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Biomedical subjects

A Moghaddam

Publications and source records attributed to A Moghaddam.

At least 19 recordsLinked to original sources
PubMed2007

[TGF-beta1 as a pathophysiological factor in fracture healing].

AIM: TGF-beta1 is an important local and systemic regulatory molecule during fracture healing. Various authors have shown differences in the systemic levels of TGF-beta1 over the time taken for bone healing in distraction osteogenesis and osteotomies. Previous studies have shown characteristic differences in the physiological levels of growth factors between normal fracture healing and delayed fracture union. The aim of the present study was to evaluate possible differences in sera levels of patients with normal and delayed union fracture healing. METHODS: Patients with long bone shaft fractures were recruited prospectively. Peripheral blood samples were collected over a period of 1 year using a standardized time schedule. At the end of the individual's investigation period, TGF-beta1 levels were determined. To achieve a homogeneous collective of patients, only those with a maximum of two fractures were included in the study. After matching for four criteria, we compared patients with normal fracture healing to patients with delayed unions. The fact of delayed union was accepted in case of failed consolidation 4 months after trauma. RESULTS: During a prospective study period of 1 year, 15 patients with normal fracture healing could be compared to 15 patients suffering from delayed union. By determining the absolute sera levels we found a typical increase of TGF-beta1 up to 2 weeks after fracture in both groups, with a subsequent decrease up to the sixth week after fracture. However, a decline in serum concentration occurred earlier in patients with delayed union, causing significantly lower TGF-beta1 levels in the non-union group 4 weeks after trauma (P=0.00006). CONCLUSION: Even with a relatively small number of patients, we could show a significant difference in serum concentrations of TGF-beta1 between the investigated groups. If these results can be verified within a larger collective, TGF-beta1 could be used as a predictive cytokine for delayed fracture healing.

Adult↗
PubMed2006

[Clinical experience with bone morphogenetic protein 7 (BMP 7) in nonunions of long bones].

BACKGROUND: Nonunions of long bone fractures are considerable therapeutic and economic problems with increasing tendency. Basic surgical options are autogenous cancellous bone grafting, rod dynamization, reamed nailing, plate fixation with compression, and bone transport techniques. If these methods fail to work, alternative treatment options are needed. MATERIAL AND METHODS: Since May 2001 treatment with recombinant human (rh) bone morphogenic protein 7 [BMP-7 or osteogenic protein 1 (OP-1)] in combination with a type one collagen carrier has gained interest. BMP 7 induces the formation of new bone by differentiation of stem cells, thereby initiating the reaction cascade of osteogenesis. Nonunions over 9 months and unsuccessful bone grafting delineate the indication. RESULTS: We report our experience with 21 patients and nonunion of long bone fractures. Between July 2002 and June 2004, 23 units of BMP 7 were implanted. The implantation sites were 7 femora, 12 tibias, 2 humeri, and 2 forearms. In ten cases BMP 7 was combined with a new osteosynthesis and bone grafting and in five patients with bone grafting alone. In contrast in eight patients BMP 7 was applied as a single procedure without any bone grafting or any change of the osteosynthesis. CONCLUSION: There were no peri- or postoperative complications. Follow-up was obtained for a minimum of 6 months. Of 23 implantations, 22 were successful with bony healing revealed by clinical and radiological evaluation. In one patient no bony consolidation of the nonunion has been seen so far. In summary, based on our results we propose BMP 7 as an additional innovative therapy of long bone nonunions.

Adult↗
PubMed2006

A rapid real-time PCR assay for determination of hepatitis C virus genotypes 1, 2 and 3a.

The genotypes of hepatitis C virus (HCV) in serum of patients have been described as independent predictors of success of antiviral therapy. Therefore, different antiviral regimens have been proposed depending on the infecting HCV genotype. HCV strain is usually determined by polymerase chain reaction (PCR) amplification of genome followed by sequencing or by line-probe assays. We report a new one step real-time PCR assay for genotyping of HCV strains that are prevalent in patients in Norway. HCV types 1, 2 and 3a were genotyped unambiguously in 37 patient serum samples with 100% correlation to genotyping by nucleotide sequence analysis and line-probe assays. Genotyping could also be confirmed against an HCV genotype panel from the National Institute for Biological Standards and Control. This assay does not require manipulation of amplified PCR products, it involves very little hands on and analysis time. This assay can be used for rapid genotyping of HCV-RNA in infected patients to aid physicians decide suitability of patients for treatment and subsequent length of treatment.

Base Sequence↗
PubMed2005

TGF-beta1 as a marker of delayed fracture healing.

Mitogens of the TGF-beta superfamily have been shown to be crucial local and systemic regulatory molecules involved in fracture healing. However, there exists only little information about systemic regulation of bone regeneration by growth factors and no reports comparing serum levels of bone growth factors between normal and failed fracture healing have been published so far. We hypothesized that quality of fracture healing might be reflected by systemic alterations of key regulatory growth factors involved in bone formation and remodeling. Therefore, the aim of this study was to evaluate possible differences in serum levels of BMP-2, BMP-4, and TGF-beta1 in patients with normal and delayed fracture healing. 103 patients with diaphyseal fractures of long bones were recruited prospectively. Peripheral blood samples were collected over a period of 6 months following a standardized time schedule. At the end of the individual investigation period, growth factor serum levels were measured using commercially available enzyme immunoassays. For the elimination of disturbing influences, patients in both groups were matched by gender, age, fracture type, and localization as well as applied technique of osteosynthesis. During a study period of 1 year, 10 patients with an atrophic type of delayed union could be retrieved and matched to 10 patients with normal fracture healing. The diagnosis of delayed union was assumed in case of failed consolidation 4 months after trauma. We found an increase of TGF-beta1 serum levels up to 2 weeks after fracture in both groups with a following return to the reference value within 6 weeks after trauma. However, decline of serum concentration occurred earlier in patients with delayed fracture healing. At 4 weeks after trauma, serum levels of TGF-beta1 were significantly lower in patients of the delayed union group. Serum levels of BMP-2 and BMP-4 were below detection level in all patients, respectively. These findings support the critical role of TGF-beta1 in fracture healing. Events during the consolidation phase seem to be dependent on sufficient availability of TGF-beta1.

Biomarkers↗
PubMed2005

Invasive aspergillosis in the hematologic and immunologic patient: new findings and key questions in leukemia.

Patients suffering from acute leukemia are at high risk for invasive aspergillosis and a large review and a recent clinical trial have shown that they represent the largest group of patients developing the disease. New host groups such as patients with multiple myeloma or low-grade lymphoproliferative disorders have contributed to an increase in the incidence of invasive aspergillosis over recent years. There are substantial differences in the diagnostic strategy and therapeutic outcome of disease between patients with a hematological malignancy and other host groups such as allogeneic hematopoietic stem cell transplant patients. Galactomannan detection ELISA test is more specific in adult patients with hematological malignancies than in hematopoietic stem cell transplantation recipients. As a result of possible improvement of the underlying immune deficiency upon recovery from neutropenia, survival is higher in leukemic patients with invasive aspergillosis than in other host groups. However, there is currently no evidence of an effective antifungal prophylaxis strategy against aspergillosis in leukemic patients. As these patients account for a majority of the aspergillosis cases, clinical trials on prophylaxis should not only be focused on allogeneic stem transplant recipients but also be designed for the patient with leukemia.

Aspergillosis↗
PubMed2001

Selection and characterisation of recombinant single-chain antibodies to the hapten Aflatoxin-B1 from naive recombinant antibody libraries.

Selection of antibodies from large repertoire phage display libraries has become a common technique for isolation of specific antibodies to antigens. Many of these libraries are shown to contain antibodies specific to haptens, but only when these haptens are derivatised or conjugated to an immobilising molecule, such as bovine serum albumin (BSA). There has been little demonstration of the suitability of naive recombinant antibody libraries for isolating antibodies that bind low molecular weight haptens in the absence of a carrier molecule and few have addressed the problems associated with selecting antibodies that only recognize the combination of hapten and the carrier molecule. We have panned two-phage antibody libraries against AflatoxinB1-BSA and screened single-chain antibody fragments for binding to AflatoxinB1-BSA and Aflatoxin-B1. Many of the antibodies isolated specifically bound AflatoxinB1-BSA, but not soluble Aflatoxin-B1 or BSA. Modification of the protocol led to isolation of single-chain fragment variable antibody domain (scFv) antibodies that specifically bound soluble Aflatoxin-B1 with an affinity of 6x10(-9) M.

Aflatoxin B1↗
PubMed2000

Expression of a novel factor, com1, is regulated by 1,25-dihydroxyvitamin D3 in breast cancer cells.

Tumor cells and their surrounding microenvironment produce a variety of factors that promote tumor growth and metastasis. We recently identified a nuclear factor, termed com1, that is up-regulated in human breast carcinoma cells on formation of experimental metastatic tumors and is assumed to act as a growth-promoting factor in breast cancer. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a potent inhibitor of growth in breast cancer both in vitro and in vivo. We compared the growth-regulatory mechanisms of nontumorigenic and estrogen-dependent MCF-7 cells with those of the tumorigenic and tamoxifen-resistant subline MCF7/ LCC2 in the presence of 1,25(OH)2D3. Proliferation of MCF7/LCC2 cells, which revealed constitutive com1 expression, was inhibited by 1,25(OH)2D3 (10(-7) M). This was strongly associated with cell cycle arrest in G1 phase, consistent with accumulation of the hypophosphorylated form of the retinoblastoma protein as well as the induction of the cyclin-dependent kinase inhibitor p21. These cell cycle events were preceded by a transient up-regulation (5-8-fold) of com1 mRNA. Furthermore, clonal growth of the MCF7/LCC2 cells was also inhibited by 1,25(OH)2D3 (10(-7) M), and when the com1-negative MCF-7 cells were stably transfected with com1, the resulting MCF7/com1 cells showed a significant decrease in colony formation. These results seem to indicate that rather than promoting growth, com1 may participate in the regulatory pathway involved in cellular growth inhibition when recruited by inhibitory signals.

Basic Helix-Loop-Helix Proteins↗
PubMed1999

Mechanisms that regulate Epstein-Barr virus EBNA-1 gene transcription during restricted latency are conserved among lymphocryptoviruses of Old World primates.

Epstein-Barr virus (EBV), the only known human lymphocryptovirus (LCV), displays a remarkable degree of genetic and biologic identity to LCVs that infect Old World primates. Within their natural hosts, infection by these viruses recapitulates many key aspects of EBV infection, including the establishment of long-term latency within B lymphocytes, and is therefore a potentially valuable animal model of EBV infection. However, it is unclear whether these LCVs have adopted or maintained the same mechanisms used by EBV to express essential viral proteins, such as EBNA-1, in the face of cell-mediated repression of EBV gene expression that occurs upon establishment of the asymptomatic carrier state. To address this issue, we determined whether the endogenous LCVs of baboon (Cercopithecine herpesvirus 12) and rhesus macaque (Cercopithecine herpesvirus 15) have the functional equivalent of the EBV promoter Qp, which mediates exclusive expression of EBNA-1 during the restricted programs of EBV latency associated with the carrier state. Our results indicate that (i) both the baboon and rhesus macaque LCVs have a genomic locus that is highly homologous to the EBV Qp region, (ii) key cis-regulatory elements of Qp are conserved in these LCV genomes and compose promoters that are functionally indistinguishable from EBV Qp, and (iii) EBNA-1 transcripts identical in structure to EBV Qp-specific EBNA-1 mRNAs are present in nonhuman LCV-infected cells, demonstrating that these Qp homologs are indeed utilized as alternative EBNA-1 promoters. These observations indicate that the molecular mechanisms which regulate EBV gene expression during restricted latency have been conserved among the LCVs. The contribution of these mechanisms to viral persistence in vivo can now be experimentally tested in nonhuman primate models of LCV infection.

Animals↗
PubMed1999

Inhibition of antigen presentation by the glycine/alanine repeat domain is not conserved in simian homologues of Epstein-Barr virus nuclear antigen 1.

Most humans and Old World nonhuman primates are infected for life with Epstein-Barr virus (EBV) or closely related gammaherpesviruses in the same lymphocryptovirus (LCV) subgroup. Several potential strategies for immune evasion and persistence have been proposed based on studies of EBV infection in humans, but it has been difficult to test their actual contribution experimentally. Interest has focused on the EBV nuclear antigen 1 (EBNA1) because of its essential role in the maintenance and replication of the episomal viral genome in latently infected cells and because EBNA1 endogenously expressed in these cells is protected from presentation to the major histocompatibility complex class-I restricted cytotoxic T-lymphocyte (CTL) response through the action of an internal glycine-alanine repeat (GAR). Given the high degree of biologic conservation among LCVs which infect humans and Old World primates, we hypothesized that strategies essential for viral persistence would be well conserved among viruses of this subgroup. We show that the rhesus LCV EBNA1 shares sequence homology with the EBV and baboon LCV EBNA1 and that the rhesus LCV EBNA1 is a functional homologue for EBV EBNA1-dependent plasmid maintenance and replication. Interestingly, all three LCVs possess a GAR domain, but the baboon and rhesus LCV EBNA1 GARs fail to inhibit antigen processing and presentation as determined by using three different in vitro CTL assays. These studies suggest that inhibition of antigen processing and presentation by the EBNA1 GAR may not be an essential mechanism for persistent infection by all LCV and that other mechanisms may be important for immune evasion during LCV infection.

Alanine↗
PubMed1998

A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma.

The role of Epstein-Barr virus (EBV) in the pathogenesis of severe, chronic active EBV infection and its complications is unclear. We investigated two Japanese patients diagnosed with severe, chronic active EBV infection who subsequently developed EBV-positive T-cell lymphoma. The patients displayed abnormally high antibody titers to EBV antigens, and had evidence of peripheral blood CD4(+) T-cell infection with EBV, 19 months and 3 months, respectively, before the diagnosis of EBV-positive T-cell lymphoma. The lymphomas were infected with monoclonal EBV and expressed the EBV latency genes EBNA-1, LMP-1, and LMP-2. Genetic studies showed that the virus detected in the T-cell lymphoma was indistinguishable, with respect to type and previously defined LMP-1 and EBNA-1 gene variations, from virus detected in the peripheral blood T cells 19 months earlier. These studies support an important pathogenetic role of T-cell infection with EBV in chronic active EBV infection and in the EBV-positive T-cell lymphoma that followed.

Antibodies, Viral↗
PubMed1998

Infection of human B lymphocytes with lymphocryptoviruses related to Epstein-Barr virus.

Lymphocryptoviruses (LCVs) naturally infecting Old World nonhuman primates are closely related to the human LCV, Epstein-Barr virus (EBV), and share similar genome organization and sequences, biologic properties, epidemiology, and pathogenesis. LCVs can efficiently immortalize B lymphocytes from the autologous species, but the ability of a given LCV to immortalize B cells from other Old World primate species is variable. We found that LCV from rhesus monkeys did not immortalize human B cells, and EBV did not immortalize rhesus monkey B cells. In this study, baboon LCV could not immortalize human peripheral blood B cells but could readily immortalize rhesus monkey B cells. Thus, efficient LCV-induced B-cell immortalization across distant Old World primate species appears to be restricted by a species-specific block. To further characterize this species restriction, we first cloned the rhesus monkey LCV major membrane glycoprotein and discovered that the binding epitope for the EBV receptor, CD21, was highly conserved. Stable infections of human B cells with recombinant amplicons packaged in rhesus monkey or baboon LCV envelopes were also consistent with a species-restricted block occurring after virus binding and penetration. Transient infections of human B cells with simian LCV resulted in latent LCV EBNA-2 gene expression and activation of cell CD23 gene expression. EBV-immortalized human B cells could be coinfected with baboon LCV, and the simian virus persisted and replicated in human B cells. Thus, several lines of evidence indicate that the species restriction for efficient LCV-induced B-cell immortalization occurs beyond virus binding and penetration. This has important implications for the study of LCV infection in Old World primate models and for human xenotransplantation where simian LCVs may be inadvertently introduced into humans.

Amino Acid Sequence↗
PubMed1997

An animal model for acute and persistent Epstein-Barr virus infection.

Epstein-Barr virus (EBV) is a human lymphocryptovirus that causes infectious mononucleosis, persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas and nasopharyngeal carcinomas. A highly similar rhesus lymphocryptovirus naturally endemic in rhesus monkeys was used to orally infect naïve animals from a pathogen-free colony. This animal model reproduced key aspects of human EBV infection, including oral transmission, atypical lymphocytosis, lymphadenopathy, activation of CD23(+) peripheral blood B cells, sustained serologic responses to lytic and latent EBV antigens, latent infection in the peripheral blood, and virus persistence in oropharyngeal secretions. This system may be useful for studying the pathogenesis, prevention, and treatment of EBV infection and associated oncogenesis.

Animals↗
PubMed1997

Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.

Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis in vivo are not well defined. Multiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the relationship of expression to estrogen receptor and vascular density was also examined. Vascular endothelial growth factor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor (TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, and thymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNase protection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidine phosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that of ER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P = 0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesis may involve a coordinate regulation of some vascular growth factors. High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normal breast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P = 0.01). Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be of value in a combined approach to therapy.

Breast Neoplasms↗
PubMed1996

Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers.

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, has been implicated in bladder cancer angiogenesis. To examine its role more clearly, we have quantified and localized its expression using Western analysis and immunohistochemistry in a series of 105 bladder cancers. We have also assessed the relationship between TP expression and other tumor parameters including quantitative angiogenesis, p53 status, ploidy, and survival. By Western analysis, TP expression was 5-fold higher in tumors than in normal bladder samples (P < 0.02). Expression was 15-fold higher in invasive tumors than in normal bladder (P < 0.001) and 8-fold higher than in superficial tumors (P < 0.005). Immunohistochemistry of the tumors showed TP was present in the neoplastic epithelium in 27% of the tumors, in the inflammatory cells in 72% of the tumors, in stromal cells in 30% of the tumors, and in tumor-associated endothelium in 11% of the tumors. Expression by Western blotting and immunohistochemistry was significantly up-regulated in tumors compared with normal bladder (P < 0.05). Tumor cell TP expression correlated with tumor grade (P < 0.02), but there was no correlation between tumor cell TP expression and tumor stage (P = 0.46), ploidy (P = 0.52), p53 expression (P = 0.9), tumor vascularity (P = 0.8), relapse-free survival (P = 0.57), or overall survival (P = 0.94). TP protein is expressed in bladder cancers, and expression is associated with an aggressive phenotype. Because TP can activate a number of cytotoxic agents, it provides a potential therapeutic target in bladder cancer.

Adult↗
PubMed1996

Breast cancer angiogenesis--new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting.

Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF beta 1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suramin in vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize. New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.

Angiogenesis Inducing Agents↗
PubMed1996

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium.

Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Although known to be generally elevated in tumours, the expression of this enzyme in breast carcinomas is unknown. Therefore, we used ribonuclease protection assays and immunohistochemistry to examine the expression of TP in 240 primary breast carcinomas. Nuclear and/or cytoplasmic TP expression was observed in the neoplastic tumour epithelium in 53% of tumours. Immunoreactivity was also often present in the stromal, inflammatory and endothelial cell elements. Although endothelial cell staining was usually focal, immunoreactivity was observed in 61% of tumours and was prominent at the tumour periphery, an area where tumour angiogenesis is most active. Tumour cell TP expression was significantly inversely correlated with grade (P = 0.05) and size (P = 0.003) but no association was observed with other tumour variables. These findings suggest that TP is important for remodelling the existing vasculature early in tumour development, consistent with its chemotactic non-mitogenic properties, and that additional angiogenic factors are more important for other angiogenic processes like endothelial cell proliferation. Relapse-free survival was higher in node-positive patients with elevated TP (P = 0.05) but not in other patient groups. This might be due to the potentiation of chemotherapeutic agents like methotrexate by TP. Therefore, this enzyme might be a prediction marker for response to chemotherapy.

Adult↗
PubMed1995

Thymidine phosphorylase is angiogenic and promotes tumor growth.

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.

Animals↗