Abstract
Experimental tumors raised in rodents represent an important preclinical tool to develop innovative anticancer compounds before clinical testing. Amongst others such models include solid ...tumors raised in syngeneic fully immunocompetent hosts and tumors spontaneously growing in genetically engineered mice (GEM) and derivate thereof. These model platforms have gained additional value since the manipulation of the immune system to fight cancer has led to tangible benefits for cancer patients. Imaging has become important part of the basic and translational research. It enables e.g. metabolic activity, volumetric and biodistribution monitoring within same individual over time. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are widely used for clinical diagnosis and disease follow up. Choosing the most suitable imaging application depends of the prioritization of features. MRI offers unprecedented soft tissue contrast, high spatial resolution and non-invasive nature renders MRI in rodents a perfect tool for preclinical work in oncological applications. Similarly to clinical setting, MRI in rodents is used for detection of the tumors, evaluation of therapeutic response and induced changes, with longitudinal follow-up for early detection of possible tumor recurrence. PET is an excellent tool to study tumor metabolism, location as well biodistribution of novel antibodies. The purpose of this work was to study molecular as well volumetric, metabolic and functional changes in syngeneic oncological mouse model using MRI, MRS and PET imaging. Our panel consists of 32 fully characterized mouse tumor models covering 12 major cancer types. We characterized those models by molecular profiling (whole exome sequencing and RNAseq), histopathological examination (tissue micro array as well as whole slide analysis of Ki67, CD31, SMA, TIL infiltration) and sensitivity towards checkpoint inhibitors. Amongst other findings we saw an enhanced activity of anti-CTLA-4 treatment in combination with anti-PD1 in 4T1 orthotopically implanted into the mammary fat pad in comparison to single agent therapy. In a follow-up study we implanted 14 mice with breast cancer cell line 4T1 orthotopically into the mammary fat pad. When tumors were palpable treatment with the checkpoint inhibitor combination started. During the course of the experiment we determined tumor volume of the primary lesion twice weekly. In addition to molecular markers, MRI, MRS and PET were applied to study changes in tumor over cancer progression. As a conclusion, several syngeneic oncological mouse models have been characterized using molecular profiling, histological techniques and in vivo imaging. These readouts provide a powerful and translational research tool together with oncological disease animal models allowing comprehensive evaluation of disease progression and treatment interventions for in vivo studies.
Citation Format: Julia Schueler, Artem Shatillo, Jussi Rytkönen, Nina Zanella, Antti Nurmi, Tuulia Huhtala. Molecular, histopathologic, MRI and PET findings in syngeneic oncologic mouse models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3041.
Abstract
Patient-derived xenografts (PDX) passaged in immunocompromised mice are a well-established system for preclinical efficacy testing of anti-cancer agents. Typically, PDXs are pre-screened ...either in vitro or via molecular analysis, and selected models are then tested in groups of 8 to 12 mice to confirm or evaluate the efficacy of a treatment relative to a vehicle control group. This approach results in highly reliable and reproducible efficacy data. However, it is often desirable to test large panels of tumor models in vivo in order to properly take genetic diversity into account. Such experiments can be cost-prohibitive in conventional study layouts, which results in fewer models being tested.
The Single Mouse Trial (SMT) format addresses the need for compound testing in larger, more diverse tumor populations. This format employs a single mouse per PDX model and treatment arm, thereby enabling the investigation of efficacy in substantially larger panels of PDX models. In order to better mirror inter-patient response diversity observed in the clinic, less emphasis is put on the statistical robustness of response data for individual models.
In the study presented here, six SoC drugs were tested in the SMT format in colorectal (cetuximab, oxaliplatin, irinotecan, 5-FU) and non-small-cell lung cancer (cetuximab, paclitaxel) PDXs, and results were compared to those obtained from standard format experiments with 5 - 10 mice per group. Dosing and schedules were adapted to clinical standards. Data for 19 CXF and 16 NSCLC models showed that in 77% of the cases, results obtained from the single mouse trial format were in line with results from standard efficacy tests. Furthermore, in 10% of the cases, efficacy was similar by trend between the two formats. Notable discrepancies were seen mainly in tumors exhibiting intermediate sensitivity.
Our findings indicate that for the drugs tested here, the risk of misjudging the efficacy in a given PDX model based on SMT is low. This risk could be further lowered by increasing group sizes to 3 mice. For the identification of biomarkers which requires accurate efficacy data, such an intermediate format between the SMT and the standard format might be advantageous.
Citation Format: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz. Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2890. doi:10.1158/1538-7445.AM2015-2890
Despite a recent shift away from anti-insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and ...targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IR-B-overexpressing cells is fully reversed by anti-IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti-IGF-IR antibody.
This study identifies total IR as a biomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression.
Patient-derived xenografts (PDX) have emerged as an important translational research tool for understanding tumor biology and enabling drug efficacy testing. They are established by transfer of ...patient tumor into immune compromised mice with the intent of using them as Avatars; operating under the assumption that they closely resemble patient tumors. In this study, we established 27 PDX from 100 resected gastric cancers and studied their fidelity in histological and molecular subtypes. We show that the established PDX preserved histology and molecular subtypes of parental tumors. However, in depth investigation of the entire cohort revealed that not all histological and molecular subtypes are established. Also, for the established PDX models, genetic changes are selected at early passages and rare subclones can emerge in PDX. This study highlights the importance of considering the molecular and evolutionary characteristics of PDX for a proper use of such models, particularly for Avatar trials.
The vegetation cover of a sand dune was surveyed ten years after the improvement of a restoration project that utilized seed sowing, seedling planting and seedling transplantation from an adjacent ...area with watering in the first months. On the upper part of the restored dune, the vegetation was sparse (53%) but more developed than that of the adjacent control area (34%), both presenting herbaceous/subshrub physiognomy with predominance of Panicum racemosum. On the slope of the restored dune, a shrub vegetation developed, presenting a percentage cover (90%) similar to that of the control area (100%). Dodonaea viscosa was the dominant species on this restored face. The establishment of arboreal and shrub species seedlings on the upper dune was good. In part, this improved the species richness, but contributed to dissimilarity between this area and the control site. A lower species richness was presented on the slope and the similarity to the control area was even lower. Plants introduced by sowing and seedling transplantation showed success and contributed to the similarity with the adjacent vegetation. Seedlings of arboreal and shrub plants survived on the upper dune. These species are represented in a more developed stage of succession, differing from the adjacent control area.
The vegetation cover of a sand dune was surveyed ten years after the improvement of a restoration project that utilized seed sowing, seedling planting and seedling transplantation from an adjacent ...area with watering in the first months. On the upper part of the restored dune, the vegetation was sparse (53%) but more developed than that of the adjacent control area (34%), both presenting herbaceous/subshrub physiognomy with predominance of Panicum racemosum. On the slope of the restored dune, a shrub vegetation developed, presenting a percentage cover (90%) similar to that of the control area (100%). Dodonaea viscosa was the dominant species on this restored face. The establishment of arboreal and shrub species seedlings on the upper dune was good. In part, this improved the species richness, but contributed to dissimilarity between this area and the control site. A lower species richness was presented on the slope and the similarity to the control area was even lower. Plants introduced by sowing and seedling transplantation showed success and contributed to the similarity with the adjacent vegetation. Seedlings of arboreal and shrub plants survived on the upper dune. These species are represented in a more developed stage of succession, differing from the adjacent control area.
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect ...causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 59% of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
•PK deficiency manifests a broad spectrum in anemia severity that moderately improves after splenectomy.•Close attention to monitoring for iron overload, gallstones, and other complications is recommended in all patients with PK deficiency.
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Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic ...pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic.
In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed.
27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 95% CI 0·27–0·37) and 82% at 8 weeks (0·18 0·14–0·23) following the week in which significant changes in population movements were recorded.
The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.
Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
The Croatian part of the Danube River extends over 188 km and comprises 58 % of the country’s overall area used for commercial freshwater fishing. To date, the heavy metal contamination of fish in ...the Croatian part of the Danube has not been studied. The main purpose of this study was to determine heavy metal levels in muscle tissue of sampled fish species and to analyze the measured values according to feeding habits of particular groups. Lead ranged from 0.015 μg
−1
dry weight in planktivorous to 0.039 μg
−1
dry weight in herbivorous fish, cadmium from 0.013 μg
−1
dry weight in herbivorous to 0.018 μg
−1
dry weight in piscivorous fish, mercury from 0.191 μg
−1
dry weight in omnivorous to 0.441 μg
−1
dry weight in planktivorous fish and arsenic from 0.018 μg
−1
dry weight in planktivorous to 0.039 μg
−1
dry weight in omnivorous fish. Among the analyzed metals in muscle tissue of sampled fish, only mercury exceeded the maximal level (0.5 mg kg
−1
) permitted according to the national and EU regulations determining maximum levels for certain contaminants in foodstuffs, indicating a hazard for consumers of fish from the Danube River.
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