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At least 829 records · Page 46Linked to original sources
PubMed2003

MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival.

Crucial event in the metastasis of cancer cells is the secretion of matrix metalloproteinases (MMPs), which are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-2 (MMP-2) is a gelatinase, which degrades basement membrane type-IV collagen. Immunohistochemistry was performed to detect MMP-2 protein in 135 infiltrative breast carcinomas. MMP-2 was studied along with clinicopathological parameters (tumor size, histological type, nuclear and histological grade, stage, lymph node status, ER, and PR), patients' survival and tissue inhibitor metalloproteinase-2 (TIMP-2), Ki-67, and p53 proteins. MMP-2 immunoreactivity was detected in the cytoplasm in cancer cells in 102 (75.6%) and in both tumor and tumor stromal cells in 37 (27.4%) of 135 cases respectively. MMP-2 reactivity in cancer cells displayed a statistically significant association with tumor size > 2 cm (p = 0.022). In tumor stromal cells a strong parallel association was observed between the expression of MMP-2 and TIMP-2 (p = 0.015), while an inverse correlation was found between MMP-2 and both Ki-67 and p53 (p = 0.033 and p = 0.034 respectively). In the subgroup with negative lymph nodes MMP-2 was also inversely associated with p53 in cancer cells (p = 0.045). Finally a statistically significant association was revealed using Kaplan-Meier and Cox's proportional hazard regression model between the MMP-2/TIMP-2 phenotype and patients' better survival (p = 0.021). Our results point out the strong relation between MMP-2 and TIMP-2 and the effect of the MMP-2/TIMP-2 phenotype in the patients' overall survival. The inverse correlation between MMP-2 and both Ki-67 and p53 can be explained by the potential inhibition of MMP-2 by TIMP-2. These results suggest the necessity of further investigation.

Adult↗
PubMed2003

Socio-economic-position overall and cause-specific mortality in an Italian rural population.

STUDY OBJECTIVE: To investigate the association between socio-economic position, overall and cause-specific mortality, and risk factors in a sample of men and women in the Italian population. DESIGN: Cohort study. MATISS Project (Malattie Aterosclerotiche Istituto Superiore di Sanità). SETTING: Rural area, Province of Latina, Lazio, central Italy. PARTICIPANTS: Baseline data were obtained for 8512 subjects (3982 men and 4530 women), 20-75 years of age, of whom 713 died during 11 (range 2; 15) years of follow-up. Education and occupation (used as measures of socio-economic position), smoking history, alcohol consumption, health status measures, blood pressure, plasma lipids and ECGs were collected at baseline. Linear and logistic regressions were performed to examine the association between socioeconomic position and risk factors. The hazard ratios (HRs) of all-cause, CVD and cancer mortality, according to educational level and occupational categories were computed using Cox proportional hazard models. MAIN RESULTS: The lower social groups had a more adverse risk factors profile with the exception of smoking habit in women and HDL cholesterol in men. The risk of death in college educated men was 50% of that found for men with no formal education. The risk of cancer in the least educated was 60% higher than for highly educated men. No clear pattern was observed in women. The HRs were not substantially changed when controlling for potential confounding factors. In both men and women mortality did not vary by occupational class. CONCLUSIONS: The association observed between education and mortality was stronger than previously reported in Italy. This may reflect changes in risk factors profile; in particular with regard to smoking habit. The effect of changes in risk factor distribution will become apparent in future mortality and morbidity patterns.

Adult↗
PubMed2000

Profound changes in the GH-IGF-I system in adolescent girls with IDDM: can IGFBP1 be used to reflect overall glucose regulation?

Disturbances in the relations between insulin, growth hormone (GH) and insulin-like growth factor I (IGF-I) may be a major cause behind deteriorated metabolic control in adolescent girls with type I diabetes. These patients have increased GH secretion and low IGF-I concentrations. The aim of this study was to identify possible endocrine mechanisms behind good and poor glycaemic control in such girls, focusing on the insulin-GH-IGF-I axis. Ten girls with well-controlled insulin-dependent diabetes mellitus (IDDM), hemoglobin A1c (HbA1c) 6.5+/-0.4% (normal range 3.9-5.2%) and nine healthy controls were investigated and compared with 11 girls with poor glucose regulation, HbA1c 10.9+/-0.4%, and their corresponding controls. Serum profiles of glucose, insulin, GH and IGF-binding protein 1 (IGFBP1) were analysed in addition to IGF-I and HbA1c. Two interesting observations were made. GH concentrations were equally elevated in the two diabetic groups regardless of metabolic control (mean 24 h GH - girls with poorly controlled diabetes 10.0+/-1.0 mU/L vs 9.8+/-1.7 - girls with well-controlled diabetes; p=ns). Likewise, the IGF-I concentrations were reduced to the same extent (233+/-19 vs 242+/-23 microg/L; p=0.75). Secondly, despite similar insulin concentrations (mean 24 h insulin - girls with poorly controlled diabetes 22.9+/-2.6 and girls with well-controlled diabetes 27.3+/-2.9 mU/L, respectively; p=0.26), there was a marked difference in IGFBP1 concentrations between the two groups with IDDM (mean IGFBP1 - girls with poorly controlled diabetes 70.5+/-9.1 microg/L vs girls with well-controlled diabetes 28.6+/-3.3; p<0.001). Despite equally elevated GH concentrations that may induce insulin resistance, the markedly lower concentrations of IGFBP1 in the well-controlled group indicate a higher hepatic insulin sensitivity in these girls compared with those with a poor control. Furthermore, in spite of similar total IGF-I concentrations, the lower IGFBP1 concentrations may result in higher IGF-I bioactivity in the well-controlled group. This may be reflected in better growth of the well-controlled group whose height of 168.7+/-0.9 vs 163.6+/-1.2 cm was significantly different (p<0.004). IGFBP1 may be a marker of overall insulinization in adolescents with type 1 diabetes, independent of the absolute insulin dose used for therapy.

Journal Article↗
PubMed2004

Values for comparison of WAIS-III index scores with overall means.

The Wechsler Adult Intelligence Scale--Third Edition (WAIS-III; Wechsler, 1997b) provides factor-based index scores but allows only for pairwise comparison of these scores, producing inflated Type I error rates and reducing profile interpretability. This article provides tables for simultaneous comparison to the overall mean index score, thus reducing error rates and aiding interpretation. The Working Memory Index or Processing Speed Index can also be specifically compared when an individual is believed to have a condition, such as a learning disability or traumatic brain injury, associated with the selective depression of these indexes. Tables for the infrequency of specific differences are also provided, allowing the practitioner to note how unusual an obtained difference is in the general population.

Adult↗
PubMed1988

The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch.

The lin-12 gene seems to control certain binary decisions during Caenorhabditis elegans development, from genetic and anatomical studies of lin-12 mutants that have either elevated or reduced levels of lin-12 activity. We report here the complete DNA sequence of lin-12: 13.5 kilobases (kb) derived from genomic clones and 4.5 kb from complementary DNA clones. It is of interest that the predicted product is a putative transmembrane protein, given that many of the decisions controlled by lin-12 activity require cell-cell interactions for the correct choice of cell fate. In addition, the predicted lin-12 product may be classified into several regions, based on amino acid sequence similarities to other proteins. These include extensive overall sequence similarity to the Drosophila Notch protein, which also is involved in cell-cell interactions that specify cell fate; a repeated motif found in proteins encoded by the yeast cell-cycle control genes cdc10 (Schizosaccharomyces pombe) and SWI6 (Saccharomyces cerevisiae); and a repeated motif exemplified by epidermal growth factor, found in many mammalian proteins.

Animals↗
PubMed1999

The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction.

The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most unusual since they are unrelated at the sequence level and they utilize completely different mechanisms to catalyze the same overall reaction. The type I enzymes catalyze a cis-dehydration of 3-dehydroquinate via a covalent imine intermediate, while the type II enzymes catalyze a trans-dehydration via an enolate intermediate. Here we report the three-dimensional structures of a representative member of each type of biosynthetic DHQase. Both enzymes function as part of the shikimate pathway, which is essential in microorganisms and plants for the biosynthesis of aromatic compounds including folate, ubiquinone and the aromatic amino acids. An explanation for the presence of two different enzymes catalyzing the same reaction is presented. The absence of the shikimate pathway in animals makes it an attractive target for antimicrobial agents. The availability of these two structures opens the way for the design of highly specific enzyme inhibitors with potential importance as selective therapeutic agents.

Binding Sites↗
PubMed1996

Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma.

Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Laurén, WHO and tumour-node-metastasis (TNM). Cox's multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters.

Aged↗
PubMed1997

Association of tumour vasculature with tumour progression and overall survival of patients with non-early gastric carcinomas.

In order to investigate the relationship between intratumoral vasculature and progression of gastric carcinomas and between vessel counts and survival of patients with non-early gastric carcinoma, we counted the intratumoral microvessels and compared their numbers with clinicopathological parameters, as well as with the patients' survival. Microvessels were stained with anti-CD34 monoclonal antibody before counting by microscopy (x200). In a group of 181 patients who had undergone tumour resection and were followed for more than 24 months the vessel counts for 83 patients with stage IV disease were significantly higher than those for patients with any other stage of disease. Among various clinicopathological variables, haematogenous metastasis, lymph node metastasis, peritoneal metastasis, stage IV disease and non-curative resection were more frequent in the patients with highly vascularized tumours (intratumoral vessel count > 155) than in those with less vascularized tumours. As a classification of stage IV disease such as haematogenous or peritoneal metastasis generally indicates non-curative resection, it can be considered that the development of stage IV disease is associated with the increase in tumour angiogenesis. Both univariate and multivariate analyses showed that the intratumoral vessel count was significantly predictive of overall survival, when tested as either a continuous or dichotomous variable. Cox hazards model analysis showed that the vessel count was one of the significant and independent prognostic variables. Patients with highly vascularized tumours were significantly more likely to die than those with less vascularized tumours. Assessment of tumour vasculature may therefore be important, not only for its prognostic value, but also as it may help to predict responses to angiogenesis-inhibiting agents.

Adult↗
PubMed2006

3' UTR seed matches, but not overall identity, are associated with RNAi off-targets.

Off-target gene silencing can present a notable challenge in the interpretation of data from large-scale RNA interference (RNAi) screens. We performed a detailed analysis of off-targeted genes identified by expression profiling of human cells transfected with small interfering RNA (siRNA). Contrary to common assumption, analysis of the subsequent off-target gene database showed that overall identity makes little or no contribution to determining whether the expression of a particular gene will be affected by a given siRNA, except for near-perfect matches. Instead, off-targeting is associated with the presence of one or more perfect 3' untranslated region (UTR) matches with the hexamer or heptamer seed region (positions 2-7 or 2-8) of the antisense strand of the siRNA. These findings have strong implications for future siRNA design and the application of RNAi in high-throughput screening and therapeutic development.

3' Untranslated Regions↗
PubMed2004

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage.

Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (P<0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

Astrocytoma↗
PubMed2005

Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts.

We examined the associations of body mass index (BMI), waist circumference, a history of diabetes, and cigarette smoking with risk of pancreatic cancer among 37,147 women and 45,906 men followed up during 560,666 person-years in the Swedish Mammography Cohort and the Cohort of Swedish Men; 136 incident cases of pancreatic cancer were diagnosed. The multivariate rate ratio (RR) of pancreatic cancer for obese women and men (BMI > or =30 kg/m(2)) was 1.81 (95% CI: 1.04-3.15) compared to those with a BMI of 20-25 kg/m(2). For a difference of 20 cm (about two standard deviations) in waist circumference, the multivariate RRs were 1.32 (95% CI: 0.73-2.37) among women and 1.74 (95% CI: 1.00-3.01) among men. Pancreatic cancer risk was associated with history of diabetes (multivariate RR: 1.88; 95% CI: 1.09-3.26) and cigarette smoking (multivariate RR for current compared with never smokers: 3.06; 95% CI: 1.99-4.72). Current smokers of > or =40 pack-years had a five-fold elevated risk compared with never smokers. Risk among past smokers approached the RR for never smokers within 5-10 years following smoking cessation. Findings from this prospective study support positive relationships of overall obesity, abdominal adiposity, diabetes and smoking with risk of pancreatic cancer.

Abdominal Fat↗
PubMed2006

A model of the natural history of screen-detected prostate cancer, and the effect of radical treatment on overall survival.

The lead time and over-detection associated with prostate-specific antigen (PSA) screening, and generational improvements in all-cause mortality, make prostate cancer outcome studies from the pre-PSA era difficult to interpret in a contemporary setting. We developed a competing-risks hazard model to estimate the natural history of screen-detected prostate cancer, and the impact of radical treatment on overall survival. The model of hazard of mortality was fitted to clinical outcome data from the pre-PSA era, and the effects of screening, generational mortality improvements and radical treatment were incorporated. Sensitivities to the choice of baseline data and values of key parameters were assessed. Lead-time estimates in men diagnosed aged 55-59 years were 14.1, 9.3 and 5.0 years for men with Gleason scores <7, 7 and >7, respectively, assuming biennial screening with 100% attendance. Central estimates of 15-year prostate cancer mortality for conservative management of screen-detected prostate cancer ranged from 0 to 2% for Gleason scores <7, 9 to 31% for Gleason score 7 and 28-72% for Gleason scores >7. For men aged 55-59 years at diagnosis, the predicted absolute 15-year survival benefit from curative treatment was 0, 12 and 26% for men with Gleason scores <7, 7 and >7, respectively. Estimates of the survival benefit of radical treatment were relatively insensitive to values of key parameters. The case for curative treatment, rather than conservative management, of screen-detected localised prostate cancer is strongest in men with high-grade disease. This conclusion contrasts with current patterns of care.

Aged↗
PubMed1999

Totally implantable central venous access ports for high-dose chemotherapy administration and autologous stem cell transplantation: analysis of overall and septic complications in 68 cases using a single type of device.

Sixty-eight patients suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose chemotherapy and autologous stem cell transplantation. They underwent placement of a central venous port via the subclavian vein for delivery of chemotherapy and reinfusion of stem cells. All patients were followed prospectively for device-related and overall complications, comprising a total of 18,213 days in situ (median: 267 days, range: 90-480). One patient experienced a pneumothorax (1.4%) spontaneously resolved, as an acute toxicity. Two patients (2.8%, 0.1 episodes/1000 days of use) were forced to have the port removed due to infection, caused by Streptococcus mitis in one case, while the causative agent was not identified by laboratory tests in the second. The other 66 patients completed the therapeutic programme, including peripheral stem cell reinfusions and supportive care, such as i.v. antibiotics, antiemetics or fluid administration and blood sample collection, without additional complications. In conclusion, the use of totally implantable central venous access ports has resulted in good long-term access to central veins, in spite of the severe neutropenia and increased septic risk of this category of oncology patients.

Adult↗
PubMed2001

Similar myeloid recovery despite superior overall engraftment in NOD/SCID mice after transplantation of human CD34(+) cells from umbilical cord blood as compared to adult sources.

Umbilical cord blood (UCB), bone marrow (BM) and mobilized peripheral blood (mPB) are used as sources of hematopoietic stem cells for transplantation. The NOD/SCID mouse model was used to compare the lineage-specific repopulating potential of CD34(+) cells derived from these sources. Six to 8 weeks after transplantation, blood, BM, spleen, liver and thymus, were harvested, and analyzed by flow cytometry using CD34, CD45, myeloid, and lymphoid lineage-specific antibodies. Fifty percent engraftment of human cells in bone marrow of mice was estimated to be reached with 0.55 x 10(6) CD34(+) UCB cells or with 7.9 x 10(6) CD34(+) cells from adult sources, illustrating a 10-fold superiority of UCB CD34(+) cells to engraft NOD/SCID mice. Lineage-specific characterization of engrafted human cells showed that the high engraftment potential of CD34(+) cells from UCB was due to a preferential B cell development (2-81%). In contrast, comparable percentages of myeloid cells were found following transplantation of CD34(+) cells from UCB, BM and mPB (1-38%), and occurred at significant levels only at relatively high doses. Since the CD34 content of UCB transplants is usually at least one log lower than of transplant from adult sources, these results correspond to the clinical findings with UCB transplantation showing a relatively high overall engraftment, but delayed myeloid recovery.

Adult↗
PubMed2003

Micrometastases in apheresis products predict shorter progression-free and overall survival in patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ABSCT).

The presence of cancer cells in autografts of breast cancer patients has been described to have prognostic value or directly lead to relapse. Previously, we demonstrated that apheresis products (APs) collected after induction chemotherapy have a significantly lower likelihood of tumor cell contamination. Here, we examine the prognostic value of micrometastases in autografts. Data from 83 patients with breast cancer treated with autologous blood stem cell transplantation were analyzed. Pan-cytokeratin-FITC conjugated antibodies were used to detect contaminating breast cancer cells in the APs. Progression and survival data analyzed on the basis of three or fewer cancer cells showed no significant differences in outcomes. Of the 83 patients, 11 had more than three cancer cells detectable in their APs. In total, 72 patients were shown to have less than three cells detectable. When patients with more than three cells were compared to patients with 0-3, we found statistically significant differences in progression-free survival. We also found a significant difference in overall survival (OS) between the two groups. No difference was observed in OS since the time of diagnosis. We conclude that patients with more than three contaminating cells in their APs have micrometastases and represent a poor prognosis group.

Adult↗
PubMed2003

ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML).

Matched unrelated donor transplants have an increased risk of severe graft-versus-host disease and transplant-related mortality (TRM). ATG has been introduced to decrease GvHD and to facilitate engraftment. We conducted a retrospective analysis of 333 patients with chronic myelogenous leukemia, who were treated with Fresenius ATG (n=145, average=90 mg/kg bw, range 40-90 mg/kg bw) or standard immunosuppression without ATG (n=188). Both groups were comparable regarding distribution of age, sex, HLA-matched vs mismatched donors. ATG Fresenius led to a faster leukocyte engraftment, decreased the incidence of acute GvHD and TRM (P=0.01 and P=0.03) and led to a significant better overall survival (70 vs 57%, P=0.03). We concluded that a prospective randomized study is needed to evaluate the definite role of ATG in hemopoietic stem cell transplantation.

Acute Disease↗
PubMedDate not supplied

Detection of a concomitant distal deletion in an inverted duplication of chromosome 3. Is there an overall mechanism for the origin of such duplications/deficiencies?

We describe the first inverted duplication of the p21.3p26 region of chromosome 3 in a child with phenotypic features of the trisomy 3p syndrome. This uncommon type of aberration was verified by multicolour fluorescence in situ hybridisation (FISH) using yeast artificial chromosome (YAC) clones from chromosome 3 (CEPH library). With a newly constructed YAC clone from the 3p26 region an unexpected subtelomeric deletion was diagnosed in the aberrant chromosome 3. Using the primed in situ labelling (PRINS) method, telomeres were found to be present on the recombinant chromosome 3. The repeated appearance of concomitant distal deletions in inverted duplications suggests that an overall mechanism exists for the origin of such duplications/deficiencies.

Chromosome Aberrations↗
PubMed2005

Time and PSA threshold model prognosticates long-term overall and disease-specific survival in prostate cancer patients as early as 3 months after external beam radiation therapy.

The specific aim of this analysis was to evaluate the capability of a time and prostate-specific antigen (PSA) threshold model to prognosticate overall survival (OS) and disease-specific survival (DSS) based on early PSA kinetics after radiotherapy for prostate cancer by retrospective review of outcomes in 918 patients. Crossing below analyzed PSA thresholds at specific defined time points reduced disease-specific death hazard ratios to relative to the cohort above threshold. The time and PSA threshold model demonstrates the ability to prognosticate OS and DSS as early as 3 months post-radiotherapy for prostate cancer.

Aged↗