Systems Biology: A Therapeutic Target for Tumor Therapy

Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems’ stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans’ cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/− dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects as adjustable sizes available for targeted biomodulatory therapies

The Population Genetics of dN/dS

Evolutionary pressures on proteins are often quantified by the ratio of substitution rates at non-synonymous and synonymous sites. The dN/dS ratio was originally developed for application to distantly diverged sequences, the differences among which represent substitutions that have fixed along independent lineages. Nevertheless, the dN/dS measure is often applied to sequences sampled from a single population, the differences among which represent segregating polymorphisms. Here, we study the expected dN/dS ratio for samples drawn from a single population under selection, and we find that in this context, dN/dS is relatively insensitive to the selection coefficient. Moreover, the hallmark signature of positive selection over divergent lineages, dN/dS>1, is violated within a population. For population samples, the relationship between selection and dN/dS does not follow a monotonic function, and so it may be impossible to infer selection pressures from dN/dS. These results have significant implications for the interpretation of dN/dS measurements among population-genetic samples

Взаимосвязь показателей кровообращения мышц бедра и плеча с координационной точностью при совершенствовании ударных баллистических движений

В работе была исследована взаимосвязь показателей кровообращения мышц бедра и плеча с координационной точностью при совершенствовании ударных баллистических движений. Для этого было сформировано две группы: в экспериментальной группе в качестве предупреждения травматизма кисти использовались боксерские перчатки (10 унций), а в контрольной - снарядные перчатки. В результате после нанесения одиночного акцентированного прямого удара правой рукой в голову по боксерскому мешку в течение раунда было получено, что в экспериментальной группе происходило увеличение интенсивности кровенаполнения задней поверхности правого бедра и увеличение венозного оттока. Можно предположить, что спортсмены экспериментальной группы больше опираются на правую ногу в заключительной фазе ударного действия, что является более правильно с биомеханической точки зрения нанесения ударов. Интенсивность кровенаполнения и венозного оттока плеча в экспериментальной группе, наоборот, падала. Это позволяет сделать предположение о том, что мышцы плеча при выполнении ударных движений лишь незначительно задействуются спортсменами старших спортивных разрядов в завершающей фазе ударного действия. Данный факт им позволяет наносить удары с большей точностью и эффективностью

Cladosporin, a fungal metabolite with potent blood and hepatic stage antimalarial activity targets lysyl-tRNA synthetase

Cladosporin, a fungal secondary metabolite, is reported to have a wide spectrum of biological activities. However, its primary target and mechanism of action is not known. Here we report that cladosporin has potent antimalarial activity and elucidate its target as the lysyl-tRNA synthetase in Saccharomyces cerevisiae (KRS1) and Plasmodium falciparum. Haploinsufficiency profiling of S. cerevisiae in the presence of cladosporin identified the krs1/KRS1 strain as hypersensitive, and over-expression of KRS1 leads to resistance. Furthermore, point mutations in the Krs1 Lysine-ATP binding-site also yield resistance. In Plasmodium falciparum addition of cladosporin rapidly inhibits protein synthesis. When plasmodial parasites were cultured in the presence of the compound to force the development of resistance, they responded by amplification of the genomic locus encoding the plasmodial lysyl-tRNA synthetase. Cladosporin inhibits both hepatic as well as blood stage parasite development, shows no cytotoxicity up to high concentrations and is thus an attractive antimalarial agent

Data from: High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions

Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Ole1p and Fas1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global 2-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology