The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease.

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

Wood cookstove use is associated with gastric cancer in Central America and mediated by host genetics.

Biomass cookstove food preparation is linked to aero-digestive cancers, mediated by ingested and inhaled carcinogens (e.g., heterocyclic amines, and polycyclic aromatic hydrocarbons). We investigated the association between gastric adenocarcinoma, wood cookstove use, H. pylori CagA infection and risk modification by variants in genes that metabolize and affect the internal dose of carcinogens. We conducted a population-based, case-control study (814 incident cases, 1049 controls) in rural Honduras, a high-incidence region with a homogeneous diet and endemic H. pylori infection, primarily with the high-risk CagA genotype. We investigated factors including wood cookstove use, H. pylori CagA serostatus, and 15 variants from 7 metabolizing genes, and the interactions between wood stove use and the genetic variants. Male sex (OR 2.0, 1.6-2.6), age (OR 1.04, 1.03-1.05), wood cookstove use (OR 2.3, 1.6-3.3), and CagA serostatus (OR 3.5, 2.4-5.1) and two SNPs in CYP1B1 (rs1800440 and rs1056836) were independently associated with gastric cancer in multivariate analysis. In the final multivariate model, a highly significant interaction (OR 3.1, 1.2-7.8) was noted between wood cookstove use and the rs1800440 metabolizing genotype, highlighting an important gene-environment interaction. Lifetime wood cookstove use associates with gastric cancer risk in the high-incidence regions of Central America, and the association is dependent on the rs1800440 genotype in CYP1B1. H. pylori CagA infection, wood cookstove use and the rs1800440 genotype, all of which are highly prevalent, informs who is at greatest risk from biomass cookstove use.

Fetal High-Risk APOL1 Genotype Increases Risk for Small for Gestational Age in Term Infants Affected by Preeclampsia.

BACKGROUND: Hypertensive disorders of pregnancy cause fetal growth restriction and increased maternal morbidity and mortality, especially in women of African ancestry. Recently, preeclampsia risk was associated with polymorphisms in the apolipoprotein L1 (APOL1) gene in women of African ancestry. OBJECTIVES: We assessed APOL1 genotype effects on pregnancies with and without preeclampsia. METHOD: We conducted an unmatched case-control study of 1,358 mother-infant pairs from two independent cohorts of black women. RESULTS: Term preeclampsia cases with high-risk APOL1 genotypes were more likely to be small for gestational age compared to APOL1 low-risk term cases (odds ratio [OR] 2.8) and APOL1 high-risk controls (OR 5.5). Among preterm pregnancies, fetal APOL1 genotype was associated with preeclampsia. CONCLUSIONS: Fetal APOL1 genotype was associated with preeclampsia in preterm infants and with altered fetal growth in term infants. This may indicate APOL1 genotype impacts a spectrum of pregnancy complications mediated by a common pathophysiological event of placental insufficiency.

Rad5 and Its Human Homologs, HLTF and SHPRH, Are Novel Interactors of Mismatch Repair.

DNA mismatch repair (MMR) repairs replication errors, and MMR defects play a role in both inherited cancer predisposition syndromes and in sporadic cancers. MMR also recognizes mispairs caused by environmental and chemotherapeutic agents; however, in these cases mispair recognition leads to apoptosis and not repair. Although mutation avoidance by MMR is fairly well understood, MMR-associated proteins are still being identified. We performed a bioinformatic analysis that implicated Saccharomyces cerevisiae Rad5 as a candidate for interacting with the MMR proteins Msh2 and Mlh1. Rad5 is a DNA helicase and E3 ubiquitin ligase involved in post-replicative repair and damage tolerance. We confirmed both interactions and found that the Mlh1 interaction is mediated by a conserved Mlh1-interacting motif (MIP box). Despite this, we did not find a clear role for Rad5 in the canonical MMR mutation avoidance pathway. The interaction of Rad5 with Msh2 and Mlh1 is conserved in humans, although each of the Rad5 human homologs, HLTF and SHPRH, shared only one of the interactions: HLTF interacts with MSH2, and SHPRH interacts with MLH1. Moreover, depletion of SHPRH, but not HLTF, results in a mild increase in resistance to alkylating agents although not as strong as loss of MMR, suggesting gene duplication led to specialization of the MMR-protein associated roles of the human Rad5 homologs. These results provide insights into how MMR accessory factors involved in the MMR-dependent apoptotic response interact with the core MMR machinery and have important health implications into how human cells respond to environmental toxins, tumor development, and treatment choices of tumors with defects in Rad5 homologs.

Antigen receptor therapy in bone metastasis via optimal control for different human life stages.

In this work we propose a bone metastasis model using power law growth functions in order to describe the biochemical interactions between bone cells and cancer cells. Experimental studies indicate that bone remodeling cycles are different for human life stages: childhood, young adulthood, and adulthood. In order to include such differences in our study, we estimate the model parameter values for each human life stage via bifurcation analysis. Results reveal an intrinsic relationship between the active period of remodeling cycles and the proliferation of cancer cells. Subsequently, using optimal control theory we analyze a possible antigen receptor therapy as a new treatment for bone metastasis. Theoretical results such as existence of optimal solutions are proved. Numerical simulations for late stages of bone metastasis are presented and a discussion of our results is carried out.

Ornithine decarboxylase (ODC1) gene variant (rs2302615) is associated with gastric cancer independently of Helicobacter pylori CagA serostatus.

The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1 variant rs2302615 was associated with gastric cancer (OR = 1.36; p = 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1 (rs530537) and TLR4 (rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1 SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4 polymorphism, rs1927914 (OR = 1.77; p = 1.85 × 10-3). In conclusion, the ODC1 variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914.

Helicobacter pylori infection causes both protective and deleterious effects in human health and disease.

Infection with Helicobacter pylori (H. pylori) is necessary but not sufficient for the development of gastric cancer, the third leading cause of cancer death globally. H. pylori infection affects over half of people globally; however, it does not affect populations uniformly. H. pylori infection rates are declining in western industrialized countries but are plateauing in developing and newly industrialized countries where gastric cancer is most prevalent. Despite H. pylori infection being the primary causative agent for gastric cancer, H. pylori infection can also cause other effects, detrimental or beneficial, throughout an individual's life, with the beneficial effects often being seen in childhood and the deleterious effects in adulthood. H. pylori is an ancient bacterium and its likelihood of affecting disease or health is dependent on both human and bacterial genetics that have co-evolved over millennia. In this review, we focus on the impact of infection and its genetic bases in different populations and diseases throughout an individual's lifespan, highlighting the benefits of individualized treatment and argue that universal eradication of H. pylori in its host may cause more harm than good for those infected with H. pylori.

A Novel Mapping Strategy Utilizing Mouse Chromosome Substitution Strains Identifies Multiple Epistatic Interactions That Regulate Complex Traits.

The genetic contribution of additive vs. non-additive (epistatic) effects in the regulation of complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate approach for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTL) were identified using a CSS-based backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. In the liver transcriptomes of offspring from this cross, we identified and mapped additive QTL regulating the hepatic expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTL for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTL pairs was approximately equal to that of the additive QTL; however, the SNPs in the epistatic QTL pairs that accounted for the largest variances were undetected in our single locus association analyses. These findings highlight the need to account for epistasis in association studies, and more broadly demonstrate the importance of identifying genetic interactions to understand the complete genetic architecture of complex traits.

What Is the Storage Effect, Why Should It Occur in Cancers, and How Can It Inform Cancer Therapy?

Intratumor heterogeneity is a feature of cancer that is associated with progression, treatment resistance, and recurrence. However, the mechanisms that allow diverse cancer cell lineages to coexist remain poorly understood. The storage effect is a coexistence mechanism that has been proposed to explain the diversity of a variety of ecological communities, including coral reef fish, plankton, and desert annual plants. Three ingredients are required for there to be a storage effect: (1) temporal variability in the environment, (2) buffered population growth, and (3) species-specific environmental responses. In this article, we argue that these conditions are observed in cancers and that it is likely that the storage effect contributes to intratumor diversity. Data that show the temporal variation within the tumor microenvironment are needed to quantify how cancer cells respond to fluctuations in the tumor microenvironment and what impact this has on interactions among cancer cell types. The presence of a storage effect within a patient's tumors could have a substantial impact on how we understand and treat cancer.

Association of preeclampsia with infant APOL1 genotype in African Americans.

BACKGROUND: Black women in the United States and Africa are at an increased risk for preeclampsia. Allelic variants in the gene for apolipoprotein LI, APOL1, are found only in populations of African ancestry, and have been shown to contribute significant risk for kidney disease. Recent studies suggest these APOL1 variants also may contribute risk for preeclampsia. METHODS: The association of preeclampsia with carriage of APOL1 risk alleles was evaluated in a case-control study of deliveries from black women at a single center in Cleveland, Ohio that included gross and histopathologic evaluations of placental tissues (395 cases and 282 controls). Using logistic regression models, associations between fetal APOL1 genotype and preeclampsia were evaluated using several case definitions based on prematurity and severity of preeclampsia, with uncomplicated term pregnancies as controls. Associations between APOL1 genotype and pathological features were also examined. RESULTS: The infant APOL1 genotype was significantly associated with preeclampsia in a dominant inheritance pattern with odds ratio of 1.41 (P=0.029, 95% CI 1.037, 1.926). Stratifying preeclampsia cases by preterm birth, significant associations were detected for both recessive (O.R.=1.70, P=0.038) and additive (O.R.=1.33, P=0.028) inheritance patterns. APOL1 genotype, however, was not significantly associated with pathological changes or other perinatal observations. CONCLUSIONS: Preeclampsia appears to be another disease associated with APOL1 variants, however, further studies are needed to increase confidence in the mode of inheritance. By understanding the association of APOL1 variants with preeclampsia, genetic screening tests for APOL1 may be useful to predict at-risk pregnancies and targeted interventions may be developed to improve pregnancy outcomes.

Hybrid Automata Library: A flexible platform for hybrid modeling with real-time visualization.

The Hybrid Automata Library (HAL) is a Java Library developed for use in mathematical oncology modeling. It is made of simple, efficient, generic components that can be used to model complex spatial systems. HAL's components can broadly be classified into: on- and off-lattice agent containers, finite difference diffusion fields, a GUI building system, and additional tools and utilities for computation and data collection. These components are designed to operate independently and are standardized to make them easy to interface with one another. As a demonstration of how modeling can be simplified using our approach, we have included a complete example of a hybrid model (a spatial model with interacting agent-based and PDE components). HAL is a useful asset for researchers who wish to build performant 1D, 2D and 3D hybrid models in Java, while not starting entirely from scratch. It is available on GitHub at https://github.com/MathOnco/HAL under the MIT License. HAL requires the Java JDK version 1.8 or later to compile and run the source code.

A Mathematical Model of Cell Cycle Dysregulation Due to Human Papillomavirus Infection.

Human papillomaviruses (HPVs) that infect mucosal epithelium can be classified as high risk or low risk based on their propensity to cause lesions that can undergo malignant progression. HPVs produce the E7 protein that binds to cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein (RB) to modulate cell cycle control. Generally, high-risk HPV E7 proteins bind to RB with a higher affinity than low-risk HPV E7s, but both are able to deactivate RB and trigger S phase progression. In uninfected cells, RB inactivation is a tightly controlled process that must coincide with growth factor stimulation to commit cells to division. High-risk HPV E7 proteins short-circuit this control by decreasing growth factor requirement for cell division. We develop a mathematical model to examine the role that RB binding affinity, growth factor concentration, and E7 concentration have on cell cycle progression. Our model predicts that high RB binding affinity and E7 concentration accelerate the [Formula: see text] to S phase transition and weaken the dependence on growth factor. This model thus captures a key step in high-risk HPV oncogenesis.

Identification of pauses during formation of HIV-1 virus like particles.

HIV Gag polymerizes on the plasma membrane to form virus like particles (VLPs) that have similar diameters to wild-type viruses. We use multicolor, dual-penetration depth, total internal reflection fluorescence microscopy, which corrects for azimuthal movement, to image the assembly of individual VLPs from the time of nucleation to the recruitment of VPS4 (a component of the endosomal sorting complexes required for transport, and which marks the final stage of VLP assembly). Using a mathematical model for assembly and maximum-likelihood comparison of fits both with and without pauses, we detect pauses during Gag polymerization in 60% of VLPs. Pauses range from 2 to 20 min, with an exponentially distributed duration that is independent of cytosolic Gag concentration. VLPs assembled with late domain mutants of Gag (which do not recruit the key endosomal sorting complexes required for transport proteins Alix or TSG101) exhibit similar pause distributions. These pauses indicate that a single rate-limiting event is required for continuation of assembly. We suggest that pauses are either related to incorporation of defects in the hexagonal Gag lattice during VLP assembly or are caused by shortcomings in interactions of Gag with essential and still undefined cellular components during formation of curvature on the plasma membrane.