Frederick R. Adler

University of Utah | UOU · Department of Biology

A time-series analysis of serum Cancer Antigen 125 (CA-125) levels was performed in 791 patients with high-grade serous ovarian cancer (HGSOC) from the Australian Ovarian Cancer Study to evaluate the development of chemoresistance and response to therapy. To investigate chemoresistance and better predict the treatment effectiveness, we examined two...

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored re...

Many organisms have the ability to learn, but the costs and benefits of learning are difficult to quantify. We construct a minimal mathematical model of learning in which a forager attempts to maximize the amount of resources (food) it collects in a changing environment. Our model has two learning parameters: α, corresponding to the duration of the...

Field cancerization is a process in which a normal tissue is replaced with pre-cancerous but histologically normal tissue. This transformed field can give rise to malignancy and contribute to tumor relapse. In this paper, we create a mathematical model of field cancerization from the perspective of cancer behavioral ecology. In our model, field can...

The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. Here, we study interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to ribociclib-induced cyclin-dependent kinase 4...

Background and Objectives Cancer biomarkers provide information on the characteristics and extent of cancer progression and help inform clinical decision-making. However, they can also play functional roles in oncogenesis, from enabling metastases and inducing angiogenesis to promoting resistance to chemotherapy. The resulting evolution could bias...

Transmission heterogeneity plays a critical role in the dynamics of an epidemic. During an outbreak of an emerging infectious disease, efforts to characterize transmission heterogeneity are generally limited to quantifications during a small outbreak or a limited number of generations of a larger outbreak. Understanding how transmission heterogenei...

New graduate students in biology programs may lack the quantitative skills necessary for their research and professional careers. The acquisition of these skills may be impeded by teaching and mentoring experiences that decrease rather than increase students’ beliefs in their ability to learn and apply quantitative approaches. In this opinion piece...

While endocrine therapy (ET) has considerably improved Stage II/III ER+ breast cancer survival rates, resistance emerges in 30-50% of patients. Recent advances have uncovered numerous cancer intrinsic and tumor-microenvironment mediated mechanisms contributing to ET resistance. However, the predominant mechanisms that prevent cure and ultimately le...

By corrupting signals for growth and survival, evolving cancer cells can engineer the tumor microenvironment (TME) to promote treatment resistance. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, co...

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, dr...

Finding a common currency for benefits and hazards is a major challenge in optimal foraging theory, often requiring complex computational methods. We present a new analytic approach that builds on the Marginal Value Theorem and giving‐up densities while incorporating the nonlinear effect of predation risk. We map the space of all possible environme...

The costs and benefits of learning for a foraging organism are difficult to quantify, and depend sensitively on the environment. We construct a minimal mathematical model of learning in which a forager learns the quality of different food types through experience. In our model, learning depends on two parameters: rate of memory updating and rate of...

Asymptomatic colonization by Staphylococcus aureus is a precursor for infection, so identifying the mode and source of transmission which leads to colonization could help target interventions. Longitudinal studies have shown that some people are persistently colonized for years, while others seem to carry S. aureus for weeks or less, and convention...

Cancer cells evolve, acquire resistance to therapy and change their environment. One resistance mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving cancer cells can engineer a pro-tumor TME. However, the specific interactions between mali...

There is often considerable uncertainty in parameters in ecological models. This uncertainty can be incorporated into models by treating parameters as random variables with distributions, rather than fixed quantities. Recent advances in uncertainty quantification methods, such as polynomial chaos approaches, allow for the analysis of models with ra...

The interplay of positive and negative interactions between drug sensitive and resistant cells determines the efficacy of treatment in heterogeneous cancer cell populations. While competition between different cell lineages within tumors has been considered in cancer evolution and progression, cooperative interactions receive far less study. We hav...

Background Airway inflammation promotes bronchiectasis and lung injury in cystic fibrosis (CF). Amplification of inflammation underlies pulmonary exacerbations of disease. We asked whether sputum inflammatory biomarkers provide explanatory information on pulmonary exacerbations. Patients and Methods We collected sputum from randomly chosen stable...

We utilize traffic density and Convolvulus arvensis leaf chemistry to understand spatial patterns linking atmospheric pollution and household income in the Salt Lake City metropolitan area, USA. We hypothesize that traffic density will explain variation in atmospheric NOx and O3 concentrations. In addition, we expect foliar %N and nitrogen isotope...

According to the National Cancer Institute, there were 9.5 million cancer-related deaths in 2018. A challenge in improving treatment is resistance in genetically unstable cells. The purpose of this study is to evaluate unsupervised machine learning on classifying treatment-resistant phenotypes in heterogeneous tumors through analysis of single cell...

When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use...

All biological systems depend on signals for coordination: signals which pass information among agents that run the gamut from cells to organisms. However, their very importance makes signals vulnerable to subversion. How can a receiver know whether a signal is honest or deceptive? In other words, are signals necessarily a reliable indicator of age...

Competition between different lineages of cells within a tumor has been included in thinking about cancer evolution and progression, but positive interactions like cooperation have received far less study. We have developed isogenic estrogen positive breast cancer cell lineages sensitive and resistant to CDK4/6 inhibition in order to investigate th...

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for patients with metastatic estrogen receptor-positive breast cancer but its value in earlier-stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single-cell RNA sequencing of serial biopsies from the...

Marine mammals rely on blubber mainly for energy storage, buoyancy, and streamlining. Mysticetes are born with a relatively thin fat layer that grows rapidly during nursing. However, little information on blubber deposition patterns is available for baleen whale calves. We measured blubber thickness at nine body locations in 350 southern right whal...

The future prevalence and virulence of SARS-CoV-2 is uncertain. Some emerging pathogens become avirulent as populations approach herd immunity. Although not all viruses follow this path, the fact that the seasonal coronaviruses are benign gives some hope. We develop a general mathematical model to predict when the interplay among three factors, cor...

We evaluated the performance of machine learning models in predicting cell state based on single cell RNA sequencing data (scRNAseq) analysis. scRNAseq quantifies the number of mRNA molecules in individual cells providing information on regulatory relationships between genes and the trajectories of distinct cell lineages in development. Different c...

Cells losing the ability to self-regulate in response to damage are a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because dam...

COVID‐19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS‐CoV‐2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID‐19 testing for symptoms at drive‐thro...

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionar...

The interplay of positive and negative interactions between drug sensitive and resistant cells determines the efficacy of treatment in heterogeneous cancer cell populations. We developed isogenic estrogen receptor positive (ER+) breast cancer cell lineages sensitive and resistant to ribociclib-induced CDK4/6 inhibition to investigate cell interacti...

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionar...

Background Accurately determining changes in tumor size during therapy is essential to evaluating response or progression. However, individual imaging methodologies often poorly reflect pathologic response and long-term treatment efficacy in patients with estrogen receptor positive (ER+) early-stage breast cancer. Mathematical models that measure t...

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread...

Choosing and optimizing treatment strategies for cancer requires capturing its complex dynamics sufficiently well for understanding but without being overwhelmed. Mathematical models are essential to achieve this understanding, and we discuss the challenge of choosing the right level of complexity to address the full range of tumor complexity from...

Cells losing the ability to self-regulate in response to damage is a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because dama...

The benefits of mammography screening have been controversial, with conflicting findings from various studies. We hypothesize that unmeasured heterogeneity in tumor aggressiveness underlies these conflicting results. Based on published data from the Canadian National Breast Screening Study (CNBSS), we develop and parameterize an individual-based me...

Significance The evolution of peripheral immune cell abundance and signaling over time, as well as how these immune cells interact with the tumor, may impact a cancer patient’s response to therapy. By developing an ecological population model, we provide evidence of a dynamic predator–prey-like relationship between circulating immune cell abundance...

The spatial distribution of cells within a tissue underlies organ function. However, these spatial distributions are often difficult to identify, making it challenging to evaluate how cells establish these patterns during development or how diseases may disrupt these patterns and impair function. To address this, we developed an image analysis tool...

We evaluated a multivariable logistic regression model predicting 5-year survival derived from a 1993–1997 cohort from the United States Cystic Fibrosis (CF) Foundation Patient Registry to assess whether therapies introduced since 1993 have altered applicability in cohorts, non-overlapping in time, from 1993–1998, 1999–2004, 2005–2010 and 2011–2016...

By involving the public, citizen science runs against the grain of an idealized science that leaves out the human element, and thus provides new opportunities for ecological research and society. We classify the goals of citizen science in ecology and environment into four broad categories: (1) scientific, (2) participant benefits, (3) community, a...

The extent that immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single cell genomic analyses...

A bstract BACKGROUND The benefits of mammography screening have been controversial, with conflicting findings from various studies. METHODS We hypothesize that unmeasured heterogeneity in tumor aggressiveness underlies these conflicting results. Based on published data from the Canadian National Breast Screening Study (CNBSS), we develop and para...

Parallels of cancer with ecology and evolution have provided new insights into the initiation and spread of cancer and new approaches to therapy. This review describes those parallels while emphasizing some key contrasts. We argue that cancers are less like invasive species than like native species or even crops that have escaped control and that e...

A large array of species distribution model (SDM) approaches has been developed for explaining and predicting the occurrences of individual species or species assemblages. Given the wealth of existing models, it is unclear which models perform best for interpolation or extrapolation of existing data sets, particularly when one is concerned with spe...

Background: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. Methods: We recruited...

Interactions in the airway ecology of cystic fibrosis may alter organism persistence and clinical outcomes. Better understanding of such interactions could guide clinical decisions. We fitted logistic regression models using generalized estimating equations to longitudinal two-year patient cohorts in the Cystic Fibrosis Foundation Patient Registry,...

Background Common cold viruses create significant health and financial burdens, and understanding key loci of transmission would help focus control strategies. This study (1) examines factors that influence when individuals transition from a negative to positive test (acquisition) or a positive to negative test (loss) of rhinovirus (HRV) and other...

The tumor suppressor protein p53 compiles information about cellular stressors to make decisions on whether the cell should survive or undergo apoptosis. However, the p53 response depends on the source of damage, displaying a 'digital' oscillatory response after ionizing radiation (IR) damage and a proportional non-oscillatory response following UV...

Territory size in social insects depends on the rules by which border conflicts are resolved. We present three mechanistic mathematical models of conflict, inspired by the behavior of the pavement ant Tetramorium immigrans, to predict the advantage of larger colonies in pairwise contests and the resulting scaling of territory size with worker force...

Determining population trends is critical for conservation. For most bird species, trends are based on count data gathered by institutions with formalized survey protocols. However, limited resources may prevent these types of surveys, especially in developing countries. Ecotourism growth and subsequent increases in opportunistic data from birdwatc...

Collective cell migration is an integral part of organismal development. We consider migration of the zebrafish primordium during development of the posterior lateral line, a sensory system that detects water movement patterns. Experiments have shown that the chemokine ligand CXCL12a and its receptors CXCR4b and CXCR7b are key players for driving m...

The decay of mRNA plays a vital role in modulating mRNA abundance, which, in turn, influences cellular and organismal processes. In plants and metazoans, three distinct pathways carry out the decay of most cytoplasmic mRNAs: The mRNA decapping complex, which requires the scaffold protein VARICOSE (VCS), removes a protective 5' cap, allowing for 5'...

Respiratory viral infections are common in the general population and one of the most important causes of asthma aggravation and exacerbation. Despite many studies, it is not well understood how viral infections cause more severe symptoms and exacerbations in asthmatics. We develop a mathematical model of two types of macrophages that play compleme...

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....

Theory relating species richness to ecosystem variability typically ignores the potential for environmental variability to promote species coexistence. Failure to account for fluctuation-dependent coexistence may explain deviations from the expected negative diversity-ecosystem variability relationship, and limits our ability to predict the consequ...

Background: Drivers of differences in C. difficile incidence across acute and long-term care facilities are poorly understood. We sought to obtain a comprehensive picture of C. difficile incidence and risk factors in acute and long-term care. Methods: We conducted a case-cohort study of persons spending at least 3 days in one of 131 acute care o...

Background: Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR...

Theory relating species richness to ecosystem variability typically ignores the potential for environmental variability to promote species coexistence. Failure to account for fluctuation-dependent coexistence mechanisms may explain observed deviations from the expected negative diversity–ecosystem variability relationship, and limits our ability to...

Importance: Most colds are caused by rhinoviruses (RV). Those caused by a subset known as the minor-group members of the RV-A species are correlated with inception and aggravation of asthma in at-risk populations. Genetically, minor-group viruses are similar to the major-group RV-A viruses from which they were derived, although they tend to elicit...

Background and aims: Corner's rule states that thicker twigs bear larger leaves. The exact nature of this relationship and why it should occur has been the subject of numerous studies. It is obvious that thicker twigs should support greater total leaf area ([Formula: see text]) for hydraulical and mechanical reasons. But it is not obvious why mean...

Antibiotic overuse has promoted the spread of antibiotic resistance. To compound the issue, treating individuals dually infected with antibiotic-resistant and antibiotic-vulnerable strains can make their infections completely resistant through competitive release. We formulate mathematical models of transmission dynamics accounting for dual infecti...

In cystic fibrosis, statistical models have been more successful in predicting mortality than the time course of clinical status. We develop a system of partial differential equations that simultaneously track mortality and patient status, with all model parameters estimated from the extensive and carefully maintained database from the Cystic Fibro...

Objective: Cystic Fibrosis related diabetes (CFRD) is a risk factor for mortality, with pathogenesis possibly related to susceptibility of CFTR deficient pancreatic b-cells to oxidative stress. Because airway infections may increase oxidative stress in CF patients, we evaluated their association with CFRD. Methods: We analyzed 23,622 patients with...

Smoothed density of FEV1% in the next year. The panels show patients with current FEV1% within 0.5 of a. 30%, b. 50%, c. 70%, and d. 100%. The dashed vertical red line is the average of FEV1% in the current year, and the solid vertical green line the average of this patient cohort in the next year. (TIFF)

Distribution of FEV1% for patients entering the database with age less than 10 for the 8 possible infection states. The states are designated in the titles as in the legend to Fig 3. (TIFF)

Trajectories predicted by the model with P. aeruginosa acquisition eliminated, Burkholderia acquisition eliminated, or when both have been eliminated. (TIFF)

Trajectories predicted by the model with MSSA acquisition eliminated, without the pairwise interaction of MSSA and P. aeruginosa, and without any bacterial interactions. (TIFF)

Coefficients of the lower dimensional models. (PDF)

Trajectories predicted by lower dimensional models with just FEV1%, FEV1% and P. aeruginosa, FEV1% and MSSA, and FEV1% and Burkholderia. (TIFF)

Coefficients of the full model with patients from 1986–1995. (PDF)

Input data for lower dimensional models. The first column shows mortality, variance in ΔFEV1% and ΔFEV1% for a model that tracks only FEV1%. The next columns present models that track FEV1% and P. aeruginosa, MSSA, and Burkholderia respectively, including a panel with acquisition (colored points and curve) or loss (black points and curve) of infect...

Trajectories predicted by the model with altered variance. Variance is increased by a factor of 5 (High variance) or decreased by a factor of 5 (Low variance) of a. FEV1%, b. P. aeruginosa, c. MSSA, and d. Burkholderia. (TIFF)

Coefficients of the full model. (PDF)

Distribution of predicted (solid lines) and observed (dashed lines) FEV1% at four ages for all patients pooled and for those testing positive for each of the three infections. Distributions are normalized to integrate to the total number of patients in that category. (TIFF)

Background: Although clinical factors affecting a person's susceptibility to Clostridium difficile infection are well-understood, little is known about what drives differences in incidence across long-term care settings. Objective: To obtain a comprehensive picture of individual and regional factors that affect C difficile incidence. Design: Mult...

Type 1 diabetes (T1D) is often triggered by a viral infection, but the T1D prevalence is rising among populations that have a lower exposure to viral infection. In an animal model of T1D, the NOD mouse, viral infection at different ages may either accelerate or delay disease depending on the age of infection and the type of virus. Viral infection m...

Introduced pathogens and other parasites are often implicated in host population‐level declines and extinctions. However, such claims are rarely supported by rigorous real‐time data. Indeed, the threat of introduced parasites often goes unnoticed until after host populations have declined severely. The recent introduction of the parasitic nest fly,...

Background: Treatments for health care–associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversin...

Significance Pathogens that invoke an immune response immediately after infection can also provide partial cross-protection against other strains of the same or closely related pathogens. This cross-protection can shape the epidemiological dynamics of multistrain pathogens when an epidemic of one strain temporarily suppresses the transmission of an...

Península Valdés (PV) in Argentina is an important calving ground for southern right whales (SRWs, Eubalaena australis). Since 2005, right whale mortality has increased at PV, with most of the deaths (~90%) being calves <3 mo old. We investigated the potential involvement of harmful algal blooms (HABs) in these deaths by examining data that include...

Treatments for health care-associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increa...

While the ongoing Ebola outbreak continues in the West Africa countries of Guinea, Sierra Leone, and Liberia, health officials elsewhere prepare for new introductions of Ebola from infected evacuees or travelers. We analyzed transmission data from patients (i.e., evacuees, international travelers, and those with locally acquired illness) in countri...

Technical Appendix. Detailed background and methods for quantitative analyses, equations used to generate model results, and results from additional sensitivity analyses.

Objectives Quantify the association of CFTR mutations of different classes and specific identities with carriage of eight clinically relevant airway infections. Methods After obtaining IRB approval, we analyzed data from the CFFPR from 2003–2011. We examined carriage of Pseudomonas aeruginosa, methicillin-sensitive and methicillin-resistant Staphy...

Objectives Investigate the stability of the five-year survival model in Liou et al (Am J Epidemiol, 153:345, 2001). Methods After obtaining IRB approval, we analyzed data from the CFFPR from 1993–2010, breaking patients into three non-overlapping cohorts starting in 1993, 1999, and 2005, and following for five years, excluding transplanted patient...

Clostridium difficile infection (CDI) is an infectious diarrheal disease that is associated with antibiotic and healthcare exposures. Although individual-level risk factors have been extensively studied, the facility-level factors that drive CDI have not.