Somatostatin Subtype‑2 Receptor-Targeted Metal-Based Anticancer Complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η6-bip)Os(4-CO2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η6-p-cym)RuCl(dap)]+ (p-cym = p-cymene) (5), and [(η6-p-cym)RuCl(imidazole-CO2H)(PPh3)]+ (6), were synthesized by using a solid-phase approach. Conjugates 35 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC50 = 63 ± 2 μM in MCF-7 cells and IC50 = 26 ± 3 μM in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC50 = 45 ± 2.6 μM in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically.

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes.

INTRODUCTION: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management. METHODS: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. RESULTS: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%. CONCLUSIONS: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.

Characterization of rapeseed (Brassica napus) oils by bulk C, O, H, and fatty acid C stable isotope analyses

Rapeseed (Brassica napus) oils differing in cultivar, sites of growth, and harvest year were characterized by fatty acid concentrations and carbon, hydrogen, and oxygen stable isotope analyses of bulk oils (delta(13)C(bulk), delta(2)H(bulk), delta(18)O(bulk) values) and individual fatty acids (delta(13)C(FA)). The delta(13)C(bulk), delta(2)H(bulk), and delta(18)O(bulk) values were determined by continuous flow combustion and high-temperature conversion elemental analyzer isotope ratio mass spectrometry (EA/IRMS, TC-EA/IRMS). The delta(13)C(FA) values were determined using gas chromatography-combustion isotope ratio mass spectrometry (GC/C/IRMS). For comparison, other C(3) vegetable oils rich in linolenic acid (flax and false flax oils) and rich in linoleic acid (poppy, sunflower, and safflower oils) were submitted to the same chemical and isotopic analyses. The bulk and molecular delta(13)C values were typical for C(3) plants. The delta(13)C value of palmitic acid (delta(13)C(16:0)) and n-3 alpha-linolenic acid (delta(13)C(18:3n-3)) differed (p < 0.001) between rape, flax, and poppy oils. Also within species, significant differences of delta(13)C(FA) were observed (p < 0.01). The hydrogen and oxygen isotope compositions of rape oil differed between cultivars (p < 0.05). Major differences in the individual delta(13)C(FA) values were found. A plant-specific carbon isotope fractionation occurs during the biosynthesis of the fatty acids and particularly during desaturation of C(18) acids in rape and flax. Bulk oil and specific fatty acid stable isotope analysis might be useful in tracing dietary lipids differing in their origin.

IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4.

Summary.  Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV). Our objective was to assess the predictive value of IL28B polymorphisms in the treatment of chronic hepatitis C of patients with HCV genotypes 4, for which data are currently limited. We analysed the association of IL28B polymorphisms with the virological response to treatment among 182 naïve chronic hepatitis C patients with HCV genotype 4, all from Syria. Associations of alleles with the response patterns were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. Sustained virological response (SVR) was achieved in 26% of rs8099917 TG/GG carriers compared with 60% of TT carriers (P < 0.0001) and 35% of rs12979860 CT/TT carriers compared with 62% of CC carriers (P = 0.0011). By multivariate analysis, the association between rs8099917 and SVR remained significant (OR = 0.19, 95% CI 0.07-0.50, for TG/GG vs TT, P = 0.0007), with the only significant covariate being advanced fibrosis (OR = 0.13, 95% CI 0.04-0.37, P = 0.0002). In conclusion, IL28B polymorphisms are the strongest predictors of response to therapy among chronic hepatitis C patients with HCV genotype 4.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Performance Analysis of Two Quantum Reaction Dynamics Codes: Time-Dependent and Time-Independent Strategies

The computer simulation of reaction dynamics has nowadays reached a remarkable degree of accuracy. Triatomic elementary reactions are rigorously studied with great detail on a straightforward basis using a considerable variety of Quantum Dynamics computational tools available to the scientific community. In our contribution we compare the performance of two quantum scattering codes in the computation of reaction cross sections of a triatomic benchmark reaction such as the gas phase reaction Ne + H2+ %12. NeH++ H. The computational codes are selected as representative of time-dependent (Real Wave Packet [ ]) and time-independent (ABC [ ]) methodologies. The main conclusion to be drawn from our study is that both strategies are, to a great extent, not competing but rather complementary. While time-dependent calculations advantages with respect to the energy range that can be covered in a single simulation, time-independent approaches offer much more detailed information from each single energy calculation. Further details such as the calculation of reactivity at very low collision energies or the computational effort related to account for the Coriolis couplings are analyzed in this paper.

Die Frauenfelder Fragmente von Konrad Flecks "Flore und Blanscheflur". Zugleich ein Beitrag zur alemannischen Handschriftenüberlieferung des 13. Jahrhunderts

Die heute im Archiv der katholischen Kirchengemeinde Frauenfeld, Schweiz, verwahrten ältesten Fragmente von ,Flore und Blanscheflur' gehören zu den bedeutendsten Zeugen der frühen mittelhochdeutschen Überlieferung. Der Aufsatz bietet eine detaillierte kodikologische, paläographische und dialektologische Untersuchung der in der neueren Forschung vernachlässigten Bruchstücke. Anhand einer genauen Autopsie der erhaltenen Reste können die materiale Struktur der ursprünglichen Vollhandschrift und auch der gestufte Prozess ihrer Makulierung rekonstruiert werden. Als ihr Besitzer im 14. Jahrhundert wird ein Frauenfelder Priester und Pfründstifter, Nikolaus Rüdiger von Messkirch, vermutet. Anlässlich der jeweils nicht eindeutigen Datierung und Lokalisierung der Fragmente werden grundsätzliche Überlegungen zu methodischen Problemen der mediävistischen Handschriftenkunde angestellt. Die Ergebnisse betreffen vor allem zwei Punkte: (1) Layoutmerkmale - im vorliegenden Fall: abgesetzt notierte Verse - sollten bei post quem-Datierungen nicht als Ausschlusskriterium, sondern nur als Indiz herangezogen werden; dabei sollte die Möglichkeit einer direkten Beeinflussung durch französische Vorbilder in Betracht gezogen werden, deren Layoute sich im deutschen Raum im Regelfall erst zeitlich versetzt etablieren. Exemplarisch wird ein bestimmtes Layoutmerkmal der Frauenfelder Fragmente - abgesetzte Verse mit an den rechten Rand gezogenen Reimpunkten - in seiner Belegdichte in der französischen und auch lateinischen Überlieferung seit dem 12. Jahrhundert aufgearbeitet. (2) Bei der Kriterienbildung zur Schriftsprachenbestimmung im Gefolge besonders des ,Historischen südwestdeutschen Sprachatlas' und der auf dem ,Corpus der altdeutschen Originalurkunden' beruhenden Systematisierungen ist für das 13. Jahrhundert zu wenig berücksichtigt worden, dass mit der deutschsprachigen Urkundenüberlieferung das gesamte Belegmaterial erst im letzten Viertel dieses Jahrhunderts einsetzt. Für die erste Hälfte des 13. Jahrhunderts, das die Entwicklung einer neuen literarischen Buchproduktion erlebte und das entsprechende graphematische Wandelerscheinungen erwarten lässt, bilden die daraus gewonnenen Sprachmerkmale keine zuverlässigen Abgrenzungskriterien. Sie sind im Einzelfall zu prüfen, wobei insbesondere im südwestdeutschen Raum aus Gründen des begrenzten Corpus Systematisierungen nur eingeschränkt möglich sind. Exemplarisch werden die Belege eines bestimmten Dialektmerkmals, des sog. ,,ch-Konsonantismus", anhand der gesamten Überlieferung aus dem südwestdeutschen Raum der ersten Jahrhunderthälfte erhoben. Es erweist sich, dass dieses als spezifisch bairisch (ostoberdeutsch) geltende Merkmal auch im alemannischen (westoberdeutschen) Raum für den fraglichen Zeitraum keine Ausnahme bildet. Dabei zeichnen sich Unterschiede in den Schreibungen weltlicher und geistlicher Texte ab.

Th2 activities induced during virgin T cell priming in the absence of IL-4, IL-13, and B cells.

Virgin T cells being primed to Th2-inducing or Th1-inducing Ags, respectively, start to synthesize IL-4 or IFN-gamma as they begin to proliferate. Parallel respective induction of B cells to produce gamma1 or gamma2a switch transcripts provides additional evidence of early divergent Th activity. This report concerns the roles of IL-4, IL-13, and B cells in these early events in vivo. Th2 responses were induced in lymph nodes against hapten-protein given s.c. with killed Bordetella pertussis adjuvant. In T cell proliferation in wild-type mice, IL-4 message up-regulation and gamma1 and epsilon switch transcript production were underway 48-72 h after immunization. The absence of IL-4, IL-13, or B cells did not alter the early T cell proliferative response. The gamma1 and epsilon switch transcript production was still induced in the absence of IL-4, IL-13, or both, but at a reduced level, while the dominance of switching to IgG1 in the extrafollicular hapten-specific plasma cell response was retained. The up-regulation of IL-4 message was not reduced or delayed in the absence of B cells and was only marginally reduced by the absence of IL-13. It is concluded that signals delivered by dendritic cells, which are not dependent on the presence of IL-4, IL-13, or B cells, can prime virgin T cells and induce the early Th2 activities studied. These early events that direct virgin T cells toward Th2 differentiation contrast with the critical later role of Th2 cytokines in selectively expanding Th2 clones and driving further IL-4 synthesis.

Further delineation of the facial 13q14 deletion syndrome in 13 retinoblastoma patients.

Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.

Laser treatment of 13 benign oral vascular lesions by three different surgical techniques

Objectives: Benign Oral Vascular Lesions (BOVLs) are a group of vascular diseases characterized by congenital, inflammatory or neoplastic vascular dilations clinically evidenced as more or less wide masses of commonly dark bluish color. If traumatized BOVLs are characterized by a great risk of hemorrhage and their treatment usually requires great caution to prevent massive bleeding. In the last decades lasers have dramatically changed the way of treatment of BOVLs permitting the application of even peculiar techniques that gave interesting advantages in their management reducing hemorrhage risks. The aim of this study was to evaluate the capabilities and disadvantages of three laser assisted techniques in the management of BOVLs. Study design: In this study 13 BOVLs were treated by three different laser techniques: the traditional excisional biopsy (EB), and two less invasive techniques, the transmucosal thermocoagulation (TMT) and the intralesional photocoagulation (ILP). Two different laser devices were adopted in the study: a KTP laser (DEKA, Florence, Italy, 532nm) and a GaAlAs laser (Laser Innovation, Castelgandolfo, Italy, 808nm) selected since their great effectiveness on hemoglobin. Results: In each case, lasers permitted safe treatments of BOVLs without hemorrhages, both during the intervention and in the post-operative period. The minimally invasive techniques (TMT and ILP) permitted even the safe resolution of big lesions without tissue loss. Conclusions: Laser devices confirm to be the gold standard in BOVLs treatment, permitting even the introduction of minimal invasive surgery principles and reducing the risks of hemorrhage typical of these neoplasms. As usual in laser surgery, it is necessary a clear knowledge of the devices and of the laser-tissue interaction to optimize the results reducing risks and disadvantages

6/9/19, Mr [Hugh C.] Wallace à la pose de la 1ère pierre du monument en commémoration de l'aide américaine [avec le président Poincaré et le député des Landes Maurice Damour, à la Pointe-de-Grave] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55781

6/9/19, M. Poincaré pose la première pierre du monument élevé en commémoration de l'aide américaine [en présence d'Hugh C. Wallace et du député des Landes Maurice Damour, à la Pointe-de-Grave] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55782