Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

Relationship between body composition and skeletal muscle eNOS.

OBJECTIVE: Owing to the relationship between nitric oxide related endothelial dysfunction, insulin resistance and cardiovascular disease in overweight individuals, we investigated if skeletal muscle endothelial nitric oxide synthase (eNOS) protein content and activity are lower in overweight than lean women. DESIGN: A total of 19 women (age 26.0+/-1.7 years) underwent a resting muscle biopsy, body composition analysis by hydrostatic weighing and peak aerobic capacity determination using indirect calorimetry (Study 1). An additional separate set of six lean (< or = 25% fat) and six overweight (>25% fat) women were subsequently studied for the determination of eNOS activity, and to better control for absolute peak aerobic capacity between lean and overweight women (Study 2). RESULTS: Skeletal muscle eNOS content was inversely related to percent body fat (r2 = 0.58, P < 0.01), and body mass index (r2 = 0.35, P < 0.05). Total eNOS activity was lower in overweight than lean women (2.09 +/- 0.22 vs 1.44 +/- 0.17 U, P < 0.05; n = 12), and was inversely related to percent body fat (r2 = 0.32, P = 0.05), and BMI (r 2 = 0.41, P < 0.05). Absolute and relative aerobic capacity were not independent predictors of skeletal muscle eNOS content (r2 = 0.11 and 0.26, respectively). CONCLUSION: There is an inverse relationship between eNOS and percent body fat that may have implications for the previously reported reduced endothelial function and insulin sensitivity in overweight women.

[The safety and immunogenicity of an heptavalent pneumococcal polysaccharide conjugate vaccine (Prevenar) administered in association with a whole-cell pertussis-based pediatric combination vaccine (DTP-IPV/PRP-T) to French infants with a two-, three-, and four-month schedule]. / Tolérance et immunogénicité d'un vaccin pneumococcique osidique conjugué heptavalent (Prevenar) administré en association avec une combinaison vaccinale pédiatrique (DTCoq-Polio/Hib) à des nourrissons selon le schéma vaccinal français à l'âge de deux, trois et quatre mois.

UNLABELLED: Invasive pneumococcal disease is presently a leading cause of mortality due to bacterial infectious diseases in French children less than 2 years of age, and only the pneumococcal conjugate vaccines induce a protective immune response for those within this vulnerable age group. MATERIAL AND METHODS: The safety and immunogenicity of a heptavalent pneumococcal polysaccharide conjugate vaccine (PREVENAR was tested in French infants immunized with the 2, 3 and 4 month French schedule as part of an open, randomized, comparative clinical study, in association with a whole-cell pertussis-based pediatric combination vaccine. RESULTS: In the PREVENAR plus DTP-IPV/Hib association group, 90.6-100% of children achieved a post-dose three threshold IgG concentration of >0.15 microg/ml against each of the seven pneumococcal serotypes. Regarding immunogenicity, no interference with the antibody response to the various antigenic components of the DTP-IPV/Hib vaccine was observed. Local reactions were significantly less frequent at the PREVENAR injection site than at the DTP-IPV/Hib injection site; there was no increase in systemic adverse events in the vaccine association group compared to the DTP-IPV/Hib alone group, further exception of fever >38 degrees C which was more frequently reported in the PREVENAR + PENTACOQ group following the second dose of vaccines (56% vs. 35%); no serious adverse event could be considered to be related to the PREVENAR immunization in this study. CONCLUSION: The heptavalent pneumococcal conjugate vaccine is immunogenic when administered at 2, 3 and 4 months. PREVENAR can be administered simultaneously with the DTP-IPV/Hib combination vaccine.

Boltulismo en una lactante / Boltulism in an infant

Se describe el caso de una paciente de 2 meses de edad, sin antecedentes mórbidos. Sus manifestaciones clínicas consistieron en constipación, rechazo alimentario e hipotonía agregándose luego dificultad respiratoria progresiva, diplejía facial y pupilas hiporreactivas. Se descartó una enfermedad metabólica e infecciosa. La punción lumbar fue normal y la TAC cerebral normal. La electromiografía fue sugerente de botulismo certificándose el diagnóstico con detección de toxina botulínica tipo A en deposiciones. Requirió ventilación mecánica por 37 días. Presenta mejoría espontánea dándose de alta a los 98 días de hospitalización con hipotonía leve

Genotoxic effects of occupational exposure in the peripheral blood lymphocytes of pesticide preparing workers in Hungary.

Venous blood samples of 240 donors including 33 industrial and 60 historical controls were investigated in order to assess the genotoxic risk of pesticide preparing workers manufacturing monochlorinated benzene in Hungary. Mutation frequencies were determined in the hypoxanthine-(guanine)-phosphoribosyl transferase genes located on the X chromosome. DNA repair capacity was estimated following hydroxyurea treatment with subsequent UV irradiation of separated lymphocytes. Smoking as confounding factor of genotoxicity was also taken into consideration. Mutation frequencies were increased among the workers exposed to monochlorinated benzene in correlation with the duration of working time, compared to the controls. Mutation frequencies were lower than expected among non-smoker, long-exposed workers. Smoking itself proved to be an effective confounding factor in the enhancement of point mutations in the case of long-exposed workers. Smoking, however, caused no significant increase in the mutation frequency among the controls, and did not influence the DNA repair capacity of any of the groups.

Discrete charge carrier transfer sites on proteins? A D.C. conductivity study on ultrathin protein films.

D.C. electrical conduction in thin protein films (200 mg/cm2; approximately 2 mu in thickness) of bovine serum albumin and its dinitrophenylated derivatives with different stoichiometric composition was investigated at 17, 20 and 23% relative humidities and at room temperature. Statistically significant decrease in conductivity due to derivatization was observed even at protein-2,4-dinitrophenol stoichiometry as low as 1:2. A charge injection mechanism based upon discrete charge carrier transfer sites could account for the observations. Analogous events may operate in cellular signaling and coding.

Stochastic studies of aging and mortality in multicellular organisms. II. The finite theory.

We extend the development of a quantitative phenomenological theory of aging rooted in order theory. An organism is represented abstractly by a chain with a finite number of links. Each link corresponds to a possible rate-limiting event or process in senescence. A link is said to break when the corresponding event occurs or the corresponding process goes to completion. The chain is said to break, and the organism subsequently to perish, when the first link breaks, whichever link that might be. Two models are introduced to describe the failure of an arbitrary link. The first requires that a link break only after sustaining a fixed amount of deterioration; the second associates a non-zero probability of failure with each level of wear. The net deterioration of an intact chain is taken, crudely, to correspond to the decline in physiological vitality sustained by an organism during senescence. Failure of an arbitrary link is described in both models by a Markov process. The corresponding mortality rate derived in each instance describes aspects of available empirical data which cannot be accounted for by either the Gompertz or power-law relations. The decline in vitality is shown in both cases to be linear over time intervals of practical interest. The influence of temperature on the senescence of poikilotherms is briefly examined. We describe the effect of temperature both on longevity and the decline in vitality; indicate how substantial discrepancies can arise in the calculation of a macroscopic, effective, activation enthalpy; and lend theoretical support to the existence of temperature--memory effects in senescence.

Charge pair model of bioenergetics: Energy transfer.

The electron tunnelling distance between redox enzymes is estimated. The energy transfer mechanism between a pair of charges is described. The dielectric degrees of freedom are incorporated into the electron transfer rate formula.

Charge pair model of bioenergetics: redox enzymes.

A model of electron transfer between redox enzymes is constructed on the assumption that the apoenzyme contains orientable units, which are tentatively identified with flipping amino acids. The model is based on the entatic state hypothesis, and the rate of electron transfer is derived.

Physical basis of charge pairing in mitochondria.

The postulate of charge pairing in the mitochondrial inner membrane is justified by applying a formula due to Fuoss to calculate the probability density for the distance between a positive and a negative charge. For dielectric constants 10 or less pairing is absolute, for 20 there is some tendency towards pairing, and at 78 it is nonexistent. Pairing, partner exchange or charge substitution, inhibition, and antiport uncoupling can be rationalized within this framework.

Theory of rate processes and the compensation rule.

The rate of intermolecular charge transfer as involved in the theory of rate processes is derived for a quadratic generalization of Holstein's one-dimensional linear polaron theory. The activation energy and the activation entropy are shown to be proportional to the number of vibrational degrees of freedom associated with each molecular site. The activation entropy is found to be negative in this model, thus decreasing the reaction rate. A spin-polaron model is introduced where the electron is coupled in a specific way to N spins at each site. In this model both the activation parameters are positive and are proportional to N. Thus, the oscillator model gives a negative and the spin model gives a positive compensation temperature.