Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A complementary way for the assessment of HCC prognosis is represented by the analysis of molecular markers. Thus, immunohistochemical assessment of proliferation can describe tumor aggressiveness, probability of local recurrence or metastasis potential, being very useful for the assessment of recurrence-free survival and survival until death. The aim of our study was to assess proliferating cell nuclear antigen activity in HCC and dysplastic nodules as compared with surrounding non-neoplasic areas. Immunohistochemical techniques were thus performed on the samples obtained by ultrasound-guided liver biopsies or intraoperative biopsies, in 32 patients with HCC, as well as in 3 patients with dysplastic nodules occurring in liver cirrhosis. Expression of PCNA within extranodular areas of the HCC patients in the absence or presence of cirrhosis, was increasing from 40% to 70%, respectively. PCNA expression further increased within intranodular areas of dysplastic nodules and HCC, to 100% and 96.88%, respectively. A progressive increase of the mean values of PCNA-LI was also observed from extranodular areas without or with cirrhosis, towards intranodular areas of dysplastic nodules and HCC (4.2%, 6.8%, 27.9%, 31.9%, respectively). Dysplastic nodules can thus be considered lesions with a high-proliferation rate, representing an early stage of hepatocarcinogenesis. This supported the current recommendations for borderline hepatocellular nodules identified by ultrasound, which indicate an aggressive treatment similar to malignant lesions. In summary, we demonstrated a progressively increasing rate of cellular proliferation, from extranodular non-neoplasic areas to intranodular areas (dysplastic nodules and HCC), as reflected by an increased expression of proliferating cell nuclear antigen labelling index.
J Cell Mol Med
PMID:Immunohistochemical assessment of proliferating cell nuclear antigen in primary hepatocellular carcinoma and dysplastic nodules. 1475 12

Tn5 insertion mutants of Xanthomonas campestris pv. vesicatoria were inoculated into tomato and screened for reduced virulence. One mutant exhibited reduced aggressiveness and attenuated growth in planta. Southern blot analyses indicated that the mutant carried a single Tn5 insertion not associated with previously cloned pathogenicity-related genes of X. campestris pv. vesicatoria. The wild-type phenotype of this mutant was restored by one recombinant plasmid (pOPG361) selected from a genomic library of X. campestris pv. vesicatoria 91-118. Tn3-gus insertion mutagenesis and sequence analyses of a subclone of pOPG361 identified a 1,929-bp open reading frame (ORF) essential for complementation of the mutants. The predicted protein encoded by this ORF was highly homologous to the previously reported pathogenicity-related HrpM protein of Pseudomonas syringae pv. syringae and OpgH of Erwinia chrysanthemi. Based on homology, the new locus was designated opgHXcv. Manipulation of the osmotic potential in the intercellular spaces of tomato leaves by addition of mannitol at low concentrations (25 to 50 mM) compensates for the opgHXcv mutation.
Mol Plant Microbe Interact 2004 Feb
PMID:Importance of opgHXcv of Xanthomonas campestris pv. vesicatoria in host-parasite interactions. 1496 29

Lyme borreliosis is a systemic infection caused by the spirochaete Borrelia burgdorferi, which is transmitted by tick bites and maintained in a delicately balanced ecological cycle. Recent increases in the population densities of tick hosts, the abundance of ticks and the proximity of man to natural tick habitats have led to an escalating worldwide incidence of Lyme borreliosis, and nonspecific clinical manifestations have yielded significant misunderstanding of the disease. After entry, B. burgdorferi activates local inflammation, yet evades host defences and facilitates dissemination by potentially masquerading with host components such as plasmin and complement. The extent of tissue injury is determined by the aggressiveness of host inflammation and immunological reactions, as well as by genetic attributes of the spirochaete. The clinical presentation can be highly varied, including early manifestations that are limited to erythema migrans and ranging to disseminated infection with arthritis, carditis, cranial nerve palsy, peripheral neuropathy, meningitis, or other manifestations. Diagnostic tests have improved, but are unhelpful during certain stages of infection. Therapy varies depending on the degree of involvement, and recovery is usually rapid and complete. Post-treatment clinical manifestations in the absence of evidence for active infection are still poorly understood. The understanding of how B. burgdorferi survives in the environment and interacts with human and mammalian hosts has improved. However, further advances in prevention and therapy depend on continued investigation of the ecological risks and improved understanding of the pathobiology of this obligate bacterial parasite.
Expert Rev Mol Med 2004 Jan 19
PMID:Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment. 1498 14

Thyroid tumors display diverse spectrum of histopathological groups with geographic variation in its prevalence. Influence of iodine deficiency (a major causative factor) in its etiology, prevalence, or aggressiveness is debatable which reflects the existence of various genetic events in pathogenesis. The present study was undertaken to study the role of Microsatellite instability (MSI) or LOH (loss of heterozygosity), an indicator of defective mismatch repair system as a genetic change and to explore it as a prognostic marker in thyroid tumors. Tumor tissues from total thyroidectomy surgical specimens and blood (matched control) of 36 patients from iodine deficient areas (10 benign; 26 malignant) were obtained after their consent. Urinary iodine analysis was done by alkali ash method for which 10 ml of urine was collected from 18 patients before surgery. Genomic DNA, isolated from tumor tissue and blood was amplified by polymerase chain reaction (PCR) using mono and dinucleotide markers - BAT-26, BAT-40, TGF(RII, IGFIIR, hMSH3, BAX, D2S123, D9S283, D9S851 and D18S58. PCR products were analysed on 8% denaturing polyacrylamide gel followed by autoradiography. Of total, 66.6% of tumors [70% (7/10) benign and 65.4% malignant cases (17/26)] showed MSI/LOH. Strong association of MSI/LOH with low iodine (P = 0.01) and with AMES risk groups i.e. age (P = 0.02), tumor size (P = 0.04) and metastases (P = 0.002) in thyroid tumors was observed. This may help in predicting the biological behaviour and strengthening the hypothesis that iodine deficiency has influence on MSI in thyroid tumors. Our results further substantiate the risk group classification and help in deciding the treatment modality in particular patient.
Exp Mol Med 2004 Apr 30
PMID:Microsatellite instability and its correlation with clinicopathological features in a series of thyroid tumors prevalent in iodine deficient areas. 1515 Apr 40

The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added (125)I-hIGFBP-2 specifically bound to the cells. Bound (125)I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for alpha5beta1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0.01), and of the p42/44 MAP-kinases of up to 40% (P<0.01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0.05), and reduced proliferation by 24% (P<0.01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with alpha5beta1-integrin.
J Mol Endocrinol 2004 Jun
PMID:Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. 1517 17

The L1 molecule has emerged as a promising new biomarker for the diagnosis and prognosis of human ovarian and endometrial tumors. It was initially described as an adhesion molecule for neural cells but its function on tumor cells is less well known. In this article, the role of L1 in promoting tumor cell adhesion and migration is discussed. The question of how L1 determination in tumor tissue samples, serum and ascites could potentially improve the diagnosis and monitoring of gynecologic tumor patients is also addressed. The presence of L1 in tissue and serum was found to be associated with recurrent disease and short survival, independently of the tumor's histological type. This provides an alternative classification of gynecologic tumors according to their aggressiveness rather than their histology. L1 expression was correlated with disease progression even in patients with Stage I endometrioid-type endometrial tumors, identifying them as high-risk patients on preoperative curettage specimens. Monitoring of soluble L1 during the follow-up period was found to signal disease progression and recurrence before clinical symptoms occur. L1-based diagnosis and prognosis has the potential to contribute to an improved disease management and could represent the basic rationale for novel tailored therapy.
Expert Rev Mol Diagn 2004 Jul
PMID:L1 (CD171) as a novel biomarker for ovarian and endometrial carcinomas. 1522 93

Breast tumors can be imaged by different modalities: mammography is the most widely used technique because of its diagnostic value, patient compliance and low costs. Some techniques such as ultrasound (US) are often indicated, while others, such as digital mammography and magnetic resonance imaging (MRI) are still under evaluation and seem to be very promising. Among the nuclear medicine techniques breast scintigraphy with (99m)Tc-labelled lipophilic cations (SestaMIBI or tetrofosmin), positron emission tomography (PET) with 18F-2-deoxy-2-fluoro-D-glucose (FDG) have been evaluated in many clinical trials. At present breast scintigraphy has limited applications due to its poor spatial resolution, which has a minimum of 8 mm. It is questionable whether single photon emission tomography (SPECT) can offer any substantially better information on the breast; however, SPECT is more accurate in detecting axillary lymph nodes. Recent approaches using breast dedicated collimators and cameras have greatly improved the SPECT resolution and sensitivity. The most interesting technique offered by nuclear medicine today are PET and lymphoscintigraphy with the intraoperative detection of handled gamma probe. The sentinel node detection has achieved a large consensus of reliability and at present it has an important place in the clinical management. In the same time many authors have acknowledged the value of PET in the differential diagnosis of breast lesions and in locoregional staging, since breast cancer is strongly avid for glucose. PET demonstrated also its efficacy in detecting axillary lymph node metastases. Even in some clinical trials its accuracy proved nearly comparable to that of lymphoscintigraphy with sentinel node biopsy, other studies showed that PET scanning does not currently have adequate spatial resolution to detect both micro- and small macrometastatic disease in axillary lymph nodes. The added value of PET in breast cancer staging is that with a single examination PET allows the characterisation of breast lesions, in addition to complete viewing of the entire body. Whole-body PET may substitute other diagnostic assessments by examining the various regions of potential tumour spread. The current diagnostic work-up for pre- and postoperative staging includes various examinations: chest X-rays, US of the abdomen, mammography of the contralateral breast. Bone scintigraphy with (99m)Tc-diphosphonates and laboratory tests can also be considered in women with large tumors or in symptomatic patients. Computed tomography (CT) and MRI may be used in order to resolve particular diagnostic problems. The current application of some of these modalities depends on the risk of the single patient of developing metastatic spread, which is revealed by a number of prognostic parameters of tumor aggressiveness and of course, clinical stage. Bone scintigraphy and PET may be useful in monitoring therapy response and in detecting tumour relapses during follow-up. In particular PET guided by tumor markers measurements shows to detect more lesions than other non nuclear medicine modalities.
Q J Nucl Med Mol Imaging 2004 Jun
PMID:Position of nuclear medicine modalities in the diagnostic work-up of breast cancer. 1524 12

Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I) and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) enzymes play a key role in regulation of fatty acid oxidation and in ketogenic pathways, respectively. Their expression are regulated by fatty acids mainly by the peroxisome proliferator-activated receptor alpha (PPARalpha). To investigate possible mechanisms through which cancer alters the lipid metabolism, we analyzed by Northern blot, the mRNA relative abundance of these proteins in liver from healthy and DMBA-induced mammary tumor-bearing rats fed a low or high corn oil diet. Serum levels of lipids, body weight and mass were also determined. Whereas mRNA steady-state levels of CPT I and mit HMG-CoA synthase were unaffected by the presence of the extra-hepatic tumor, the cancer state seemed to modify the regulation of the expression of these genes by high fat diet. We hypothesize that putative changes in PPARalpha mRNA levels could have contributed to such alterations. These results, together with changes in serum lipid profiles, body weight and mass, indicate fat mobilization and non-enhanced oxidation rates despite a high-fat feeding. This effect of the cancer state could be related to tumor aggressiveness and suggest a preferential redirection of long-chain fatty acids into energetic and specific pathways of the cancer cells.
Int J Mol Med 2004 Aug
PMID:Influence of DMBA-induced mammary cancer on the liver CPT I, mit HMG-CoA synthase and PPARalpha mRNA expression in rats fed a low or high corn oil diet. 1525 79

The contribution of VEGF (vascular endothelial growth factor) to angiogenesis and tumor aggressiveness has been shown in several tumor types, but no comparative data regarding the impact of the VEGF-subtypes on endothelial and tumor cell protection are available. Therefore, we analysed the cytoprotective effects of the two major soluble VEGF-subtypes, VEGF-121 and -165, on HUVEC cell cultures (human umbilical vein endothelial cells) and squamous cell carcinoma (SCC) cell lines after ionizing radiation. We performed clonogenic analyses and proliferation assays for evaluation of cell survival and proliferative activity. Experiments were performed employing different intensities up to 8 Gy with or without added recombinant VEGF-121 or -165 and compared to non-irradiated cultures. To evaluate a possible contribution of the VEGF-receptors, we performed immunohistochemical stainings of VEGF-R1 (flt), -R2 (KDR,flk), and Neuropilin-1. In the SCC cell lines and HUVEC cultures, cell survival and proliferative activity were reduced in a dosage-dependent manner. The addition of VEGF-121 yielded a significant increase of resistance from 1.2 to 2.7 Gy (+125%) for killing 50% of subjected cells, while VEGF-165 was less effective in this regard (+83%). Conversely, in HUVEC cultures, 50%-survival was increased more strongly by VEGF-165 compared to VEGF-121 (+100% vs. +43%). Accordingly, proliferation was more intensely stimulated in HUVECs by VEGF-165 than by VEGF-121. VEGF-receptors were expressed in all cell cultures analysed at comparable levels. We conclude that the two VEGF-subtypes differentially increase the survival of tumor and endothelial cells after irradiation in vitro. We hypothesise, that the release of VEGF by the tumor protects tumor cells and endothelium resulting in increased radiation resistance.
Int J Mol Med 2005 Jan
PMID:VEGF-subtype specific protection of SCC and HUVECs from radiation induced cell death. 1558 41

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors.
 ...
PMID:c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. 1558 32


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