholipase C did not affect TFF1 binding to the cell membrane. Our results demonstrate for the first time that TFF1 is associated with the cell membrane of MCF-7 cells and is not linked via a GPI anchor.

Breast Neoplasms↗
PubMed2004

Differential effects of toremifene on doxorubicin, vinblastine and Tc-99m-sestamibi in P-glycoprotein-expressing breast and head and neck cancer cell lines.

The effect of toremifene on P-glycoprotein-mediated multidrug resistance (MDR) in breast and head and neck cancer cell lines was measured in vitro and in vivo. Pgp expression was low and high, respectively, in drug-sensitive (MCF7-S, KB) and drug-resistant (MCF7-R, MCF7-R1, KBV1) cell lines. Toremifene (7.5 microM) significantly enhanced cytoplasmic and nuclear accumulation of doxorubicin in drug-resistant cells. Toremifene (10 microM) increased the in vitro cytotoxicity of doxorubicin in drug-resistant breast cancer cells (13-fold and 21-fold for MCF7-R and MCF7-R1, respectively) without affecting the sensitivity of MCF7-S cells. Similarly, toremifene (10 microM) caused a 12-fold increase in the sensitivity of KBV1 cells to vinblastine. In contrast, toremifene (5 microM) reduced the net uptake of the radiolabelled Pgp substrate, Tc-99m-sestamibi, in the Pgp-overexpressing cell lines by factors of 0.32 and 0.42 for MCF7-R1 and KBV1 cells, respectively (p < 0.01), and, to a lesser extent, by corresponding factors of 0.89 and 0.86 in the drug-sensitive cell lines (p < 0.05 and p > 0.05, respectively). In nude mice bearing both KB and KBV1 xenograft tumours, significantly higher tumour levels of Tc-99m-sestamibi were recorded in KB tumours compared with KBV1 tumours. After 3 days of treatment with intraperitoneal toremifene (25 mg/kg), tumour levels of Tc-99m-sestamibi were reduced in KB and KBV1 tumours but only statistically significantly for KB tumours. Toremifene is a potent MDR modulating agent with respect to chemotherapeutic agents but has the opposite effect with respect to Tc-99m-sestamibi. This finding is of importance in view of the widespread use of Tc-99m-sestamibi as an imaging surrogate for a chemotherapeutic agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation.

BACKGROUND: Growth factor, cytokine and chemokine-induced activation of PI3K enzymes constitutes the start of a complex signalling cascade, which ultimately mediates cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. The PI3K enzyme family is divided into 3 classes; class I (subdivided into IA and IB), class II (PI3K-C2alpha, PI3K-C2beta and PI3K-C2gamma) and class III PI3K. Expression of these enzymes in human tissue has not been clearly defined. METHODS: In this study, we analysed the immunohistochemical topographical expression profile of class IA (anti-p85 adaptor) and class II PI3K (PI3K-C2alpha and PI3K-C2beta) enzymes in 104 formalin-fixed, paraffin embedded normal adult human (age 33-71 years, median 44 years) tissue specimens including those from the gastrointestinal, genitourinary, hepatobiliary, endocrine, integument and lymphoid systems. Antibody specificity was verified by Western blotting of cell lysates and peptide blocking studies. Immunohistochemistry intensity was scored from undetectable to strong. RESULTS: PI3K enzymes were expressed in selected cell populations of epithelial or mesenchymal origin. Columnar epithelium and transitional epithelia were reactive but mucous secreting and stratified squamous epithelia were not. Mesenchymal elements (smooth muscle and endothelial cells) and glomerular epithelium were only expressed PI3K-C2alpha while ganglion cells expressed p85 and PI3K-C2beta. All three enzymes were detected in macrophages, which served as an internal positive control. None of the three PI3K isozymes was detected in the stem cell/progenitor compartments or in B lymphocyte aggregates. CONCLUSIONS: Taken together, these data suggest that PI3K enzyme distribution is not ubiquitous but expressed selectively in fully differentiated, non-proliferating cells. Identification of the normal in vivo expression pattern of class IA and class II PI3K paves the way for further analyses which will clarify the role played by these enzymes in inflammatory, neoplastic and other human disease conditions.

Journal Article↗
PubMed2003

The thyroid hormone receptor-associated protein TRAP220 is required at distinct embryonic stages in placental, cardiac, and hepatic development.

Recent work indicates that thyroid hormone receptor-associated protein 220 (TRAP220), a subunit of the multiprotein TRAP coactivator complex, is essential for embryonic survival. We have generated TRAP220 conditional null mice that are hypomorphic and express the gene at reduced levels. In contrast to TRAP220 null mice, which die at embryonic d 11.5 (E11.5), hypomorphic mice survive until E13.5. The reduced expression in hypomorphs results in hepatic necrosis, defects in hematopoiesis, and hypoplasia of the ventricular myocardium, similar to that observed in TRAP220 null embryos at an earlier stage. The embryonic lethality of null embryos at E11.5 is due to placental insufficiency. Tetraploid aggregation assays partially rescues embryonic development until E13.5, when embryonic loss occurs due to hepatic necrosis coupled with poor myocardial development as observed in hypomorphs. These findings demonstrate that, for normal placental function, there is an absolute requirement for TRAP220 in extraembryonic tissues at E11.5, with an additional requirement in embryonic tissues for hepatic and cardiovascular development thereafter.

Animals↗
PubMed2003

Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer.

Fluorescence lifetime imaging (FLIM) depends on the fluorescence decay differences between tissues to generate image contrast. In the present study FLIM has been applied to fixed (but unstained) breast cancer tissues to demonstrate the feasibility of this approach for histopathological assessment. As the FLIM method relies on natural autofluorescence, it may be possible to circumvent tissue processing altogether and so FLIM has the potential to be a powerful new method of in vivo tissue imaging via an endoscopic or per-operative approach in a variety of organs, as well as a research tool for in vivo animal models of disease. Unstained, alcohol-fixed tissue samples from 13 patients were stimulated by laser pulses at 415 nm. The temporal decay of the autofluorescence was imaged over a period of 2 ns after cessation of the pulse. The decay rate at each image pixel was calculated as the 'lifetime' factor tau. A tissue classification scheme was used to define regions in each image. The average lifetimes of different tissue regions were compared. A total of 167 tissue regions were measured. Within individual fields, stroma had a larger tau (slower decay) than epithelium (p < 0.001). Within individual patients (taking the mean tau of a given tissue type across all fields from each patient), there was a statistically significant difference between benign and malignancy-associated stroma (p < 0.05). Also, benign collagen had a longer tau than benign epithelium (p < 0.05). Multivariate analysis showed a significant difference between benign stroma, malignancy-associated stroma, blood vessels, and malignant epithelium (p < 0.05). Statistically significant differences between benign and malignancy-associated stroma were obtained even with small patient numbers, indicating that lifetime-based instruments can be developed for real-time diagnostic imaging with microscopic resolution.

Breast Neoplasms↗
PubMed2002

Analysis of epitopes on endometrial epithelium by scanning immunoelectron microscopy.

Scanning immunoelectron microscopy was applied to human endometrial epithelium for the first time to simultaneously determine epitope localisation and cellular architecture. The method was established using HMFG1, an antibody to a glycoform of the MUC1 mucin. This was chosen because of the potential importance of MUC1 in connection with endometrial receptivity. Biopsies of mid-secretory phase endometrium were labelled using HMFG1 and silver-enhanced, gold-conjugated secondary antibody was then visualised by back-scattered electron imaging. The method provided a highly specific localisation of the HMFG1 epitope to the ciliated and "ciliogenic" cells of the endometrial surface. In contrast, no reactivity was evident on the microvillous cells and endometrial pinopodes. The potential to integrate the study of the molecular and ultrastructural changes that occur in the endometrium by using scanning immunoelectron microscopy offers a powerful means of expanding our understanding of the adaptation of the endometrium in preparation for embryo implantation.

Adult↗
PubMed2002

Expression of a truncated Brca1 protein delays lactational mammary development in transgenic mice.

To address the hypothesis that certain disease-associated mutants of the breast-ovarian cancer susceptibility gene BRCA1 have biological activity in vivo, we have expressed a truncated Brca1 protein (trBrca1) in cell-lines and in the mammary gland of transgenic mice. Immunofluorescent analysis of transfected cell-lines indicates that trBRCA1 is a stable protein and that it is localized in the cell cytoplasm. Functional analysis of these cell-lines indicates that expression of trBRCA1 confers an increased radiosensitivity phenotype on mammary epithelial cells, consistent with abrogation of the BRCA1 pathway. MMTV-trBrca1 transgenic mice from two independent lines displayed a delay in lactational mammary gland development, as demonstrated by altered histological profiles of lobuloalveolar structures. Cellular and molecular analyses indicate that this phenotype results from a defect in differentiation, rather than altered rates of proliferation or apoptosis. The results presented in this paper are consistent with trBrca1 possessing dominant-negative activity and playing an important role in regulating normal mammary development. They may also have implications for germline carriers of BRCA1 mutations.

Animals↗
PubMed2002

MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis.

This study examines the coexpression of MUC1 mucin and trefoil factor 1 (TFF1) and their relationship to progression of renal cell carcinoma (RCC). Immunohistochemistry was performed on tumor and adjacent normal tissue from clear-cell RCC (n = 60) and tissues from normal controls (n = 5) using a set of well-characterized monoclonal antibodies recognizing different epitopes of MUC1 and TFF1. Results of immunohistochemistry were compared with clinical parameters, including tumor grade, tumor size, presence of metastasis, and progression-free survival of patients after surgery. In normal tissue, MUC1 and TFF1 were absent from the normal proximal tubular epithelium but were identified in distal and collecting tubular epithelium. In RCC, increased MUC1 expression positively correlated to tumor progression. MUC1 recognized by HMFG1 was associated with large tumor size (P < .05), distant metastasis (P < .05), and invasion of large veins (P < .05). Expression of the under-glycosylated form of MUC1 recognized by SM3 was found to correlate to time to progression (recurrence, metastasis, or death of patient; P < .001). Expression of TFF1 did not significantly correlate with any prognostic parameters. However, there was a significant correlation (P < .01) between TFF1 and MUC1 expression (HMFG2 epitope) in RCCs. These results are consistent with the following conclusions: (1) MUC1 may be an independent prognostic marker in RCC; (2) TFF1 is frequently coexpressed with MUC1 and may act synergistically; and (3) RCC may originate from distal tubular epithelium.

Adult↗
PubMed2002

99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer.

UNLABELLED: Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo. METHODS: Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry. RESULTS: Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min. CONCLUSION: (99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.

ATP Binding Cassette Transporter, Subfamily B↗