Devotions for Lent 2023 Hymns of Lent

This Lent, we will continue reflecting on hymns of faith, namely, some of our most beloved Lenten hymns. 10 such hymns have been chosen to fill the 40(+) days of Lent. Therefore, this devotional, different from previous editions, does not proceed on a weekly basis, but merely flows from one hymn to the next. Also different from previous editions, the devotional reflections are specifically based on the stanzas of the selected hymns. Therefore, each day’s reflection features the text of the hymn stanza, a devotion based on that stanza, a prayer, and then a Scripture passage or passages for further meditation. I pray these reflections may be of edification for you during this Lenten season.https://scholar.csl.edu/osp/1022/thumbnail.jp

MDCK Cystogenesis Driven by Cell Stabilization within Computational Analogues

The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles

At the Biological Modeling and Simulation Frontier

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine

Overcoming barriers to tumor genomic profiling through direct-to-patient outreach

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339Y.L. has received research funding from AstraZeneca, GSK, and REPARE Therapeutics unrelated to this work. C.A. has received consulting fees from Eisai, Merk, Roche/Genentech, Abbvie, AstraZeneca and Repare Therapeutics and clinical trial funding from AstraZeneca. M.Y. has served as a consultant for Janssen Research and Development. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, Loxo Oncology/Lilly and is on the Scientific Advisory Board of Envisagenics Inc and Harmonic Discovery Inc.; O.A.-W. has received prior research funding from H3B Biomedicine, Loxo Oncology/Lilly, and Nurix Therapeutics unrelated to the current manuscript. M.B. has served as a consultant for Eli Lilly, PetDx and received research funding from Grail. J.G.B has served as a consultant for Jazz Pharmaceuticals, was an uncompensated consultant on a DSMB for Springworks, Merck and Pfizer and served on pediatric advisory boards for BMS and Eisai. She receives institutional research support (but no salary support) for clinical trials from Roche, Merck, Amgen, Lilly, BMS, Eisai, Novartis, Loxo-oncology, Cellectar and Bayer. S.A.F. has received research support from AstraZeneca, Genentech/Roche, and Decibel Therapeutics is a consultant/advisory board member for Merck and BioNTech, and owns stock in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, ByHeart, 76Bio, Vida Ventures, Inconovir, and Doximity. A.D. served as a consultant for Incyte, EUSA Pharma, Loxo Oncology and receives research support from Roche and Takeda. R.A.S. was paid annually for serving as assistant editor for one of the USCAP society journals. H.A-A. has served as a consultant for AstraZeneca and Paige.AI. D.R.F. has received research funding from Telix Pharmaceuticals, Decibel Therapeutics, Astellas, Royalties from Up-to-Date, and has served as a consultant for BioNTech. E.M.V. has served as an advisor/Consultant to Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, Serinus Bio, has received research support from Novartis, BMS, Sanofi, and has equity interests in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio. E.L.D. discloses unpaid editorial support from Pfizer, Inc, and paid advisory board membership with Day One Biopharmaceuticals and Springworks Therapeutics. D.B.S. has served as a consultant for/received honorarium from Pfizer, Loxo Oncology/Lilly, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, and BridgeBio. The remaining authors declare no potential conflicts of interest

The context-specific role of germline pathogenicity in tumorigenesis.

Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management