Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Radiothérapie externe accélérée postopératoire des carcinomes épidermoïdes localement évolués de la sphère ORL: étude prospective de phase II [Prospective study of accelerated postoperative radiation therapy in patients with squamous-cell carcinoma of the head and neck]

PURPOSE: To assess the feasibility and efficacy of accelerated postoperative radiation therapy (RT) in patients with squamous-cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Between December 1997 and July 2001, 68 patients (male to female ratio: 52/16; median age: 60-years (range: 43-81) with pT1-pT4 and/or pN0-pN3 SCCHN (24 oropharynx, 19 oral cavity, 13 hypopharynx, 5 larynx, 3 unknown primary, 2 maxillary sinus, and 2 salivary gland) were included in this prospective study. Postoperative RT was indicated because extracapsular infiltration (ECI) was observed in 20 (29%), positive surgical margins (PSM) in 20 (29%) or both in 23 patients (34%). Treatment consisted of external beam RT 66 Gy in 5 weeks and 3 days. Median follow-up was 15 months. RESULTS: According to CTC 2.0, acute morbidity was acceptable: grade 3 mucositis was observed in 15 (22%) patients, grade 3 dysphagia in 19 (28%) patients, grade 3 skin erythema in 21 (31%) patients with a median weight loss of 3.1 kg (range: 0-16). No grade 4 toxicity was observed. Median time to relapse was 13 months; we observed only three (4%) local and four (6%) regional relapses, whereas eight (12%) patients developed distant metastases without any evidence of locoregional recurrence. The 2 years overall-, disease-free survival, and actuarial locoregional control rates were 85, 73 and 83% respectively. CONCLUSION: The reduction of the overall treatment time using postoperative accelerated RT with weekly concomitant boost (six fractions per week) is feasible with local control rates comparable to that of published data. Acute RT-related morbidity is acceptable.

Isolation and characterization of major histocompatibility complex (MHC) class II B genes in the Barn owl (Aves: Tyto alba)

We isolated major histocompatibility complex class II B (MHCIIB) genes in the Barn owl (Tyto alba). A PCR-based approach combined with primer walking on genomic and complementary DNA as well as Southern blot analyses revealed the presence of two MHCIIB genes, both being expressed in spleen, liver, and blood. Characteristic structural features of MHCIIB genes as well as their expression and high non-synonymous substitution rates in the region involved in antigen binding suggest that both genes are functional. MHC organization in the Barn owl is simple compared to passerine species that show multiple duplications, and resembles the minimal essential MHC of chicken.

Cenomanian (early Late Cretaceous) ammonoid faunas of Western Europe - Part II: Diversity patterns and the end-Cenomanian anoxic event

Diversity patterns of ammonoids are analyzed and compared with the timing of anoxic deposits around the Cenomanian/Turonian (C/T) boundary in the Vocontian, Anglo-Paris, and Monster basins of Western Europe. Differing from most previous studies, which concentrate on a narrow time span bracketing the C/T boundary, the present analysis covers the latest Albian to Early Turonian interval for which a high resolution, ammonoid-based biochronology, including 34 Unitary Associations zones, is now available. During the latest Albian-Middle Cenomanian interval, species richness of ammonoids reveals a dynamical equilibrium oscillating around an average of 20 species, whereas the Late Cenomanian-Early Turonian interval displays an equilibrium centered on an average value of 6 species. The abrupt transition between these two successive equilibria lasted no longer than two Unitary Associations. The onset of the decline of species richness thus largely predates the spread of oxygen-poor water masses onto the shelves, while minimal values of species richness coincide with the Cenomanian-Turonian boundary only. The decline of species richness during the entire Late Cenomanian seems to result from lower origination percentages rather than from higher extinction percentages. This result is also supported by the absence of statistically significant changes in the extinction probabilities of the poly-cohorts. Separate analyses of species richness for acanthoceratids and heteromorphs, the two essential components of the Cenomanian ammonoid community, reveal that heteromorphs declined sooner than acanthoceratids. Moreover, acanthoceratids showed a later decline at the genus level than at the species level. Such a decoupling is accompanied by a significant increase in morphological disparity of acanthoceratids, which is expressed by the appearance of new genera. Last, during the Late Cenomanian, paedomorphic processes, juvenile innovations and reductions of adult size dominated the evolutionary radiation of acanthoceratids. Hence, the decrease in ammonoid species richness and their major evolutionary changes significantly predates the spread of anoxic deposits. Other environmental constraints such as global flooding of platforms, warmer and more equable climate, as well as productivity changes better correlate with the timing of diversity changes and evolutionary patterns of ammonoids and therefore, provide more likely causative mechanisms than anoxia alone.

The abrupt climate change at the Eocene-Oligocene boundary and the emergence of South-East Asia triggered the spread of sapindaceous lineages.

Background and Aims Paleoclimatic data indicate that an abrupt climate change occurred at the Eocene-Oligocene (E-O) boundary affecting the distribution of tropical forests on Earth. The same period has seen the emergence of South-East (SE) Asia, caused by the collision of the Eurasian and Australian plates. How the combination of these climatic and geomorphological factors affected the spatio-temporal history of angiosperms is little known. This topic is investigated by using the worldwide sapindaceous clade as a case study. Methods Analyses of divergence time inference, diversification and biogeography (constrained by paleogeography) are applied to a combined plastid and nuclear DNA sequence data set. Biogeographical and diversification analyses are performed over a set of trees to take phylogenetic and dating uncertainty into account. Results are analysed in the context of past climatic fluctuations. Key Results An increase in the number of dispersal events at the E-O boundary is recorded, which intensified during the Miocene. This pattern is associated with a higher rate in the emergence of new genera. These results are discussed in light of the geomorphological importance of SE Asia, which acted as a tropical bridge allowing multiple contacts between areas and additional speciation across landmasses derived from Laurasia and Gondwana. Conclusions This study demonstrates the importance of the combined effect of geomorphological (the emergence of most islands in SE Asia approx. 30 million years ago) and climatic (the dramatic E-O climate change that shifted the tropical belt and reduced sea levels) factors in shaping species distribution within the sapindaceous clade.

Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems.

The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of losartan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol Na/d) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet. Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. With losartan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsorption of sodium with both antagonists. A direct proximal tubular natriuretic effect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modify the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems.

Iowa Department of Transportation Fiscal Year 2010 Report of Savings by Using Video Conferencing Through Iowa Communications Network to the Iowa General Assembly Pursuant to Iowa Code § II 84 Acts and Joint Resolutions Enacted at the 1994 Regular Session of the 75th General Assembly of the State of Iowa

Introduction and summary Iowa Code § 8D.10 requires certain state agencies to prepare an annual report to the General Assembly certifying the identified savings associated with that state agency’s use of the Iowa Communications Network (ICN). This report covers estimated cost savings related to video conferencing via ICN for the Iowa Department of Transportation (DOT). In FY 2010, the DOT did not conduct any sessions utilizing ICN’s video conferencing system. Therefore, no cost savings were calculated for this report.

Towards a theory of the credit-risk balance sheet (II). The evolution of its structure

This article has an immediate predecessor, upon which it is based and with which readers must necessarily be familiar: Towards a Theory of the Credit-Risk Balance Sheet (Vallverdú, Somoza and Moya, 2006). The Balance Sheet is conceptualised on the basis of the duality of a credit-based transaction; it deals with its theoretical foundations, providing evidence of a causal credit-risk duality, that is, a true causal relationship; its characteristics, properties and its static and dynamic characteristics are analyzed. This article, which provides a logical continuation to the previous one, studies the evolution of the structure of the Credit-Risk Balance Sheet as a consequence of a business¿s dynamics in the credit area. Given the Credit-Risk Balance Sheet of a company at any given time, it attempts to estimate, by means of sequential analysis, its structural evolution, showing its usefulness in the management and control of credit and risk. To do this, it bases itself, with the necessary adaptations, on the by-now classic works of Palomba and Cutolo. The establishment of the corresponding transformation matrices allows one to move from an initial balance sheet structure to a final, future one, to understand its credit-risk situation trends, as well as to make possible its monitoring and control, basic elements in providing support for risk management.

Towards a theory of the credit-risk balance sheet (II). The evolution of its structure

This article has an immediate predecessor, upon which it is based and with which readers must necessarily be familiar: Towards a Theory of the Credit-Risk Balance Sheet (Vallverdú, Somoza and Moya, 2006). The Balance Sheet is conceptualised on the basis of the duality of a credit-based transaction; it deals with its theoretical foundations, providing evidence of a causal credit-risk duality, that is, a true causal relationship; its characteristics, properties and its static and dynamic characteristics are analyzed. This article, which provides a logical continuation to the previous one, studies the evolution of the structure of the Credit-Risk Balance Sheet as a consequence of a business¿s dynamics in the credit area. Given the Credit-Risk Balance Sheet of a company at any given time, it attempts to estimate, by means of sequential analysis, its structural evolution, showing its usefulness in the management and control of credit and risk. To do this, it bases itself, with the necessary adaptations, on the by-now classic works of Palomba and Cutolo. The establishment of the corresponding transformation matrices allows one to move from an initial balance sheet structure to a final, future one, to understand its credit-risk situation trends, as well as to make possible its monitoring and control, basic elements in providing support for risk management.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

Simulations in evolution. II. Relative fitness and the propagation of mutants.

In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous article presented a histogram model [1] consisting in populations of individuals whose number changed under the influence of variation and/or fitness, the total population remaining constant. Individuals are classified into bins, and the content of each bin is calculated generation after generation by an Excel spreadsheet. Here, we apply the histogram model to a stable population with fitness F(1)=1.00 in which one or two fitter mutants emerge. In a first scenario, a single mutant emerged in the population whose fitness was greater than 1.00. The simulations ended when the original population was reduced to a single individual. The histogram model was validated by excellent agreement between its predictions and those of a classical continuous function (Eqn. 1) which predicts the number of generations needed for a favorable mutation to spread throughout a population. But in contrast to Eqn. 1, our histogram model is adaptable to more complex scenarios, as demonstrated here. In the second and third scenarios, the original population was present at time zero together with two mutants which differed from the original population by two higher and distinct fitness values. In the fourth scenario, the large original population was present at time zero together with one fitter mutant. After a number of generations, when the mutant offspring had multiplied, a second mutant was introduced whose fitness was even greater. The histogram model also allows Shannon entropy (SE) to be monitored continuously as the information content of the total population decreases or increases. The results of these simulations illustrate, in a graphically didactic manner, the influence of natural selection, operating through relative fitness, in the emergence and dominance of a fitter mutant.

Structural changes in latosols of the cerrado region: II - soil compressive behavior and modeling of additional compaction

Currently in Brazil, as in other parts of the world, the concern is great with the increase of degraded agricultural soil, which is mostly related to the occurrence of soil compaction. Although soil texture is recognized as a very important component in the soil compressive behaviors, there are few studies that quantify its influence on the structural changes of Latosols in the Brazilian Cerrado region. This study aimed to evaluate structural changes and the compressive behavior of Latosols in Rio Verde, Goiás, through the modeling of additional soil compaction. The study was carried out using five Latosols with very different textures, under different soil compaction levels. Water retention and soil compression curves, and bearing capacity models were determined from undisturbed samples collected on the B horizons. Results indicated that clayey and very clayey Latosols were more susceptible to compression than medium-textured soils. Soil compression curves at density values associate with edaphic functions were used to determine the beneficial pressure (σ b) , i.e., pressure with optimal water retention, and critical pressure (σcrMAC), i.e., pressure with macroporosity below critical levels. These pressure values were higher than the preconsolidation pressure (σp), and therefore characterized as additional compaction. Based on the compressive behavior of these Latosols, it can be concluded that the combined preconsolidation pressure, beneficial pressure and critical pressure allow a better understanding of compression processes of Latosols.

Highlands of the upper Jequitinhonha valley, Brazil: II - mineralogy, micromorphology, and landscape evolution¹

Palm swanp formations, the so-called veredas, typically occur in the Brazilian biome known as "Cerrado" (savanna-like vegetation), especially on flattened areas or tablelands (chapadas). The aim of this study was to characterize the mineralogy and micromorphology of soil materials from a representative toposequence of the watershed of the vereda Lagoa do Leandro, located in Minas Novas, state of Minas Gerais, Brazil, on plains in the region of the upper Jequitinhonha valley, emphasizing essential aspects of their genesis and landscape evolution. The toposequence is underlain by rocks of the Macaúbas group and covered with detrital and metamorphic rocks (schists of Proterozoic diamictites). The soil profiles were first pedologically described; samples of the disturbed and undisturbed soils were collected from all horizons for further micromorphological and mineralogical analyses. The mineralogical analysis was mainly based on powder X ray diffractometry (XRD) and micromorphological descriptions of thin sections under a petrographic microscope. The soils from the bottom to the top of this toposequence were classified as: Typic Albaquult (GXbd), Xanthic Haplustox, gray color, here called "Gray Haplustox" ("LAC"), Xanthic Haplustox (LA) and Typic Haplustox (LVA). The clay mineralogy of all soils was found to be dominated by kaolinite. In soil of LA and LVA, the occurrence of goethite, gibbsite, and anatase was evidenced; "LAC" also contained anatase and the GXbd, illite, anatase, and traces of vermiculite. The micromorphological analyses of the LVA, LA and "LAC" soils showed the prevalence of a microaggregate-like or granular microstructure, and aggregate porosity has a stacked/packed structure, which is typical of Oxisols. A massive structure was observed in GXbd material, with the presence of illuviation cutans of clay minerals and iron compounds. Paleogleissolos, which are strongly weathered, due to the action of the excavating fauna , and resulted in the present "LAC". The GXbd at the base of the vereda preserved the physical, mineralogical and micromorphological properties that are typical of a pedogenesis with a strong influence of long dry periods.

Inauguration of the state capitol at Des Moines, Iowa : address delivered before the twentieth General Assembly by Hon. John A. Kasson, upon the invitation of the governor and General Assembly, January 17, 1884.

This brochure is the printed copy of the speech made by Hon. John A. Kasson to the Twentieth General Assembly for the Inauguration of the Iowa State Capitol