N G van Kampen 1981 Amsterdam: North-Holland xiv + 419 pp price Dfl 180 This is a book which, at a lower price, could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes, as well as those who just enjoy a beautifully written book. It provides an extensive graduate-level introduction which is clear, cautious, interesting and readable.

https://iopscience.iop.org/article/10.1088/0031-9112/34/4/040/pdf

Stochastic Processes in Physics and Chemistry

KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

1980 Preface * 1999 Preface * 1999 Acknowledgements * Introduction * 1 Circular Logic * 2 Phase Singularities (Screwy Results of Circular Logic) * 3 The Rules of the Ring * 4 Ring Populations * 5 Getting Off the Ring * 6 Attracting Cycles and Isochrons * 7 Measuring the Trajectories of a Circadian Clock * 8 Populations of Attractor Cycle Oscillators * 9 Excitable Kinetics and Excitable Media * 10 The Varieties of Phaseless Experience: In Which the Geometrical Orderliness of Rhythmic Organization Breaks Down in Diverse Ways * 11 The Firefly Machine 12 Energy Metabolism in Cells * 13 The Malonic Acid Reagent ('Sodium Geometrate') * 14 Electrical Rhythmicity and Excitability in Cell Membranes * 15 The Aggregation of Slime Mold Amoebae * 16 Numerical Organizing Centers * 17 Electrical Singular Filaments in the Heart Wall * 18 Pattern Formation in the Fungi * 19 Circadian Rhythms in General * 20 The Circadian Clocks of Insect Eclosion * 21 The Flower of Kalanchoe * 22 The Cell Mitotic Cycle * 23 The Female Cycle * References * Index of Names * Index of Subjects

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/596B270197FE27DE5FABB598B6210622/S0025557200150892a.pdf/div-class-title-span-class-italic-the-geometry-of-biological-time-span-by-a-t-winfree-pp-544-dm68-corrected-second-printing-1990-isbn-3-540-52528-9-springer-div.pdf

The geometry of biological time , by A. T. Winfree. Pp 544. DM68. Corrected Second Printing 1990. ISBN 3-540-52528-9 (Springer)

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Small molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 have created new opportunities for the treatment of advanced hormone-receptor positive (HR+) breast cancer and show promise in other malignancies. Three CDK4/6 inhibitors, palbociclib (PD0332991; Ibrance), ribociclib (LEE011; Kisqali), and abemaciclib (LY2835219), which have been approved or are in late stage trials, are reported to be broadly similar although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique adverse effects profile. Differences in pharmacokinetics and relative potency for CDK4 versus CDK6 are postulated to account for these differences. In this paper, we use molecular and functional profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors. We show that abemaciclib, but not ribociclib or palbociclib, is a potent inhibitor of kinases other than CDK4/6, including CDK1/Cyclin B, which appears to cause arrest in the G2 phase of the cell cycle, and CDK2/Cyclin E/A, which is implicated in resistance to palbociclib. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2-3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active even in retinoblastoma protein (pRb)-deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is completely ineffective. The degree of polypharmacology of small molecule drugs is increasingly viewed as an important consideration in their design, with implications for efficacy, toxicity, and acquired resistance. In the case of CDK4/6 inhibitors, we propose that abemaciclib polypharmacology elicits unique molecular responses that are likely to be therapeutically advantageous. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells. We expect such understanding to assist in stratifying patient populations and ordering sequential therapies when resistance arises. Citation Format: Hafner M, Mills CE, Subramanian K, Chen C, Boswell SA, Everley RA, Juric D, Sorger PK. Advantageous polypharmacology of abemaciclib revealed by omics profiling of CDK4/6 inhibitors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-02.

Abstract PD4-02: Advantageous polypharmacology of abemaciclib revealed by omics profiling of CDK4/6 inhibitors

Recently structural kinetic modeling has been proposed as an intermediary approach between a full kinetic descrip- tion of metabolic networks and a static constrained-based analysis of them. It extends the null-space analysis by a local stability analysis yielding a parametrization of the Jacobian in terms of saturation levels of the involved re- actions with respect to their substrate metabolite concen- tration. These levels are normalized and stay within well- defined bounds for every reaction. We utilize results from robust control theory to determine subintervals of satu- ration levels that render the steady state asymptotically stable. In particular we apply Kharitonov's theorem and parametric Lyapunov functions in conjunction with inter- val computation. A glycolytic pathway model comprising 12 reactions is used to illustrate the methods

Semi-quantitative stability analysis constrains saturation levels in metabolic networks

The target profiles of many drugs are established early in their development and are not systematically revisited at the time of approval, raising the question whether human therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five distinct phenotypic and biochemical assays to compare approved inhibitors of the cyclin-dependent kinases CDK4/6 (palbociclib, ribociclib, and abemaciclib) that are promising therapies for hormone-receptor positive breast cancer. We find that transcriptional, proteomic and phenotypic changes induced by the three drugs differ significantly and that abemaciclib has activates overlapping those of the older generation CDK inhibitor alvocidib. Abemaciclib9s activities arise from inhibition of kinases other than CDK4/6 including CDK2/Cyclin A/E and CDK1/Cyclin B. Our data suggest the potential for differential use in the clinic and argue that a multi-faceted experimental and computational approach is necessary to obtain a reliable picture of kinase inhibitor target spectrum.

https://www.biorxiv.org/content/early/2018/11/13/211680.full.pdf

Multi-omics profiling establishes the polypharmacology of FDA Approved CDK4/6 inhibitors and its impact on drug response

CDK4/6 inhibitors are a promising class of targeted therapies, with three molecules (palbociclib, ribociclib, and abemaciclib) approved for advanced hormone-receptor positive (HR+) breast cancers. With hope of building on this success, clinical trials across multiple oncology indications have been initiated. The determinants of response to CDK4/6 inhibitors, beyond pRb-deficiency and Cyclin-E amplification, remain unclear as limited clinical data have been published in indications other than HR+ breast cancers. Here, we measured the response to palbociclib across a panel of tumor cell lines from multiple indications and were able to build a computational model predictive of drug response using the expression of a handful of transcripts. This model revealed cellular states that are related to palbociclib resistance, such as G1-S entry deregulation, or sensitivity, such as competent p53 pathway and high KRAS signaling. As validation of our model, we compared its predictions with dependency scores from Project Achilles and found good correlations between predicted sensitivity and dependence on CDK4 and CCND1. By applying the predictive model on TCGA data, our analysis uncovered indications, disease subtypes, and genomic alterations that are related to the predicted response to palbociclib in addition to Rb-deficiency and Cyclin-E amplification. As expected, HR+ breast cancer was predicted to be among the most sensitive diseases, along with prostate, thyroid, and some renal cancers. Among non-small cell lung cancers, squamous-cell tumors are predicted to be more resistant than adenocarcinomas. In adenocarcinomas, BRAF and KRAS mutations are predicted to be associated with increased responsiveness. Combining these results with published biomarkers of resistance to standard of care therapies reveals indications in which CDK4/6 inhibitors can be potential combination partners. These results may guide the design of new trials for CDK4/6 therapies and the evaluation of better stratification biomarkers. Citation Format: Marc Hafner, Nicholas Dompe, Wei Zhou, Eva Lin, Milena Durrbaum, Anneleen Daemen, Melissa R. Junttila, Ciara Metcalfe, Karl Merrick. Predictive model of palbociclib response reveals indications in which CDK4/6 inhibitor can be a potential combination partner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4410.

Marc Hafner

Papers

Abstract PD4-02: Advantageous polypharmacology of abemaciclib revealed by omics profiling of CDK4/6 inhibitors

Semi-quantitative stability analysis constrains saturation levels in metabolic networks

Multi-omics profiling establishes the polypharmacology of FDA Approved CDK4/6 inhibitors and its impact on drug response

Abstract 4410: Predictive model of palbociclib response reveals indications in which CDK4/6 inhibitor can be a potential combination partner

DeepDyeDrop: an image-based approach to quantify the phenotypic response of cancer cells to therapeutics (Conference Presentation)