A comprehensive sensitivity analysis of microarray breast cancer classification under feature variability

Background  

Large discrepancies in signature composition and outcome concordance have been observed between different microarray breast cancer expression profiling studies. This is often ascribed to differences in array platform as well as biological variability. We conjecture that other reasons for the observed discrepancies are the measurement error associated with each feature and the choice of preprocessing method. Microarray data are known to be subject to technical variation and the confidence intervals around individual point estimates of expression levels can be wide. Furthermore, the estimated expression values also vary depending on the selected preprocessing scheme. In microarray breast cancer classification studies, however, these two forms of feature variability are almost always ignored and hence their exact role is unclear.     

Test Based on Independent,but Non-identically Distributed Random Variables

The binomial test is applied for the problem of testing a hypothesis based on a sample of independent, but non-identically distributed random variables. The used basic idea is that each random variable indicates the presence of the hypothesis. Hence each random variable is transformed such that the binomial test can be used as a simple procedure.     

FISH in der Diagnostik hämatologischer Neoplasien

All hematological malignancies are characterized by considerable clinical heterogeneity. The diverse entities can be subdivided into a variety of prognosis-defining subtypes on the basis of cytogenetic aberrations and molecular mutations. To adapt the intensity of treatment to the patient’s individual risk profile, an exact classification of the subtypes on the basis of genetic markers is essential. Diverse fluorescent in situ hybridization (FISH) techniques thereby play a central role in interaction with classic chromosome banding analyses for clarifying findings of chromosome analyses, such as in the acute leukemias, or for classifying the diverse subtypes, as in the non-Hodgkin’s lymphomas. Depending on the disease, the clinical impact of FISH varies. It is used as the method of choice for genetic characterization (e.g., in multiple myeloma) or is used in combination with chromosome banding analysis. Furthermore, interphase FISH is essential when rapid confirmation of the diagnosis is needed, as in acute promyelocytic leukemia with the t(15;17)/PML-RARA rearrangement, for which therapy with all-trans retinoic acid (ATRA) should be immediately started.     

Pränatale Detektion fetaler chromosomaler Aberrationen im 1. und 2. Trimenon

Modern noninvasive methods of prenatal medicine, in particular first-trimester-screening, enable early risk evaluation of the most common forms of aneuploidy. With over 4000 certified gynecologists in Germany, this method nowadays represents the standard in prenatal risk evaluation. The importance of classic genetic sonography during the second trimester by detection of soft markers for aneuploidy has declined. However, detailed sonography during the second trimester remains the gold standard for the detection of congenital anomalies. Therefore, the specialist in prenatal medicine must be able to recognize soft markers during this examination in order to re-evaluate the maternal risk for aneuploidy.     

Ionenkanalerkrankungen des Gehirns – monogene Migräneformen

As opposed to the common, genetically complex types of migraine, there are a few rare monogenic migraine variants. The prototype is familial hemiplegic migraine (FHM), a severe subtype of migraine with aura, for which three causative genes (FHM1–3), all of which are involved in ion translocation in the CNS, have been identified. This review summarizes the current knowledge about the clinical symptomatology, (differential) diagnosis, treatment, genetics, and pathophysiology of FHM. Clinically and genetically overlapping disorders, such as episodic ataxia type 2 (EA-2), spinocerebellar ataxia type 6 (SCA-6) and alternating hemiplegia of childhood (AHC) are briefly discussed, and novel genes which have been occasionally associated with HM or migraine are critically evaluated. Finally, monogenic (vascular) syndromes, in which migraine is part of the phenotypic spectrum, are discussed.     

Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice

In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages.     

Mud mounds: A polygenetic spectrum of fine-grained carbonate buildups

Summary This research report contains nine case studies (part II to X) dealing with Palaeozoic and Mesozoic mud mounds, microbial reefs, and modern zones of active micrite production, and two parts (I and XI) summarizing the major questions and results. The formation of different types ofin situ formed micrites (automicrites) in close association with siliceous sponges is documented in Devonian, Carboniferous, Triassic, Jurassic and Cretaceous mounds and suggests a common origin with a modern facies found within reef caves. Processes involved in the formation of autochthonous micrites comprise: (i) calcifying mucus enriched in Asp and Glu, this type presumably is linked to the formation of stromatolites, thrombolites and massive fabrics; (ii) protein-rich substances within confined spaces (e.g. microcavities) result in peloidal pockets, peloidal coatings and peloidal stromatolites, and (iii) decay of sponge soft tissues, presumably enriched with symbiotic bacteria, lead to the micropeloidal preservation of parts of former sponge bodies. As a consequence, there is strong evidence that the primary production of micrite in place represents the initial cause for buildup development. The mode of precipitation corresponds to biologically-induced, matrix-mediated mineralization which results in high-Mg-calcites, isotopically balanced with inorganic cements or equilibrium skeletal carbonates, respectively. If distinct automicritic fabrics are absent, the source or origin of micrite remains questionable. However, the co-occurring identifiable components are inadequate, by quantity and physiology, to explain the enhanced accumulation of fine-grained calcium carbonate. The stromatolite reefs from the Permian Zechstein Basin are regarded as reminiscent of ancestral (Precambrian) reef facies, considered the precursor of automicrite/sponge buildups. Automicrite/sponge buildups represent the basic Phanerozoic reef type. Analogous facies are still present within modern cryptic reef habitats, where the biocalcifying carbonate factory is restricted in space.     

Evolutionary relationships among the male and female mitochondrial DNA lineages in the Mytilus edulis species complex

A novel form of mitochondrial DNA (mtDNA) inheritance has previously been documented for the blue mussel (Mytilus edulis). Female mussels inherit their mtDNA solely from their mother while males inherit mtDNA from both their mother and their father. In males, the paternal mtDNA is preferentially amplified so that the male gonad is highly enriched for the paternal mtDNA that is then transmitted from fathers to sons. We demonstrate that this mode of mtDNA inheritance also operates in the closely related species M. galloprovincialis and M. trossulus. The evolutionary relationship between the male and female mtDNA lineages is estimated by phylogenetic analysis of 455 nucleotides from the large subunit ribosomal RNA gene. We have found that the male and female lineages are highly divergent; the divergence of these lineages began prior to the speciation of the three species of blue mussels. Further, the separation between the male and female lineages is estimated to have occurred between 5.3 and 5.7 MYA.