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PubMed1986

Discordant changes between immunoreactive ACTH and beta-endorphin in rat brain and pituitary during early development.

UNLABELLED: Discordant changes in brain concentrations of immunoreactive (IR-) adrenocorticotropic hormone (ACTH) or beta-endorphin, peptides derived from pro-opiomelanocortin (POMC), have been reported during the latter part of development and with subsequent aging. These changes were believed to be due to age-related alterations in the regulation of metabolism of POMC-related peptides. However, concentrations of IR-ACTH and IR-beta-endorphin have not been simultaneously studied during early development when many changes in brain development and behavior are occurring. To determine whether concentrations of IR-ACTH and IR-beta-endorphin change during early development and whether changes are discordant, concentrations of IR-ACTH and IR-beta-endorphin were measured in several brain regions and pituitary in rats at 10, 29 and 80 days after birth. Whereas IR-ACTH in extrahypothalamic brain increased at day 29, and decreased at day 80, it did not change in hypothalamus and pituitary. Between day 10 and 29, IR-beta-endorphin rose in all brain regions, but subsequent changes in different tissues were variable at day 80. Because concentration changes can be mediated by alterations in one or more regulatory mechanisms, chromatographic profiles of hypothalamus and amygdala and molar ratios of all tissues were subsequently studied to give further insight into the mechanisms of the discordant changes. Molecular profiles of hypothalamic IR-ACTH and amygdalar IR-beta-endorphin exhibited lesser proportions of large molecular forms and greater proportions of ACTH and beta-endorphin during development. Molar ratios of IR-ACTH/IR-beta-endorphin in all tissues and ratios of ACTH1-39/beta-endorphin in hypothalamus and amygdala changed during development. CONCLUSIONS: (1) changes in IR-ACTH and IR-beta-endorphin occur in rat pituitary and several brain regions at different ages during early development and are frequently discordant; (2) molecular profiles suggested that the activity of processing enzymes for POMC and its derivatives vary in hypothalamus and amygdala with respect to type of derivative, brain region, and developmental age; and (3) changes in some molecular profiles and changes in molar ratios of IR-ACTH/IR-beta-endorphin and ratios of ACTH1-39/beta-endorphin suggest that changes in processing and possibly changes in neurosecretion and degradation contribute to concentration changes independent of possible alterations in biosynthesis of POMC.

Adrenocorticotropic Hormone↗

PubMed2006

Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers.

Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer (< or = 45 years old) and conventional gastric cancers. Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays. These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi2 test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P<0.0001 and P = 0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P = 0.001), overexpression of C/EBP-beta (P<0.001) and cytoplasmic HuR (P = 0.016). COX-2 was significantly associated with p53 positivity (P = 0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype. Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implications.

Adult↗

PubMed2006

Direct comparison of Au(3)(+) and C(60)(+) cluster projectiles in SIMS molecular depth profiling.

The sputtering properties of two representative cluster ion beams in secondary ion mass spectrometry (SIMS), C(60)(+) and Au(3)(+), have been directly compared. Organic thin films consisting of trehalose and dipalmitoylphosphatidylcholine (DPPC) are employed as prototypical targets. The strategy is to make direct comparison of the response of a molecular solid to each type of the bombarding cluster by overlapping the two ion beams onto the same area of the sample surface. The ion beams alternately erode the sample while keeping the same projectile for spectral acquisition. The results from these experiments are important to further optimize the use of cluster projectiles for SIMS molecular depth profiling experiments. For example, Au(3)(+) bombardment is found to induce more chemical damage as well as Au implantation when compared with C(60)(+). Moreover, C(60)(+) is found to be able to remove the damage and the implanted Au effectively. Discussions are also presented on strategies of enhancing sensitivity for imaging applications with cluster SIMS.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor CJ-13,610.

5-Lipoxygenase (5-LO) is a crucial enzyme in the synthesis of the bioactive leukotrienes (LTs) from arachidonic acid (AA), and inhibitors of 5-LO are thought to prevent the untowarded pathophysiological effects of LTs. In this study, we present the molecular pharmacological profile of the novel nonredox-type 5-LO inhibitor CJ-13,610 that was evaluated in various in vitro assays. In intact human polymorphonuclear leukocytes (PMNL), challenged with the Ca(2+)-ionophore A23187, CJ-13,610 potently suppressed 5-LO product formation with an IC(50)=0.07 microm. Supplementation of exogenous AA impaired the efficacy of CJ-13,610, implying a competitive mode of action. In analogy to ZM230487 and L-739.010, two closely related nonredox-type 5-LO inhibitors, CJ-13,610 up to 30 microm failed to inhibit 5-LO in cell-free assay systems under nonreducing conditions, but inclusion of peroxidase activity restored the efficacy of CJ-13,610 (IC(50)=0.3 microm). In contrast to ZM230487 and L-739.010, the potency of CJ-13,610 does not depend on the cell stimulus or the activation pathway of 5-LO. Thus, 5-LO product formation in PMNL induced by phosphorylation events was equally suppressed by CJ-13,610 as compared to Ca(2+)-mediated 5-LO activation. In transfected HeLa cells, CJ-13,610 only slightly discriminated between phosphorylatable wild-type 5-LO and a 5-LO mutant that lacks phosphorylation sites. In summary, CJ-13,610 may possess considerable potential as a potent orally active nonredox-type 5-LO inhibitor that lacks certain disadvantages of former representatives of this class of 5-LO inhibitors.

Arachidonate 5-Lipoxygenase↗

PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗

PubMed1994

Molecular genetic profiles of colitis-associated neoplasms.

BACKGROUND/AIMS: A major long-term risk for patients with chronic idiopathic colitis is the development of colorectal dysplasia and adenocarcinoma. The presence or absence of specific genetic changes in these lesions will provide important insights into the relationship of colitis-associated dysplasia and the development of carcinoma. METHODS: A case-study approach was used to develop detailed molecular genetic profiles of advanced dysplasias and carcinomas from six patients with ulcerative colitis or Crohn's colitis. RESULTS: Numerous genetic alterations were identified in each of the dysplasias and carcinomas profiled. These genetic alterations involved many of the same targets found in sporadic colorectal tumors and included multiple sites of allelic deletion, microsatellite instabilities, and mutations of the K-ras, p53, and APC genes. The progression of dysplasia to carcinoma was often accompanied by an accumulation of these mutations. CONCLUSIONS: Genetic alterations are common in colitis-associated neoplasia, just as in sporadic colorectal neoplasia. This could have important implications for the evaluation and treatment of patients with colitis.

Adenocarcinoma↗

PubMed2005

A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which approximately 40% of the patients respond well to current chemotherapy, but the prognosis for the other 60% is poor. The Leukemia/Lymphoma Molecular Profiling Project (LLMPP) used microarray technology to define a molecular profile for each of 240 patients with DLBCL and develop a molecular outcome predictor score that accurately predicted patient survival. Data from our laboratory and others suggest that alterations in antioxidant defense enzyme levels and redox environment can be oncogenic and affect the response to glucocorticoid treatment, one of the components of combination chemotherapy regimens for lymphoma. The goal of the current study was to reanalyze the LLMPP microarray data to determine whether the levels of antioxidant defense enzymes and redox proteins were correlated with prognosis in DLBCL. We found that patients with DLBCL with the worst prognosis, according to the outcome predictor score, had decreased expression of catalase, glutathione peroxidase, manganese superoxide dismutase, and VDUP1, a protein that inhibits thioredoxin activity. The data suggest that the patients with the worst prognosis combine a decrease in antioxidant defense enzyme expression with an increase in thioredoxin system function (the redox signature score).

Animals↗

PubMed2026

Pathologic diagnosis of thyroid nodules with preoperatively detected tumor protein 53 mutations: A tricenter series of 32 cases.

BACKGROUND: Mutations in the tumor protein 53 gene (TP53 mutation) in thyroid nodules are quoted to confer a high (80%) probability of malignancy when detected on the ThyroSeq v3 genomic classifier if associated with other molecular alterations. However, TP53 mutation also occurs in benign and low-risk thyroid neoplasms. Thus, the risk of malignancy in nodules harboring TP53 mutation is not well characterized. METHODS: Of 4,575 molecularly profiled preoperative fine-needle aspiration samples, 36 (0.8%) were identified harboring TP53 mutation. The study included 32 cases in which the pathology diagnosis was obtained from surgical specimens. RESULTS: The reviewed diagnosis was benign/low-risk neoplasms in 11 (34%), carcinoma-American Thyroid Association low risk of recurrence in 7 (22%), carcinoma-American Thyroid Association low-intermediate risk in 6 (19%), and carcinoma-American Thyroid Association high risk in 8 (25%). In the entire cohort and the indeterminate fine-needle aspiration category (Bethesda III-IV), the risk of malignancy was 66% and 56%, respectively. All 11 cases with a reviewed diagnosis of benign or low-risk neoplasms had their tumor capsule submitted entirely for histologic examination, and 64% had total thyroidectomy. In 30 cases comprehensively molecularly profiled, the molecular alterations were substratified into 4 groups: TP53 mutation alone (n = 5, 17%), TP53 mutation with copy number alteration (n = 9, 30%), TP53 mutation with other mutations but no copy number alteration (n = 9, 30%), and TP53 mutation with other mutations and copy number alteration (n = 7, 23%). The risk of malignancy for each group was 40%, 44%, 67%, and 100%, respectively. The frequency of American Thyroid Association-high-risk malignancy, which would often lead to a recommendation for total thyroidectomy, was 20%, 11%, 22%, and 43%, respectively. The risk of malignancy was higher in cases with additional mutations and copy number alteration (7/7, 100%) than in those with TP53 alone or with concomitant copy number alteration only (6/14, 43%) (P = .018). CONCLUSION: Thirty four percent of nodules with TP53 mutation with or without concomitant molecular alterations were benign/low-risk thyroid neoplasms and treated by total thyroidectomy in the majority of cases. Risk of malignancy increased significantly to 100% when TP53 mutation co-occurred with other mutations and copy number alterations. Since American Thyroid Association high-risk carcinomas were found in only 25% of TP53-mutated nodules, thyroid lobectomy may be considered as the initial treatment, in the appropriate clinical context.

Journal Article↗

PubMed1990

Molecular species profiles of acidic phospholipids in lung fractions of adult and perinatal rabbits.

The molecular species of phosphatidylglycerol (PG) and phosphatidylinositol (PI) in pulmonary surfactant and membrane fractions of adult and perinatal rabbit lungs were analyzed by high-performance liquid chromatography of the dinitrobenzoyl derivatives of the diacylglycerols (DGs), derived from the two acidic phospholipids. The PG in both surfactant and membrane fractions of adult lungs consisted mainly of the 16:0/16:0 species, followed in order by 16:0/18:1 and 16:0/18:2 species. In contrast, the prominent molecular species of PI in the membrane fractions were 18:0/20:4 and 16:0/18:1, while surfactant PI consisted mainly of 16:0/18:1 and 16:0/18:2, containing only 3% of 16:0/16:0. In the perinatal rabbit lungs, a compositional change between surfactant PG and PI was found, i.e., an increase in PG and a decrease in PI. The molecular species compositions of PG and PI in the perinatal lungs were generally the same as those observed in the adult lungs. It should, therefore, be noted that the species profiles of surfactant PG and PI, particularly in the content of 16:0/16:0 and 18:0/20:4, are not similar, but distinctly different from each other in both adult and developing lungs. Therefore, the present results strongly suggest two possibilities; (1) both acidic phospholipids which appear in pulmonary surfactant may originate from different pools of CDP-DGs having different molecular species; and/or (2) surfactant PG and PI may be synthesized by individual enzymes having different substrate specificities for different CDP-DGs in alveolar type II cells.

Animals↗

PubMed1991

Differentiation of the genus Listeria from other gram-positive species based on low molecular weight (LMW) RNA profiles.

Low molecular weight RNA (LMW RNA; 5S rRNA and tRNAs) profiles of several Gram-positive species were generated on 9% denaturing polyacrylamide gels. The profiles of five Listeria spp. (L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri and L. welshimeri) were identical when cultured in three different media (APT, BHI and TSBYE), either shaken or statically, both at 30 and 37 degrees C. Twenty-six strains from 15 other species representing seven different genera were also compared. Each species exhibited a characteristic profile. Strain variants of the same species gave identical profiles. The technique represents a simple, reproducible approach to the identification of species and possibly of relationships between species. The taxonomic and phylogenetic implications, particularly with respect to Listeria spp., Brochothrix thermosphacta and the lactic acid bacteria, are considered.

Gram-Positive Bacteria↗

PubMed2002

The value of microarray techniques for quantitative gene profiling in molecular diagnostics.

There has been an explosion of interest in microarray technologies that allow the quantification of whole-genome RNA expression data. The apparent correlation of expression profiles with clinically relevant parameters such as disease outcome has raised expectations with respect to the clinical usefulness of the data generated. Yet the accuracy and biological relevance of these data remain contentious, even in basic research applications. Therefore, numerous issues related to format, quality, validation and interpretation remain to be resolved before microarray profiling can become a diagnostic tool of clinical relevance for routine work.

Gene Expression Profiling↗

PubMed2006

Cytomics as a new potential for drug discovery.

At the single-cell level in conjunction with data-pattern analysis, high-content screening by image analysis or flow cytometry of clinical cell- or tissue-section samples provides differential molecular profiles for the personalized prediction of therapy-dependent disease progression in patients. The molecular reverse-engineering of these molecular profiles, which is the exploration of molecular pathways, backwards, to the origin of the observed molecular differentials, by systems biology has the potential to detect new drug targets in knowledge spaces, typically inaccessible to traditional hypotheses. Furthermore, predictive medicine, by cytomics in stratified patient groups, opens a new way for personalized (or individualized) medicine, as well as for the early detection of adverse drug reactions in patients.

Cytological Techniques↗

PubMed2026

Genomic profiling as an option for ovarian cancer diagnostics.

INTRODUCTION: Ovarian cancer (OC) is a highly heterogeneous and lethal gynecological malignancy. Precision oncology has shifted the management paradigm to comprehensive molecular profiling. Genomic-based diagnostics are now a clinical necessity for accurate prognostic stratification and the rational selection of targeted therapeutics, such as PARP and immune checkpoint inhibitors. AREAS COVERED: This review evaluates current literature regarding the distinct genomic landscapes defining OC histotypes to underlined the role of molecular profiling in the diagnostic field of OC. We discuss the practical implementation, technical aspect, and clinical validity of the main molecular diagnostic platforms, focusing on tissue-based Comprehensive Genomic Profiling (CGP) and Homologous Recombination Deficiency (HRD). Furthermore, we explore emerging translational data on liquid biopsy (LBx) applications. EXPERT OPINION: While current tissue-based methodologies provide critical baseline data, the OC diagnostic paradigm must pivot from static testing to proactive and longitudinal tracking. Integrating advanced LBx approaches enables a real-time monitoring of dynamic parameters as minimal residual disease (MRD) and acquired resistance. Integrating these dynamic blood-based assays with multi-omic profiling and artificial intelligence (AI)-driven tools allows a full understanding of the complex tumor behavior.

Humans↗

PubMed2005

Gene expression profiling identifies molecular subtypes of inflammatory breast cancer.

Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of approximately 8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form.

Adenocarcinoma↗

PubMed2004

Phospholipid molecular species profiles of tectiviruses infecting Gram-negative and Gram-positive hosts.

The phospholipid (PL) molecular species compositions of bacteriophages PRD1 and Bam35 as well as their respective hosts were determined quantitatively using liquid chromatography/electrospray ionization mass-spectrometry (LC-ESI-MS) and backed up by gas-chromatographic/mass-spectrometric (GC-MS) analysis of the total fatty acids (FAs). The results showed that both viruses contain significantly more phosphatidylglycerol (PG) and less phosphatidylethanolamine (PE) than the host membranes. Only modest differences in the molecular species composition of the viruses and their respective hosts were observed, indicating that the virus assembly process is relatively nonselective in respect of the fatty acid (FA) proportion of phospholipids (PL). These data indicate that the PL composition of these two viruses is largely, albeit not exclusively, determined by the availability of phospholipids in the host membrane.

Bacillus Phages↗

PubMed2003

A clinically relevant model of human pancreatic adenocarcinoma identifies patterns of metastasis associated with alterations of the TGF-beta/Smad4 signaling pathway.

UNLABELLED: Genetic alterations impacting the TGF-beta/Smad4 pathway are found in nearly all pancreatic adenocarcinomas, and recent reports have identified a relationship between DPC4/Smad4 expression and patient survival. In this study we use a clinically relevant animal model of pancreatic cancer to examine the impact of these genetic changes on the biology of pancreatic cancer. METHODS: Using high-density oligonucleotide DNA microarray technology, a comprehensive examination of the components of the TGF-beta/Smad4 pathway was performed on three human pancreatic adenocarcinoma cell lines. The in vitro and in vivo growth characteristics of these cell lines was then compared. Finally, using a clinically relevant orthotopic xenograft model of pancreatic cancer, primary tumor growth and metastases were measured for pancreatic tumors derived from each cell line. RESULTS: Examination of the TGF-beta/Smad4 pathway components identified that these three cell lines possess molecular profiles consistent with approximately 90% of pancreatic adenocarcinoma tumors in patients. A significant discrepancy between in vitro and in vivo growth characteristics of each cell line was identified. When tumors from each cell line were established in nu/nu mice, each cell line exhibited distinct metastatic profiles. Data from these studies is consistent, with clinical observations concerning DPC4/Smad4 and patient outcome. CONCLUSION: Using an orthotopic model of tumor growth and metastasis identifies distinct metastatic profiles associated with molecular alterations of the TGF-beta/Smad4 pathway and provides insight with regard to the biologic consequences of these changes.

Adenocarcinoma↗

PubMed1997

Dietary eritadenine modifies plasma phosphatidylcholine molecular species profile in rats fed different types of fat.

The effect of dietary eritadenine on plasma phosphatidylcholine (PC) molecular species composition was investigated in relation to its hypocholesterolemic action in rats fed different types of fats (olive oil, corn oil and linseed oil; 100 g/kg diet). Eritadenine supplementation (50 mg/kg diet) significantly decreased the plasma total cholesterol concentration, irrespective of dietary fat sources, and without change in the order of plasma cholesterol concentration among the fat groups (corn oil > olive oil > linseed oil). Eritadenine significantly decreased the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) in liver microsomes of all the fat groups, while the PC:PE ratio was unaffected by dietary fat type. The fatty acid and molecular species composition of plasma PC was affected either directly or indirectly by the fatty acid composition of dietary fats. The proportion of linoleic acid and linoleic acid-containing molecular species (16:0-18:2 and 18:0-18:2) in plasma PC was the highest in rats fed linseed oil, despite the fact that linoleic acid concentration of linseed oil was only 1/3 that of corn oil. Eritadenine supplementation significantly increased the proportion of linoleic acid and linoleic acid-containing molecular species, especially 16:0-18:2, in plasma PC, irrespective of dietary fat source. Altered plasma PC molecular species composition, as represented by an increase in 16:0-18:2 PC, might contribute to the hypocholesterolemic action of eritadenine.

Adenine↗

PubMed1995

Antithrombin III affinity dependence on the anticoagulant, antiprotease, and tissue factor pathway inhibitor actions of heparins.

To investigate AT-III affinity dependence on heparin's actions, heparin (UH) was fractionated on an AT-III-Sepharose column into a high (HAH) and a low affinity (LAH) fraction. Molecular profiling revealed a molecular weight of 11.8 kDa for (UH), 12.6 kDa for HAH, and 10.6 kDa for LAH. The USP anticoagulant potencies were found to be: UH = 160 U/mg, HAH = 198 U/mg, and LAH = 42 U/mg. The anticoagulant effects of each of these fractions were proportionate to the USP potencies. However, protease generation inhibitory activities did not follow the same order. All fractions were also tested for their interactions with tissue factor pathway inhibitor (TFPI). No significant differences were noted on the anti-Xa effects of TFPI with these fractions. Administration of each fraction to primates resulted in equivalent release of TFPI. In a model of jugular vein clamping induced venous occlusion, all agents produced a dose-dependent antithrombotic action. HAH produced a 60 to 70% stronger antithrombotic effect than LAH or UH. Simultaneous administration of TFPI markedly augmented the antithrombotic actions of both UFH and LAH. The effect of TFPI on the antithrombotic activity of HAH was weaker than that on LAH. These observations suggest that AT-III affinity is not the sole determinant of the antithrombotic actions of heparin. The endogenous release of TFPI may contribute to the antithrombotic actions of heparin and related glycosaminoglycans. Furthermore, TFPI is capable of AT-III independent amplification of the antithrombotic actions of both UH and LAH, suggesting a crucial role of this polyvalent inhibitor in the control of thrombogenesis.

Animals↗