In Search of Simplification: the Use of Topological Complexity Indices to Guide Retrosynthetic Analysis

Topological complexity indices NS, NT, NS(lpe), NT(lpe), twc and wcx are used to rank the one-bond disconnections of bicyclo[2.2.1]heptane, spiro[3.3]heptane and their aza derivatives with respect to the degree of simplification they afford. Selected two-bond disconnections of bicyclo[2.2.1]heptane and its aza derivatives are also evaluated. Simplification principles are derived which are useful for guiding the retrosynthetic analysis of complex target molecules. Comparison with the LHASA rules for strategic bonds reveals a great deal of similarity and some important differences

German cancer statistics 2004

Background: For years the Robert Koch Institute (RKI) has been annually pooling and reviewing the data from the German population-based cancer registries and evaluating them together with the cause-of-death statistics provided by the statistical offices. Traditionally, the RKI periodically estimates the number of new cancer cases in Germany on the basis of the available data from the regional cancer registries in which registration is complete; this figure, in turn, forms the basis for further important indicators. Methods: This article gives a brief overview of current indicators - such as incidence, prevalence, mortality, survival rates - on the most common types of cancer, as well as important ratios on the risks of developing and dying of cancer in Germany. Results: According to the latest estimate, there were a total of 436,500 new cancer cases in Germany in 2004. The most common cancer in men is prostate cancer with over 58,000 new cases per annum, followed by colorectal and lung cancer. In women, breast cancer remains the most common cancer with an estimated 57,000 new cases every year, also followed by colorectal cancer. These and further findings on selected cancer sites can be found in the current brochure on “Cancer in Germany”, which is regularly published by the RKI together with the Association of Population-based Cancer Registries in Germany (GEKID). In addition, the RKI made cancer-prevalence estimates and calculated current morbidity and mortality risks at the federal level for the first time. According to these figures, the 5-year partial prevalence - i.e. the total number of cancer patients diagnosed over the past five years who are currently still living - exceeds 600,000 in men; the figure is about the same among women. Here, too, the most common cancers are prostate cancer in men and breast cancer in women. The lifetime risk of developing cancer, which is more related to the individual, is estimated to be higher among men (48.5%) than among women (40.3%). In roughly rounded figures, therefore, about every second person in Germany develops cancer in the course of their lives. One in four men and one in five women die of cancer. Conclusions: In recent years, population-based cancer registration in Germany has come significantly closer to the aim of the complete, nationwide coverage of cancer. The continuous improvements in the data situation help describe cancer development in Germany

Piwil 2 Expression Is Correlated with Disease-Specific and Progression-Free Survival of Chemotherapy-Treated Bladder Cancer Patients

Piwi-like 2 (Piwil 2) belongs to the family of Argonaute genes/proteins. The expression of Piwil 2 is associated with stem cells. A role in tumorigenesis and/or tumor progression is proposed for different cancers but not yet for bladder cancer (BCa). We investigated Piwil 2 expression by immunohistochemistry in a cohort of 202 BCa patients treated by cystectomy and adjuvant chemotherapy. The association between Piwil 2 expression and disease-specific (DSS) or progression-free survival (PFS) was calculated using Kaplan-Meier analyses and univariate/multivariate Cox regression hazard models. In a multivariate Cox regression analysis, Piwil 2 expression, either in the cytoplasm or the nucleus, was significantly associated with DSS and PFS. A weak cytoplasmic staining pattern was associated with poor DSS and tumor progression (relative risk [RR] = 2.7, P = 0.004, and RR = 2.4, P = 0.027). Likewise, absent nuclear Piwil 2 immunoreactivity was associated with poor DSS and tumor progression (RR = 2.3, P = 0.023, and RR = 2.2, P = 0.022). BCa patients whose tumors exhibited a combination of weak cytoplasmic and absent nuclear immunoreactivity had a 6-fold increased risk of tumor-related death (P = 0.005) compared with patients with strong expression. Considering only patients with high-grade G3 tumors, a 7.8-fold risk of tumor-associated death and a 3.6-fold risk of tumor progression were detected independently of the histologic tumor subtype or the chemotherapy regimen. In summary, a combination of weak cytoplasmic and absent nuclear expression of Piwil 2 is significantly associated with an increased risk of DSS and tumor progression. This indicates that Piwil 2 could be a valuable prognostic marker for high-risk BCa patients

Quantitative real-time RT-PCR of CD24 mRNA in the detection of prostate cancer

BACKGROUND: Gene expression profiling has recently shown that the mRNA for CD24 is overexpressed in prostate carcinomas (Pca) compared to benign or normal prostate epithelial tissues. Immunohistochemical studies have reported the usefulness of anti-CD24 for detecting prostate cancer over the full range of prostate specimens encountered in surgical pathology, e.g. needle biopsies, transurethral resection of prostate chips, or prostatectomies. It is a small mucin-like cell surface protein and thus promises to become at least a standard adjunctive stain for atypical prostate biopsies. We tested the usefulness of real-time RT-PCR for specific and sensitive detection of CD24 transcripts as a supplementary measure for discriminating between malignant and benign lesions in prostatic tissues. METHODS: Total RNA was isolated from snap-frozen chips in 55 cases of benign prostatic hyperplasia (BPH) and from frozen sections in 59 prostatectomy cases. The latter contain at least 50% malignant epithelia. Relative quantification of CD24 transcripts was performed on the LightCycler instrument using hybridization probes for detection and porphobilinogen deaminase transcripts (PBGD) for normalization. RESULTS: Normalized CD24 transcript levels showed an average 2.69-fold increase in 59 Pca-cases (mean 0.21) when compared to 55 cases of BPH (mean 0.08). This difference was highly significant (p < 0.0001). The method has a moderate specificity (47.3%) but a high sensitivity (86.4%) if the cutoff is set at 0.0498. CD24 expression levels among Pca cases were not statistically associated with the tumor and lymph-node stage, the grading (WHO), the surgical margins, or the Gleason score. CONCLUSION: The present study demonstrates the feasibility of quantitative CD24 RNA transcript detection in prostatic tissues even without previous laser microdissection

Extraction of Accurate Biomolecular Parameters from Single-Molecule Force Spectroscopy Experiments

The atomic force microscope (AFM) is able to manipulate biomolecules and their complexes with exquisite force sensitivity and distance resolution. This capability, complemented by theoretical models, has greatly improved our understanding of the determinants of mechanical strength in proteins and revealed the diverse effects of directional forces on the energy landscape of biomolecules. In unbinding experiments, the interacting partners are usually immobilized on their respective substrates via extensible linkers. These linkers affect both the force and contour length (Lc) of the complex at rupture. Surprisingly, while the former effect is well understood, the latter is largely neglected, leading to incorrect estimations of Lc, a parameter that is often used as evidence for the detection of specific interactions and remodeling events and for the inference of interaction regions. To address this problem, a model that predicts contour length measurements from single-molecule forced-dissociation experiments is presented that considers attachment position on the AFM tip, geometric effects, and polymer dynamics of the linkers. Modeled data are compared with measured contour length distributions from several different experimental systems, revealing that current methods underestimate contour lengths. The model enables nonspecific interactions to be identified unequivocally, allows accurate determination of Lc, and, by comparing experimental and modeled distributions, enables partial unfolding events before rupture to be identified unequivocally

Information Indices with High Discriminative Power for Graphs

In this paper, we evaluate the uniqueness of several information-theoretic measures for graphs based on so-called information functionals and compare the results with other information indices and non-information-theoretic measures such as the well-known Balaban index. We show that, by employing an information functional based on degree-degree associations, the resulting information index outperforms the Balaban index tremendously. These results have been obtained by using nearly 12 million exhaustively generated, non-isomorphic and unweighted graphs. Also, we obtain deeper insights on these and other topological descriptors when exploring their uniqueness by using exhaustively generated sets of alkane trees representing connected and acyclic graphs in which the degree of a vertex is at most four

Exploring Statistical and Population Aspects of Network Complexity

The characterization and the definition of the complexity of objects is an important but very difficult problem that attracted much interest in many different fields. In this paper we introduce a new measure, called network diversity score (NDS), which allows us to quantify structural properties of networks. We demonstrate numerically that our diversity score is capable of distinguishing ordered, random and complex networks from each other and, hence, allowing us to categorize networks with respect to their structural complexity. We study 16 additional network complexity measures and find that none of these measures has similar good categorization capabilities. In contrast to many other measures suggested so far aiming for a characterization of the structural complexity of networks, our score is different for a variety of reasons. First, our score is multiplicatively composed of four individual scores, each assessing different structural properties of a network. That means our composite score reflects the structural diversity of a network. Second, our score is defined for a population of networks instead of individual networks. We will show that this removes an unwanted ambiguity, inherently present in measures that are based on single networks. In order to apply our measure practically, we provide a statistical estimator for the diversity score, which is based on a finite number of samples

Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients

Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the ‘Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4–94.9%), a specificity of 79.4% (95% CI: 69.6–87.1%), a positive-predictive value of 79.6% (95% CI: 70.0–87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2–94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ⩾2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the ‘Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ⩾2