Doxorubicin cardiotoxicity: possible role of digoxin in its prevention.

Twenty-nine patients with gynaecological cancers who received over 400 mg of doxorubicin were monitored electrocardiographically to determine whether cardiac glycosides countered the adverse effects of high total doses of doxorubicin. Minor electrocardiographical changes were noted in five out of six patients who were not receiving a cardiac glycoside and four out of six who were receiving ouabain, and none of the 16 who were receiving digoxin. One other patient on digoxin stopped taking it and developed cardiomyopathy. One patient on ouabain also developed cardiomyopathy. So far nine patients on digoxin have received between 550 and 1000 mg/m2 of doxorubicin without ill effect. Cardiac glycosides are thought to prevent doxorubicin cardiomyopathy by competitively inhibiting doxorubicin at its receptor sites, but ouabain has a much shorter half life than doxorubicin and its metabolites and so is less effective than digoxin.     

On null hypotheses in survival analysis

The conventional nonparametric tests in survival analysis, such as the log‐rank test, assess the null hypothesis that the hazards are equal at all times. However, hazards are hard to interpret causally, and other null hypotheses are more relevant in many scenarios with survival outcomes. To allow for a wider range of null hypotheses, we present a generic approach to define test statistics. This approach utilizes the fact that a wide range of common parameters in survival analysis can be expressed as solutions of differential equations. Thereby, we can test hypotheses based on survival parameters that solve differential equations driven by cumulative hazards, and it is easy to implement the tests on a computer. We present simulations, suggesting that our tests perform well for several hypotheses in a range of scenarios. As an illustration, we apply our tests to evaluate the effect of adjuvant chemotherapies in patients with colon cancer, using data from a randomized controlled trial.     

Four-cluster analysis: a simple method to test phylogenetic hypotheses

A simple statistical test for comparing three alternative phylogenetic hypotheses for four monophyletic groups is presented. This test is based on the minimum-evolution principle, and it does not require any information regarding the branching order within each monophyletic group. It is computationally efficient and can be easily extended to five or more monophyletic groups.      

Patch distribution of interstitial communities: prevailing factors

1. Community structure of interstitial invertebrates was studied in the sediments of two gravel bars in a bypass section of the Rhone River (France), in relation to hydrological patchiness and to major geomorphological characteristics of the sampling areas. Hydrological patchiness was characterized by upweiling or downwelling zones while geomorphological characteristics were concerned mainly with position towards the head or tail of each bar, which presented different environmental conditions. 2. Longitudinal profiles of the two bars, at 0.5 and 1.0m below the substrate surface, were compared. At each station 10-l samples were taken using mobile standpipes and a Bou—Rouch pump. During low-water conditions, replicate samples were taken in both the head-bar and tail-bar regions to confirm the results. Physicochemical parameters were used to differentiate surface water from ground water (conductivity, alkalinity, silica, nitrates, sulphates and temperature) and to detect hydrological patterns. 3. Two different situations were observed within the gravel bars. In the first one, the upweiling zone was situated in the tail bar and downwelling zone in the head bar. The reverse was observed in gravel bar 2 where the head-bar region formed the upweiling zone and the tail-bar region formed the downwelling zone. 4. In the first situation, the distribution of interstitial assemblages corresponded with the observed hydrological patterns: epigean fauna characterized the downwelling zone and stygofauna characterized the upweiling zone. The interstitial fauna seemed to be strictly linked to the mode of water movement within the sediments. Hydrological patchiness therefore appeared to be an important factor for the structure of interstitial assemblages. 5. In the second case there was no relationship between the hydrological and the biological pattern. Epigean fauna and hypogean fauna were scattered all along the gravel bar. These results suggest that geomorphology is a second important factor governing the composition and structure of interstitial assemblages. A precise structure was obtained when hydrological and geomorphological characteristics were superimposed (case 1). When they were opposed (case 2) all the species responded according to their individual ecological requirements.     

A finite element analysis of masticatory stress hypotheses

Understanding how the skull transmits and dissipates forces during feeding provides insights into the selective pressures that may have driven the evolution of primate skull morphology. Traditionally, researchers have interpreted masticatory biomechanics in terms of simple global loading regimes applied to simple shapes (i.e., bending in sagittal and frontal planes, dorsoventral shear, and torsion of beams and cylinders). This study uses finite element analysis to examine the extent to which these geometric models provide accurate strain predictions in the face and evaluate whether simple global loading regimes predict strains that approximate the craniofacial deformation pattern observed during mastication. Loading regimes, including those simulating peak loads during molar chewing and those approximating the global loading regimes, were applied to a previously validated finite element model (FEM) of a macaque (Macaca fascicularis) skull, and the resulting strain patterns were compared. When simple global loading regimes are applied to the FEM, the resulting strains do not match those predicted by simple geometric models, suggesting that these models fail to generate accurate predictions of facial strain. Of the four loading regimes tested, bending in the frontal plane most closely approximates strain patterns in the circumorbital region and lateral face, apparently due to masseter muscle forces acting on the zygomatic arches. However, these results indicate that no single simple global loading regime satisfactorily accounts for the strain pattern found in the validated FEM. Instead, we propose that FE models replace simple cranial models when interpreting bone strain data and formulating hypotheses about craniofacial biomechanics.     

Paleoecology and coalescence: phylogeographic analysis of hypotheses from the fossil record

The application of principles from coalescence theory to genealogical relationships within species can provide insights into the process of diversification and the influence of biogeography on distributional patterns. There are several features that make some organisms more suitable for detailed studies of historical processes; in particular, limited dispersal, which serves to conserve the patterns of genetic variation that developed during colonization. We describe the potential benefits of studies that integrate analyses of genetic variation with information from the fossil pollen record and present recent examples of the application of quantitative methods of phylogeographic analysis.     

Proteomic analysis of rat atrial secretory granules: a platform for testable hypotheses

The recent development of powerful proteomic tools has enabled investigators to directly examine the population of proteins present in defined biological systems. We report here the first proteomic analysis of atrial secretory granules. Approximately 100 distinct protein components of the atrial secretory granule proteome were detected using subcellular fractionation and one-dimensional SDS-PAGE in conjunction with peptide mass fingerprinting by MALDI-TOF mass spectrometry. Of this number, 61 proteins were clearly identified by high probability data matches and repeated observation. The majority of the proteome was found to be membrane-associated with the most prominent proteins being peptidylglycine alpha-amidating monooxygenase (PAM) and pro-atrial natriuretic peptide (pro-ANP). This proteomic analysis of the rat atrium secretory granule produced an assembly of proteins with a diverse array of reported functions. The identified proteins fall into seven functional categories: (1) granular transport, docking and fusion; (2) signal transduction; (3) calcium-binding/calcium-dependent; (4) cellular architecture/chaperoning; (5) peptide/protein processing; (6) hormone; (7) proton transport. The novel finding of several protein processing enzymes and signal transduction proteins offer new perspectives on how pro-ANP is stored and processed to ANP during release. Accordingly, defining the proteome of the atrial secretory granule provides a framework for the development of new hypotheses that address key mechanisms governing granule function and ANP secretion.     

Protectors against doxorubicin-induced cardiotoxicity: Flavonoids

Doxorubicin is a widely used anthracycline anticancer agent. Its use may cause cardiomyopathy: in fact, the development of cumulative dose-related cardiotoxicity forms the major limitation of clinical doxorubicin use. We therefore searched for protective agents that combine iron-chelating and oxygen radical-scavenging properties. Moreover, any novel protector should not interfere with the cytostatic activity of doxorubicin. After extensive in vitro screening we found that flavonoids could serve this purpose. In particular 7-monohydroxyethylrutoside almost completely protected against the negative inotropic action of doxorubicin in the electrically paced mouse left atrium model. In vivo it gave full protection at 500 mg/kg intraperitoneally against the doxorubicin-induced ST-interval lengthening in the ECG. Moreover, this protector did not influence the antitumor effect of doxorubicin either in vitro using the human ovarian cell lines A2780 and OVCAR-3 and the human breast cancer cell line MCF-7 or in vivo in A2780 and OVCAR-3 subcutaneous xenografts in nude mice. Comparison of various iron chelators suggest that iron, in contrast to the general assumption, might not play a crucial role in the oxidative stress-induced toxicity of doxorubicin. Moreover, incubation of vascular endothelial cells with doxorubicin produced overexpression of adhesion molecules, which could be inhibited by 7-monohydroxyethylrutoside. From a study in human volunteers, we conclude that an intravenous dose of 1500 mg/m² of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity.     

Cdk7: Open questions beyond the prevailing model

Comment on: Ganuza M, et al. EMBO J 2012; 31:2498-510.     

Radiotelemetric analysis of the effects of prevailing wind direction on Mormon cricket migratory band movement

During outbreaks, flightless Mormon crickets [Anabrus simplex Haldeman (Orthoptera: Tettigoniidae)] form large mobile groups known as migratory bands. These bands can contain millions of individuals that march en masse across the landscape. The role of environmental cues in influencing the movement direction of migratory bands is poorly understood and has been the subject of little empirical study. We examined the effect of wind direction on Mormon cricket migratory band movement direction by monitoring the local weather conditions and daily movement patterns of individual insects traveling in bands over the same time course at three close, but spatially distinct sites. Although weather conditions were relatively homogeneous across sites, wind directions tended to be more variable across sites during the morning hours, the period during which directional movement begins. Migratory bands at different sites traveled in distinctly different directions. However, we failed to find any evidence to suggest that the observed variation in migratory band movement direction was correlated with local wind direction at any time during the day. These results support the notion that the cues mediating migratory band directionality are likely to be group specific and that a role for landscape-scale environmental cues such as wind direction is unlikely.     

被子植物花的起源:假说和证据

达尔文的 令人讨厌之谜 ,即被子植物的起源和早期演化 ,一直是植物系统学研究领域的热点 .被子植物区别于其它植物类群的一个显著特征就是花 ,因此 ,解决被子植物的起源之谜很大程度上取决于对被子植物花器官起源的研究 .对被子植物花器官的详尽研究已经在形态、解剖、古植物、形态发生、分子等方面积累了大量的证据 ,植物学家基于这些证据为被子植物花器官的起源提出了各种各样的解释 .综述了迄今为止被子植物花器官起源的主要学说流派 ,如 :真花学说、假花学说、生殖叶学说、生殖茎节学说、生花植物学说、新假花学说、古草本学说和 ANITA学说等 .根据研究手段和获得证据的方式 ,作者将被子植物花器官起源研究划分为 5个阶段 ,并简要阐述了各个阶段的代表学说和主要研究特点     

Genomic outlier profile analysis: mixture models, null hypotheses, and nonparametric estimation

In most analyses of large-scale genomic data sets, differentialexpression analysis is typically assessed by testing for differencesin the mean of the distributions between 2 groups. A recentfinding by Tomlins and others (2005) is of a different typeof pattern of differential expression in which a fraction ofsamples in one group have overexpression relative to samplesin the other group. In this work, we describe a general mixturemodel framework for the assessment of this type of expression,called outlier profile analysis. We start by considering thesingle-gene situation and establishing results on identifiability.We propose 2 nonparametric estimation procedures that have naturallinks to familiar multiple testing procedures. We then developmultivariate extensions of this methodology to handle genome-widemeasurements. The proposed methodologies are compared usingsimulation studies as well as data from a prostate cancer geneexpression study.     

Human breasts: Unsupported hypotheses reviewed

Unlike other apes, human females’ breasts develop before first pregnancy and are permanently enlarged. Evidence suggests breasts act as signals to males but the critical data required to confirm this are lacking. These facts have led to a number of hypotheses about the evolutionary and adaptive significance of the human breast which fall into two groups. Those that address the presence of breasts in humans are (a) that they act as releasers of male sexual behaviour, (b) that they enable females to hide their reproductive condition, and (c) that they allow infants to nurse from their mother’s hip. Those that address variability in breast size are (d) that large breasts indicate lactational potential, (e) ability of mothers to invest prenatally in offspring, (f) mother’s fecundity, and (g) her longevity. Each hypothesis is reviewed and evaluated using logical or empirical arguments. Possible ways in which the adaptive significance of human breasts can be determined in contemporary populations are outlined.     

Verification of monogenic hypotheses in a hybridological analysis of quantitative traits

A method for evaluation of genetic parameters and for verification of the hypothesis of monogenic inheritance of a quantitative character in the process of its hybridological analysis is considered. For certain characters (tryptophan hydroxylase activity in the brain stem and hemispheres in males of two strains of mice, as well as in the F1 and F2 hybrids of these strains), the efficiency of the minimum chi-square method for the evaluation of parameters of the model is demonstrated.