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PubMed2002

Immunohistochemical study of pro-apoptotic factors Bax, Fas and CPP32 in urinary bladder cancer: prognostic implications.

Apoptosis is a process which can retard the progress of malignant tumours. In the present study we investigated the immunohistochemical expression of three pro-apoptotic proteins (Bax, Fas receptor and caspase 3 - CPP32) as well as the apoptotic index (TUNEL Index) in 53 urothelial carcinomas of the urinary bladder. We examined all possible relationships between these factors and clinicopathological variables, as well as the patients' disease free survival. All three markers, and in particular the Fas receptor, were detectable in a remarkable proportion of specimens, however, none of the markers examined was associated with any clinicopathological parameter. In multivariate statistical analysis, Bax emerged as an independent predictor of a favourable prognosis. It is noteworthy that none of the pro-apoptotic markers examined was directly linked with the apoptotic rate of the malignant cells.

Apoptosis↗
PubMedDate not supplied

Flow cytochemical analysis of peripheral lymphocytes in chronic B-lymphocytic leukemia. Prognostic role of the blast count determined by the H*1 system and its correlation with morphologic features.

Peripheral blood samples from 148 previously untreated patients with chronic B-lymphocytic leukemia (B-CLL) were analyzed with the Technicon H*1 flow cytometer. The absolute number and the percentage values of both LUCs (large unstained cells) and blasts were correlated with survival, as well as with well-known prognostic factors including morphological subtypes of lymphoid cells. Results showed that patients at the most advanced clinical stages (Rai: III and IV; Binet: C) had the highest percentage and count of both LUCs and blasts. Furthermore, the proportion of LUC positively correlated with the following prognostic factors: peripheral lymphocytosis (greater than 50 x 10(9)/l); marked splenomegaly (greater than 10 cm UCM); % of circulating prolymphocytes, % immunoblasts, and % LGL. Our data analysis further revealed that chemotherapy produced a greater reduction of both the LUCs and of the blast count than of that of small lymphocytes. An increase in LUC count was found to coincide with deterioration of clinical status (progressive changes in the clinical stages, occurrence of prolymphocytoid transformation). A rapid increase in blast count was found to occur in concomitance with the development of Richter's syndrome, and correlated positively with the number of peripheral immunoblasts determined by light microscopy. Moreover, a blast percentage higher than 7% had the strongest predictive relation to survival rate when compared with other hematological parameters (lymphocytosis greater than 50 x 10(9)/l, % of LUCs greater than 12%, LUC to lymphocyte ratio greater than 16%, LUCs count greater than 2.2 x 10(9)/l). In the light of these findings, it may be suggested that the presence both of larger proportions of LUCs and of blasts measured with the flow cytometry may be considered unfavorable prognostic factors in B-CLL. However, based on morphological and multivariate statistical analyses, the blast count proved to be the most important prognostic parameter determined by the H*1 system in B-CLL.

Adult↗
PubMed1998

Multivariate karyometric approach in differential diagnosis of follicular thyroid neoplasms. A study of 31 cases.

A retrospective analysis of 19 follicular adenomas, 12 minimally invasive follicular carcinomas and 3 widely invasive follicular carcinomas of the thyroid was performed on 5-microm-thick Feulgen-stained paraffin sections by means of a semiautomatic system for picture analysis. The major aim was to assess the potential of multiparameter karyometry for separation of the first two tumour types. Sixteen planimetric and densitometric features were defined in each case on 200-300 randomly selected nuclei and processed by a number of uni- and multivariate statistical methods. Despite predominantly significant ANOVA results a substantial overlap between tumour groups limited the practical usefulness of any karyometric feature alone. Factor and cluster analyses indicated independence of planimetric and densitometric parameters from each other, which was of crucial importance in finding an optimal subset of variables for discriminant analysis. The classification rule derived from the latter procedure was checked by the "jack-knife" method, by classification of 3 widely invasive cancers and by hierarchical tumour clustering. Sensitivity and specificity of the model for detection of malignancy were 100% and 94.7%, respectively. A multivariate karyometric approach, when applied correctly, can be a useful tool for differentiation between follicular adenomas and minimally invasive follicular carcinomas of the thyroid.

Adenocarcinoma, Follicular↗
PubMed2006

Testosterone levels in men with erectile dysfunction.

OBJECTIVE: To investigate the frequency of hypogonadism in men with erectile dysfunction (ED) and to assess which factors are related with low testosterone levels. PATIENTS AND METHODS: In all, 165 men with ED were assessed; the evaluation included: hormonal profiles, serum total and free testosterone (using Vermeulen's formula) levels, and self-reported questionnaires on erectile function and desire domains of the International Index of Erectile Function. The frequency of hypogonadism was established using total and free testosterone levels as diagnostic criteria. The factors that might influence testosterone levels were evaluated by univariate and multivariate statistical analysis, and a logistic regression was used to determine which factors can predict free testosterone levels below normal limits (biochemical hypogonadism). RESULTS: Using the total testosterone levels, 4.8% of the men were hypogonadal, whereas when using the free testosterone levels, 17.6% were hypogonadal. In the univariate analyses, not smoking and hypertension were associated with lower total and free testosterone levels. Ageing, absence of nocturnal erections and a lower erectile function score were only associated with lower free testosterone serum levels. There was no association between total and free testosterone levels and desire. In the multivariate analysis, only total testosterone levels were related to hypertension, while free testosterone levels were related to age and nocturnal erections. For biochemical hypogonadism, simple logistic regression analysis selected age, erectile function score and aetiological diagnosis of ED as predictors. In the multivariate analysis only the erectile function score had significant independent prognostic value. CONCLUSIONS: The frequency of hypogonadism is higher when free testosterone levels are used for diagnosis. The total and free testosterone levels were not related to the level of sexual desire in men with ED. The free testosterone levels could be related to the quality and frequency of nocturnal erections, and when ED is more severe, it is more probable that free testosterone levels are below the 'normal' limit.

Age Factors↗
PubMed1995

Binding of anticancer drugs to human serum albumin studied by reversed-phase chromatography.

The interaction of eight commercial anticancer drugs with human serum albumin (HSA) was studied by charge-transfer reversed-phase thin-layer chromatography in neutral, acidic, basic and ionic environments (NaCl and CaCl2) and the relative strength of interaction was calculated. Each drug interacted with HSA in a neutral environment, and the pH and the presence of mono- and divalent cations markedly affected the strength of interaction. The capacity of anticancer drugs to interact with HSA depended considerably on their molecular structure. Various multivariate statistical methods such as principal component analysis and cluster analysis indicated that the steric parameters of anticancer drugs have a considerable impact on their capacity to bind to HSA. The influence of electronic parameters on the HSA-drug interaction was of secondary importance.

Antineoplastic Agents↗
PubMed1998

A long-term analysis of 620 patients with malignant melanoma at a major referral center.

BACKGROUND: A univariate and multivariate statistical analysis of a single surgeon's experience with resectable malignant melanoma during 26 years (November 1970 to August 1996) was conducted. METHODS: Six hundred twenty consecutive patients were registered. Univariate analysis of disease-free survival (DFS) and melanoma survival (MS) was calculated by the Kaplan-Meier method and correlated to American Joint Committee on Cancer stage, thickness, ulceration, site, lymph node involvement, age, sex, type, and excision margins. Linear trends, log-rank test, and pairwise comparisons were used to discriminate differences in survival curves. A Cox proportional hazards model was used for multivariate analysis and determination of relative risk. RESULTS: Univariate analysis of stage, thickness (in millimeters), ulceration, lymph node involvement, age, type, and margins of excision were predictive of DFS (5 years, 85.7%; 10 years, 82.5%) and MS (5 years, 92.2%; 10 years, 87.8%) (P < .01). Multivariate analysis revealed correlations with thickness, ulceration, and age in predicting DFS (relative risk = 2.75, 2.21, and 1.47, respectively) and MS (relative risk = 2.66, 2.47, and 1.48, respectively). The 5-year MS rate was 73.3% and 93.3% for patients with positive and negative lymph nodes, respectively. Of 133 patients who underwent lymph node dissection, 28 (21.1%) had nodal metastases. Patients with primary melanomas thicker than 4 mm had 50% metastatic involvement of their lymph nodes. CONCLUSIONS: Our findings reveal that thickness, ulceration, and age are the most important predicting factors in DFS and MS. The data support including ulceration and age in modifying American Joint Committee on Cancer staging for melanoma.

Adult↗
PubMed2005

Local and systemic immune and inflammatory responses to Helicobacter pylori strains.

Colonization with Helicobacter pylori eventuates in varied clinical outcomes, which relate to both bacterial and host factors. Here we examine the relationships between cagA status, serum and gastric juice antibody responses, and gastric inflammation in dyspeptic patients. Serum, gastric juice, and gastric biopsy specimens were obtained from 89 patients undergoing endoscopy. H. pylori colonization and cagA status were determined by histology, culture, and PCR methods, and acute inflammation and chronic inflammation in the gastric mucosa were scored by a single pathologist. Serum and gastric juice antibodies to H. pylori whole-cell and CagA antigens were determined by enzyme-linked immunosorbent assay. Relationships between variables were sequentially analyzed using univariate and multivariate statistical methods. Of the 89 subjects, 62 were colonized by H. pylori. By univariate analyses, levels of serum immunoglobulin G (IgG) and IgA and gastric juice IgA antibodies against whole-cell and CagA antigens each were significantly higher in the H. pylori-positive group than in the H. pylori-negative group (P<0.001). H. pylori and CagA sero-positivities were both significantly associated with enhanced inflammation in gastric antrum and body (P<0.02). The presence of gastric juice antibodies to H. pylori antigens was associated with more severe gastric inflammation. However, in multivariate analyses, only the presence of serum antibodies against CagA and, to a lesser extent, whole-cell antigens remained significantly associated with acute and chronic inflammation in antrum and body (P<0.05). Thus, serum antibody response to CagA correlates with severity of gastric inflammation. Furthermore, given the relationships demonstrated by multivariate analysis, determination of gastric juice antibodies may provide a better representation of serum, rather than secretory, immune response.

Adult↗
PubMed1996

Quantitative structure-metabolism relationships for substituted benzoic acids in the rabbit: prediction of urinary excretion of glycine and glucuronide conjugates.

1. Quantitative relationships between molecular physicochemical properties of 24 substituted benzoic acids and their metabolic fate in the rabbit have been investigated using computational chemistry and multivariate statistical methods. 2. A total of 34 molecular properties were calculated for each compound using computational chemistry and were related statistically to the % molar recovery of glycine and glucuronide conjugates excreted in the urine of rabbits for the 24 compounds. 3. Compounds were successfully classified according to their dominant metabolic fate based on urinary excretion data, where stepwise linear regression analysis of the theoretical property data achieved good predictive fits for observed versus predicted % molar urinary recovery as glucuronide conjugates (r2 = 0.79) and % molar urinary recovery as glycine conjugates (r2 = 0.66). 4. Quantitative prediction of the urinary excretion of glucuronide and glycine conjugates of the parent compounds was achieved based on a statistical model using calculated molecular physicochemical parameters. Interpretation of the molecular properties, which are important for predicting the metabolic class, should give new insights into basic mechanisms of drug metabolism and underlying molecular recognition events that determine disposition and metabolism.

Animals↗
PubMedDate not supplied

Automated severity classification of AIDS hospitalizations.

To validate an automated AIDS severity-of-illness prognostic algorithm, 2,113 discharge summaries of HIV-infected patients were merged with the Problem-Oriented Medical Synopsis (POMS) and an HIV risk registry. The combination of a medically derived classification and staging algorithm with multivariate statistical techniques was used for automated severity-of-illness disease staging and prognostic assignment. The model correctly predicted the outcomes of 82% of all cases (death, survivorship) at discharge, and 66% of deaths.

Algorithms↗
PubMed1995

The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation.

PURPOSE: Current methods to clinically define head and neck tumor bulk are qualitative and imprecise. Although the American Joint Committee on Cancer (AJCC) staging system is important for this purpose, limitations exist. This study will investigate the prognostic value of computed tomography (CT) derived tumor volume measurements in comparison to AJCC stage and other significant variables. MATERIALS AND METHODS: Seventy-six patients with advanced head and neck squamous cell carcinoma were treated with concomitant boost accelerated superfractionated irradiation. Doses ranged from 68.4-73.8 Gy (median 70.2 Gy). Good quality pretherapy CT scans were available in 51 patients. Total tumor volume (TTV) estimates were derived from these scans using digital integration of primary tumor and metastatic lymphadenopathy. Actuarial and multivariate statistical techniques were applied to analyze local control. RESULTS: Thirty-six-month local control was 63%. TTV ranged from 5-196 cm3 (median 35 cm3) for all cases, 5-142 cm3 (median 17 cm3) for those controlled, and 16-196 cm3 (median 47 cm3) for local failures. There was a significant increase in failures above 35 cm3. Univariate analysis found that TTV, T-stage, N-stage, and primary site were each significant prognostic variables. Local control for TTV < or = 35 cm3 was 92% at 36 months vs. 34% for TTV > 35 cm3 (p = 0.0001). Multivariate analysis, however, found that TTV, primary site, and sex were important as independent variables; T and N stage were not independently significant unless TTV was removed from the model. CONCLUSIONS: This study demonstrates the prognostic significance of TTV in advanced carcinoma of the head and neck. This variable appears to be a more predictive than AJCC clinical stage. Quantitative tumor volume measurements may prove to be a useful parameter in future analyses of head and neck cancer.

Carcinoma, Squamous Cell↗
PubMedDate not supplied

Prediction of polar surface area and drug transport processes using simple parameters and PLS statistics.

Modeling of the calculated polar surface area of drugs with rapidly derived descriptors (i.e., the number of hydrogen bonds accepting oxygen and nitrogen atoms and the number of hydrogen atoms bonded to these) using partial least squares projection to latent structures (PLS) analysis is described. The statistical analysis showed strong relationships between the hydrogen-bonding descriptors and the calculated polar surface area of five chemically diverse sets of drugs (R2>0.93 and Q2>0.69, n = 11, 20, 45, 70, and 74, respectively). The statistical models (using H-bonding descriptors and log P) of transport across Caco-2 cells (n = 11), brain-blood partitioning (two data sets, n = 45 and 70) and percent intestinal absorption (n = 20) showed R2 = 0.92, 0.72, 0.76, and 0.81 and Q2 = 0.74, 0.75, 0.71, and 0.73, respectively. The inclusion of log P improved two models, had no effect on one model, and had a slightly negative impact on one model. The combination of H-bonding descriptors with log P is similar to the Lipinski "rule-of-five" mnemonic. However, by using a multivariate statistical method (e.g., PLS), the prediction becomes quantitative instead of qualitative. Good statistical models were derived which permit fast computational screening and prioritization of virtual compound libraries.

Blood-Brain Barrier↗
PubMed2004

Nanoprobe NMR spectroscopy and in vivo microdialysis: new analytical methods to study brain neurochemistry.

Nuclear magnetic resonance (NMR) spectroscopy was used to study the chemical composition of cerebrospinal fluid (CSF) microdialysate from the rat brain. In vivo microdialysis techniques were used in several brain regions including the frontal cortex, amygdala, striatum, nucleus accumbens and third ventricle and dialysate samples (20microl) were subsequently analyzed by one and two-dimensional 1H NMR experiments using a Varian nanoprobe. Neurochemical resonances were assigned on the basis of published chemical shifts [Lindon et al., Ann. Rep. NMR Spectrosc. 38 (1999) 1-88], correlation experiments and addition of standard compounds. Glucose, lactate, formate, pyruvate, creatinine, gamma-hydroxybutyrate, acetate, glutamate, glycine, tyrosine, isoleucine, leucine, alanine and choline were some of the neurochemicals unambiguously assigned. Additional studies in the frontal cortex showed that amino acids such as glutamate, alanine and isoleucine were sensitive to local tetrodotoxin (TTX) infusion. The NMR spectra were also subjected to multivariate statistical methods to compare the different brain regions examined. To our knowledge, the present experiments are the first to describe the combination of nanoprobe NMR technology with in vivo microdialysis for the analysis of brain neurochemistry in freely-moving rats.

Animals↗
PubMed2007

Multianalyte chemical identification and quantitation using a single radio frequency identification sensor.

We demonstrate an approach for multianalyte chemical identification and quantitation using a single conventional radio frequency identification (RFID) tag that has been adapted for chemical sensing. Unlike other approaches of using RFID sensors, where a special tag should be designed at a much higher cost, we utilize a conventional RFID tag and coat it with a chemically sensitive film. As an example, we demonstrate detection of several vapors of industrial, health, law enforcement, and security interest (ethanol, methanol, acetonitrile, water vapors) with a single 13.56-MHz RFID tag coated with a solid polymer electrolyte sensing film. By measuring simultaneously several parameters of the complex impedance from such an RFID sensor and applying multivariate statistical analysis methods, we were able to identify and quantify several vapors of interest. With a careful selection of the sensing film and measurement conditions, we achieved parts-per-billion vapor detection limits in air. These RFID sensors are very attractive as ubiquitous multianalyte distributed sensor networks.

Acetonitriles↗
PubMed2000

Natural immunoglobulins (contribution to a debate on biomedical education).

Immunology has contributed to biomedical education in many important ways since the creation of scientific medicine in the last quarter of the 19th century. Today, immunology is a major area of biomedical research. Nevertheless, there are many basic problems unresolved in immunological activities and phenomena. Solving these problems is probably necessary to devise predictable and safe ways to produce new vaccines, treat allergy and autoimmune diseases and perform safe transplants. This challenge involves not only technical developments but also changes in attitude, of which the most fundamental is to abandon the traditional stimulus-response perspective in favor of more "systemic" views. Describing immunological activities as the operation of a complex multi connected network, raises biological and epistemological issues not usually dealt with in biomedical education. Here we point to one example of systemic approaches. A new form of immunoblot (Panama blot), by which the reaction of natural immunoglobulins with complex protein mixtures may be analyzed by a special software and multivariate statistics, has been recently used to characterize human autoimmune diseases. Our preliminary data show that Panama blots can also be used to characterize global (systemic) immunological changes in chronic human parasitic diseases, such as malaria and schistosomiasis mansoni, that correlate with the clinical status.

Animals↗
PubMed1998

Identifying global anatomical differences: deformation-based morphometry.

The aim of this paper is to illustrate a method for identifying macroscopic anatomical differences among the brains of different populations of subjects. The method involves spatially normalizing the structural MR images of a number of subjects so that they all conform to the same stereotactic space. Multivariate statistics are then applied to the parameters describing the estimated nonlinear deformations that ensue. To illustrate the method, we compared the gross morphometry of male and female subjects. We also assessed brain asymmetry, the effect of handedness, and interactions among these effects.

Adult↗
PubMed2003

Study of the cultivar-composition relationship in Sicilian olive oils by GC, NMR, and statistical methods.

The aim of this research is to find if there is direct evidence relating the fatty acid composition of olive oils to specific cultivars grown within a well-limited geographical region. To group olive oils according to their own cultivars,(13)C high-field nuclear magnetic resonance (NMR) and gas chromatography (GC) were used to analyze 60 extra virgin olive oils from the same Italian region (southwestern Sicily) obtained from four monovarietal cultivars. The (13)C NMR spectrum provides information about glycerol triesters of olive oils, i.e., about the acyl composition of major components and about the fatty acids' positional distribution on the glycerol moiety. GC gives the complete fatty acid profile of olive oil samples. Selection of NMR and GC peaks on the basis of their sensitivity to the different cultivars was performed by using multivariate analysis of variance (MANOVA). Principal component analysis, tree clustering analysis, multidimensional scaling (MDS), and linear discriminant analysis (LDA) were then performed on the MANOVA-selected peaks. Results obtained from (13)C NMR and GC techniques combined with the multivariate statistical procedure are in good agreement and prove the usefulness of fatty acids analysis to group the monovarietal olive oils belonging to the same cultivars. Grouping of olive oils according to their cultivars occurs for particular (13)C resonances all belonging to fatty chains in the sn 1,3 position of the glycerol moiety.

Analysis of Variance↗
PubMedDate not supplied

Tumor angiogenesis predicts clinical outcome of node-positive breast cancer patients treated with adjuvant hormone therapy or chemotherapy.

PURPOSE: Experimental studies suggest that angiogenesis is necessary for breast cancer progression and metastasis and that it may play a role in responsiveness to some chemotherapeutic agents and to tamoxifen. To investigate whether angiogenesis predicts the clinical outcome of patients with node-positive breast cancer, we determined intratumoral microvessel density in a series of patients treated with either adjuvant hormone therapy (n=84) or chemotherapy (n= 107). PATIENTS AND METHODS: We monitored 191 patients for a median of 62 months. Intratumoral microvessel density was measured using light microscopy, and microvessels were immunostained using the anti-CD31 antibody. Microvessels were carefully counted (per 200x field) in the most vascularized area of each tumor. The results of intratumoral microvessel density were analyzed by both univariate and multivariate statistical analysis and were correlated with clinical outcome. RESULTS: In univariate analysis, intratumoral microvessel density was significantly associated with relapse-free survival and overall survival, both in patients who received adjuvant hormone therapy and those who received chemotherapy. In the group treated with adjuvant hormone therapy, estrogen receptor status was also predictive for both relapse-free and overall survival. The number of involved nodes was predictive for overall survival. In patients treated with adjuvant chemotherapy, the number of involved nodes, tumor size, and progesterone receptor status were significantly predictive for relapse-free and overall survival. Multivariate analysis showed that intratumoral microvessel density was the strongest independent predictor of outcome in both treatment groups. CONCLUSIONS: Intratumoral microvessel density is an independent predictive indicator in node-positive breast cancer patients treated with either adjuvant chemotherapy or adjuvant hormone therapy. Assessment of tumor angiogenesis may therefore be useful in selection of those patients who are more likely to benefit from conventional adjuvant therapies (i.e., those with minimally vascularized tumors) from those with highly vascularized and more aggressive tumors, for whom novel forms of systemic therapy are advocated.

Adult↗
PubMed2005

Field validation of antioxidant enzyme biomarkers in mussels (Perna viridis) and clams (Ruditapes philippinarum) transplanted in Hong Kong coastal waters.

Green-lipped mussels, Perna viridis, and Manila clams, Ruditapes philippinarum were sourced from "clean" sites in the Hong Kong region, depurated in a laboratory using uncontaminated filtered seawater for 8 days, and transplanted to a suspected gradient of chemically polluted sites in Hong Kong. After 14- and 28-days of field exposure, several antioxidant parameters including glutathione S transferase (GST), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) were quantified in gill and hepatopancreas tissues. Whole body tissue concentrations of polycyclic aromatic hydrocarbons (PAHs), petroleum hydrocarbons (PHCs), polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs) were determined in pooled site samples. Chemical analyses indicated that: (a) clams had higher levels of PAHs, PHCs, DDTs and PCBs, whereas mussels had higher hexachlorocyclohexane (HCHs) and there was no difference between species for dieldrin and remaining OCs; (b) Kat O should not be continued as a "clean" reference site for Hong Kong, because of the levels of contaminants measured and (c) PAH concentrations in the current survey were similar to those previously measured. Toxicological conclusions were: (a) antioxidant responses were different between species; (b) CAT and GST have highest utility in clams for field use in Hong Kong, whereas CAT in both gill and hepatopancreas tissue showed most potential in mussels; (c) significant induction of antioxidant responses over day 0 (excluding GPx in both tissues, and GST in mussel hepatic tissue); (d) groups of contaminants do not consistently induce antioxidant responses and (e) organochlorines and PCBs correlated significantly with CAT and GST in clam hepatopancreas and with CAT in mussel gill and hepatic tissue. Multivariate statistical techniques indicated little relationship between the site patterns for antioxidant responses and the contaminant gradients identified in body burden analysis.

Analysis of Variance↗