Climate change affects bird nesting phenology: Comparing contemporary field and historical museum nesting records.

Global climate change impacts species and ecosystems in potentially harmful ways. For migratory bird species, earlier spring warm-up could lead to a mismatch between nesting activities and food availability. CO2 provides a useful proxy for temperature and an environmental indicator of climate change when temperature data are not available for an entire time series. Our objectives were to (a) examine nesting phenology over time; (b) determine how nesting phenology relates to changes in atmospheric CO2 concentration; and (c) demonstrate the usefulness of historical museum collections combined with modern observations for trend analyses. We assessed changes in nesting dates of 72 bird species in the Upper Midwest of the United States by comparing contemporary lay dates with those obtained from archived, historical museum nest records over a 143-year period (1872-2015). Species-specific changes in lay date per one unit change in the CO2 residual ranged from -0.75 (95% CI: -1.57 to -0.10) to 0.45 (95% CI: -0.29 to 1.43). Overall, lay dates advanced ~10 days over the 143-year period. Resident, short-distance migrants and long-distance migrants lay dates advanced by ~15, 18 and 16 days on average respectively. Twenty-four species (33.3%) significantly advanced, one (1.4%) significantly delayed and we failed to detect an advance or delay in lay date for 47 species (65.3%). Overall mean advance in first lay date (for the species that have significantly advanced laying date) was 25.1 days (min: 10.7, max: 49.9). Our study highlights the scientific importance of both data gathering and archiving through time to understand phenological change. The detailed archived information reported by egg collectors provide the early data of our study. As with studies of egg-shell thinning and pesticide exposure, our use of these data illustrates another scientific utility of egg collections that these pioneer naturalists never imagined. As museums archive historical data, these locations are also ideal candidates to store contemporary field data as it is collected. Together, such information will provide the ability to track, understand and perhaps predict responses to human-driven environmental change.

When a pest is not a pest: Birds indirectly increase defoliation but have no effect on yield of soybean crops.

Natural habitats near agricultural systems can be sources of both ecosystem services and disservices on farms. Ecosystem disservices, those aspects of an ecosystem that have negative impacts on humans, may disproportionately affect conservation decisions made by farmers. Birds, in particular, can have complex effects on crops, ranging from positive to neutral to negative. Therefore, it is important to quantify them in a meaningful way. Birds may be more abundant on farms near natural areas and may provide ecosystem services by consuming insect pests. However, when birds consume beneficial predatory arthropods rather than pest species (intraguild predation), they can provide a disservice to the farmer if the intraguild predation decreases crop yield. We studied bird intraguild predation in Illinois (USA) at six soybean fields adjacent to grasslands that provided source habitat for bird populations. We placed cages over soybean crops, which excluded birds but allowed access to arthropods, and measured differences in leaf damage and crop yield of plants in control and exclosure plots. We also conducted point counts at each site to quantify the bird communities. We found that plants within the bird exclosures had lower levels of leaf damage by pests than those in control plots, but there was no resulting effect on crop yield. We also found that sites with higher bird abundance had higher levels of leaf damage by pests, but bird species richness was not a significant predictor of leaf damage. These results suggest that although birds may have released pests through intraguild predation, there was no net disservice when considering crop yield, the variable most important to stakeholders.

Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors.

BACKGROUND: Approximately 50% of cancer patients eventually develop a syndrome of prolonged weight loss (cachexia), which may contribute to primary resistance to immune checkpoint inhibitors (ICI). This study utilised radiomics analysis of 18F-FDG-PET/CT images to predict risk of cachexia that can be subsequently associated with clinical outcomes among advanced non-small cell lung cancer (NSCLC) patients treated with ICI. METHODS: Baseline (pre-therapy) PET/CT images and clinical data were retrospectively curated from 210 ICI-treated NSCLC patients from two institutions. A radiomics signature was developed to predict the cachexia with PET/CT images, which was further used to predict durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) following ICI. RESULTS: The radiomics signature predicted risk of cachexia with areas under receiver operating characteristics curves (AUCs) ≥ 0.74 in the training, test, and external test cohorts. Further, the radiomics signature could identify patients with DCB from ICI with AUCs≥0.66 in these three cohorts. PFS and OS were significantly shorter among patients with higher radiomics-based cachexia probability in all three cohorts, especially among those potentially immunotherapy sensitive patients with PD-L1-positive status (p < 0.05). CONCLUSIONS: PET/CT radiomics analysis has the potential to predict the probability of developing cachexia before the start of ICI, triggering aggressive monitoring to improve potential to achieve more clinical benefit.

Special Collection on Ecological and Evolutionary Approaches to Cancer Control: Cancer Finds a Conceptual Home.

Despite a century of intense investigation, cancer biology and treatment remain plagued by unanswered questions. Even basic questions regarding the fundamental forces driving the formation of cancer remain controversial. Recent approaches view cancer in the context of a complex web of interactions among cancer cells of the tumor, together with their interactions with the many cells and constituents of the complex and highly dynamic tumor microenvironment. As seen in this special collection, we believe that viewing cancer as a process of evolution driven by ongoing ecological processes playing out within a dynamic environment offers many insights and potential new pathways for cancer control.

Resistance is not the end: lessons from pest management.

The "war on cancer" began over 40 years ago with the signing of the National Cancer Act of 1971. Currently, complete eradication has proven possible in early stage premetastatic disease with increasingly successful early detection and surgery protocols; however, late stage metastatic disease remains invariably fatal. One of the main causes of treatment failure in metastatic disease is the ability of cancer cells to evolve resistance to currently available therapies. Evolution of resistance to control measures is a universal problem. While it may seem that the mechanisms of resistance employed by cancer cells are impossible to control, we show that many of the resistance mechanisms are mirrored in agricultural pests. In this way, we argue that measures developed in the agricultural industry to slow or prevent pesticide resistance could be adopted in clinical cancer biology to do the same. The agriculture industry recognized the problem of pesticide resistance and responded by developing and enforcing guidelines on resistance management and prevention. These guidelines, known as integrated pest management (IPM), do not encourage eradication of pests but instead strive to maintain pests, even with the presence of resistant strains, at a level that does not cause economic damage to the crops. Integrated pest management inspired management of metastatic cancer could result in the slowing or curtailing of widespread resistance to treatment, reducing overall drug usage, and increasing the survival and quality of life of patients with cancer. Using IPM principles as a foundation and shifting the goal of treatment of metastatic disease to long-term management will require close monitoring of evolving tumor populations, judicious application of currently available therapies, and development of new criteria of success.

Insights From the Ecology of Information to Cancer Control.

Uniquely in nature, living systems must acquire, store, and act upon information. The survival and replicative fate of each normal cell in a multicellular organism is determined solely by information obtained from its surrounding tissue. In contrast, cancer cells as single-cell eukaryotes live in a disrupted, heterogeneous environment with opportunities and hazards. Thus, cancer cells, unlike normal somatic cells, must constantly obtain information from their environment to ensure survival and proliferation. In this study, we build upon a simple mathematical modeling framework developed to predict (1) how information promotes population persistence in a highly heterogeneous environment and (2) how disruption of information resulting from habitat fragmentation increases the probability of population extinction. Because (1) tumors grow in a highly heterogeneous microenvironment and (2) many cancer therapies fragment tumors into isolated, small cancer cell populations, we identify parallels between these 2 systems and develop ideas for cancer cure based on lessons gleaned from Anthropocene extinctions. In many Anthropocene extinctions, such as that of the North American heath hen (Tympanuchus cupido cupido), a large and widespread population was initially reduced and fragmented owing to overexploitation by humans (a "first strike"). After this, the small surviving populations are vulnerable to extinction from environmental or demographic stochastic disturbances (a "second strike"). Following this analogy, after a tumor is fragmented into small populations of isolated cancer cells by an initial therapy, additional treatment can be applied with the intent of extinction (cure). Disrupting a cancer cell's ability to acquire and use information in a heterogeneous environment may be an important tactic for causing extinction following an effective initial therapy. Thus, information, from the scale of cells within tumors to that of species within ecosystems, can be used to identify vulnerabilities to extinction and opportunities for novel treatment strategies.

The Intersection of Regional Anesthesia and Cancer Progression: A Theoretical Framework.

The surgical stress and inflammatory response and volatile anesthetic agents have been shown to promote tumor metastasis in animal and in-vitro studies. Regional neuraxial anesthesia protects against these effects by decreasing the surgical stress and inflammatory response and associated changes in immune function in animals. However, evidence of a similar effect in humans remains equivocal due to the high variability and retrospective nature of clinical studies and difficulty in directly comparing regional versus general anesthesia in humans. We propose a theoretical framework to address the question of regional anesthesia as protective against metastasis.This theoretical construct views the immune system, circulating tumor cells, micrometastases, and inflammatory mediators as distinct populations in a highly connected system. In ecological theory, highly connected populations demonstrate more resilience to local perturbations but are prone to system-wide shifts compared with their poorly connected counterparts. Neuraxial anesthesia transforms the otherwise system-wide perturbations of the surgical stress and inflammatory response and volatile anesthesia into a comparatively local perturbation to which the system is more resilient. We propose this framework for experimental and mathematical models to help determine the impact of anesthetic choice on recurrence and metastasis and create therapeutic strategies to improve cancer outcomes after surgery.

Birds suppress pests in corn but release them in soybean crops within a mixed prairie/agriculture system.

Birds provide ecosystem services (pest control) in many agroecosystems and have neutral or negative ecological effects (disservices) in others. Large-scale, conventional row crop agriculture is extremely widespread globally, yet few studies of bird effects take place in these agroecosystems. We studied indirect effects of insectivorous birds on corn and soybean crops in fields adjacent to a prairie in Illinois (USA). We hypothesized that prairie birds would forage for arthropods in adjacent crop fields and that the magnitude of services or disservices would decrease with distance from the prairie. We used bird-excluding cages over crops to examine the net effect of birds on corn and soybean grain yield. We also conducted DNA metabarcoding to identify arthropod prey in fecal samples from captured birds. Our exclosure experiments revealed that birds provided net services in corn and net disservices in soybeans. Distance from prairie was not a significant predictor of exclosure treatment effect in either crop. Many bird fecal samples contained DNA from both beneficial arthropods and known economically significant pests of corn, but few economically significant pests of soybeans. Song Sparrows (Melospiza melodia), one of our most captured species, most commonly consumed corn rootworms, an economically significant pest of corn crops. We estimated that birds in this system provided a service worth approximately US $275 ha-1 in corn yield gain, and a disservice valued at approximately $348 ha-1 in soybean yield loss. Our study is the first to demonstrate that birds can provide substantial and economically valuable services in field corn, and disservices in soybean crops. The contrasting findings in the 2 crop systems suggest a range of bird impacts within widespread agroecosystems and demonstrate the importance of quantifying net trophic effects.

Las aves brindan servicios ecosistémicos (control de plagas) en muchos agro-ecosistemas y tienen efectos ecológicos neutrales o negativos (deservicios) en otros. La agricultura convencional a gran escala de cultivos en hilera está ampliamente distribuida a escala global, pero a pesar de esto se han realizado pocos estudios de los efectos de las aves en estos agro-ecosistemas. Estudiamos los efectos indirectos de las aves insectívoras en cultivos de maíz y soja en campos adyacentes a una pradera en Illinois (EEUU). Hipotetizamos que las aves de pradera forrajearían en busca de artrópodos en los campos de cultivo adyacentes y que la magnitud de los servicios o deservicios disminuiría con la distancia desde la pradera. Usamos jaulas de exclusión de aves sobre los cultivos para examinar el efecto neto de las aves en el rendimiento de granos de maíz y soja. También utilizamos el método de código de barras de ADN para identificar presas de artrópodos en las muestras de heces de las aves capturadas. Nuestros experimentos de exclusión revelaron que las aves brindaron servicios netos en el maíz y deservicios netos en la soja. La distancia a las praderas no fue un predictor significativo del efecto del tratamiento de exclusión en ninguno de los cultivos. Muchas muestras de heces de aves contuvieron ADN tanto de artrópodos benéficos como de plagas económicamente significativas de maíz, pero de pocas plagas económicamente significativas de soja. Melospiza melodia, una de nuestras especies más capturadas, mayormente consumió el gusano de la raíz del maíz, una plaga económicamente significativa de este cultivo. Estimamos que las aves en este sistema brindaron un servicio valuado en aproximadamente US $275 ha­1 de ganancias en rendimiento de maíz, y un deservicio valuado en aproximadamente $348 ha­1 de pérdidas en rendimiento de soja. Nuestro estudio es el primero en demostrar que las aves pueden brindar servicios substanciales y económicamente valiosos en los campos de maíz y deservicios en los cultivos de soja. Los hallazgos contrastantes en los dos sistemas de cultivo sugieren un rango de impactos de las aves dentro de los agro-ecosistemas ampliamente distribuidos y demuestra la importancia de cuantificar los efectos tróficos netos.

Patch use in the arctic ground squirrel: effects of micro-topography and shrub encroachment in the Arctic Circle.

We investigated the roles of vegetation structure, micro-topographic relief, and predator activity patterns (time of day) on the perception of predatory risk of arctic ground squirrels (Urocitellus parryii), an abundant pan-Arctic omnivore, in Arctic Circle tundra on the North Slope of Alaska, where tundra vegetation structure has been predicted to change in response to climate. We quantified foraging intensity by measuring the giving-up densities (GUDs) of the arctic ground squirrels in experimental foraging patches along a heath-graminoid-shrub moist tundra gradient. We hypothesized that foraging intensity of arctic ground squirrels would be greatest and GUDs lowest, where low-stature vegetation or raised micro-topography improves sightlines for predator detection. Furthermore, GUDs should vary with time of day and reflect 24-h cycles of varying predation risk. Foraging intensity varied temporally, being highest in the afternoon and lowest overnight. During the morning, foraging intensity was inversely correlated with the normalized difference vegetation index (NDVI), a proxy for vegetation productivity and cover. Foraging was additionally measured within landscapes of fear, confirming that vegetative and topographic obstructions of sightlines reduces foraging intensity and increases GUDs. We conclude that arctic ground squirrels may affect Arctic Circle vegetation of tundra ecosystems, but these effects will vary spatially and temporally.

Insectivorous birds consume an estimated 400-500 million tons of prey annually.

In this paper, we present an estimate of the predation impact of the global population of insectivorous birds based on 103 (for the most part) published studies of prey consumption (kg ha-1 season-1) of insectivorous birds in seven biome types. By extrapolation-taking into account the global land cover of the various biomes-an estimate of the annual prey consumption of the world's insectivorous birds was obtained. We estimate the prey biomass consumed by the world's insectivorous birds to be somewhere between 400 and 500 million metric tons year-1, but most likely at the lower end of this range (corresponding to an energy consumption of ≈ 2.7 × 1018 J year-1 or ≈ 0.15% of the global terrestrial net primary production). Birds in forests account for > 70% of the global annual prey consumption of insectivorous birds (≥ 300 million tons year-1), whereas birds in other biomes (savannas and grasslands, croplands, deserts, and Arctic tundra) are less significant contributors (≥ 100 million tons year-1). Especially during the breeding season, when adult birds feed their nestlings protein-rich prey, large numbers of herbivorous insects (i.e., primarily in the orders Coleoptera, Diptera, Hemiptera, Hymenoptera, Lepidoptera, and Orthoptera) supplemented by spiders are captured. The estimates presented in this paper emphasize the ecological and economic importance of insectivorous birds in suppressing potentially harmful insect pests on a global scale-especially in forested areas.

Having our yards and sharing them too: the collective effects of yards on native bird species in an urban landscape.

Residential yards comprise a substantial portion of urban landscapes, and the collective effects of the management of many individual yards may "scale up" to affect urban biodiversity. We conducted bird surveys and social surveys in Chicago-area (Illinois, USA) residential neighborhoods to identify the relative importance of yard design and management activities for native birds. We found that groups of neighboring yards, in the aggregate, were more important for native bird species richness than environmental characteristics at the neighborhood or landscape scale. The ratio of evergreen to deciduous trees in yards and the percentage of yards with trees and plants with fruits or berries were positively associated with native bird species richness, whereas the number of outdoor cats had a negative association. The number of birdfeeders was not an important predictor for native species richness. We also found that migratory birds were observed on transects with more wildlife-friendly features in yards, and nonnative birds were observed on transects with greater numbers of outdoor cats and dogs. Our results highlight the potential importance of residential matrix management as a conservation strategy in urban areas.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

Immunomodulatory and pro-oncologic effects of ketamine and isoflurane anesthetics in a murine model.

INTRODUCTION: Volatile and intravenous anesthetics may worsen oncologic outcomes in basic science animal models. These effects may be related to suppressed innate and adaptive immunity, decreased immunosurveillance, and disrupted cellular signaling. We hypothesized that anesthetics would promote lung tumor growth via altered immune function in a murine model and tested this using an immunological control group of immunodeficient mice. METHODS: Lewis lung carcinoma cells were injected via tail vein into C57BL/6 immunocompetent and NSG immunodeficient mice during exposure to isoflurane and ketamine versus controls without anesthesia. Mice were imaged on days 0, 3, 10, and 14 post-tumor cell injection. On day 14, mice were euthanized and organs fixed for metastasis quantification and immunohistochemistry staining. We compared growth of tumors measured from bioluminescent imaging and tumor metastasis in ex vivo bioluminescent imaging of lung and liver. RESULTS: Metastases were significantly greater for immunocompromised NSG mice than immunocompetent C57BL/6 mice over the 14-day experiment (partial η2 = 0.67, 95% CI = 0.54, 0.76). Among immunocompetent mice, metastases were greatest for mice receiving ketamine, intermediate for those receiving isoflurane, and least for control mice (partial η2 = 0.88, 95% CI = 0.82, 0.91). In immunocompetent mice, significantly decreased T lymphocyte (partial η2 = 0.83, 95% CI = 0.29, 0.93) and monocyte (partial η2 = 0.90, 95% CI = 0.52, 0.96) infiltration was observed in anesthetic-treated mice versus controls. CONCLUSIONS: The immune system appears central to the pro-metastatic effects of isoflurane and ketamine in a murine model, with decreased T lymphocytes and monocytes likely playing a role.

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI.

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups (p=0.16). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration (p < 0.001). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Scale-dependent neighborhood effects: shared doom and associational refuge.

A resource's susceptibility to predation may be influenced by its own palatability and the palatability of its neighbors. We tested for effects of plant chemical defenses on seed survival by manipulating the frequency of palatable and less palatable sunflower seeds in food patches subject to harvest by fox squirrels (Sciurus niger) and gray squirrels (Sciurus carolinensis). We varied resource distributions at three scales: among stations (aggregates of patches ca. 50 m apart), among patches immediately adjacent to each other, and within patches. When food patches were segregated into high-palatability and low-palatability stations (Experiment 1), seeds suffered greater mortality at stations with high levels of palatable seeds. In the same experiment, within patches, squirrels selected strongly for palatable seeds over less palatable seeds. When high- and low-palatability food patches were placed together at the same stations (Experiment 2), increasing densities of co-occurring palatable seeds amplified the mortality of less palatable seeds, indicating "shared doom." When palatable and less palatable seeds were partitioned into micropatches (Experiment 3), associational effects disappeared, as predicted. Furthermore, selectivity in less palatable patches increased as the initial densities of palatable seeds increased, and selectivity in palatable patches decreased as the initial densities of less palatable seeds increased. Foraging theory predicts associational effects among prey that vary in palatability. Our results show how the type and magnitude of associational effects emerge from the interplay among the spatial scale of prey heterogeneity, the diet selection strategy, and the scale-dependent foraging responses of the consumer.

Immunosuppressive niche engineering at the onset of human colorectal cancer.

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune "cold" ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: a modeling study based on longitudinal tumor measurements.

Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, [Formula: see text] Gy [Formula: see text] 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, [Formula: see text] Gy [Formula: see text] 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost ([Formula: see text] Gy [Formula: see text] 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/- boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(- boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.

Cycling hypoxia selects for constitutive HIF stabilization.

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the "Warburg Effect". We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.