bluuebunny/crossref_metadata_2025 huggingface dataset:
Transsphenoidal Optic Canal Decompression for Traumatic Optic Neuropathy Assisted by a Computed Tomography Image Postprocessing Technique
Authors: Li J. , Ran Q. S. , Hao B. , Xu X. , Yuan H. F.
Published: August 2020

The endoscopic transethmoidal approach is favored for the lack of external scars, a wide field of view, and rapid recovery time. But the effect of iatrogenic trauma should not be ignored due to the removal of the uncinate process and anterior and posterior ethmoidal sinus. Anatomically, the optic nerve is close to the sphenoid sinus and Onodi cell. In order to preserve the uncinate process and ethmoidal sinus, we perform endoscopic transsphenoidal optic canal decompression (ETOCD), which is less invasive. However, the anatomy of sphenoid sinus is quite variable, and the anatomical landmarks are rare. Therefore, identifying the position of optic canal is particularly important during surgery. To solve this, we use a postprocessing technique to identify the position of the optic nerve and internal carotid artery on the sphenoid sinus wall. Our results find that VA in 13 patients improved, with a total improve rate of 59.1%. No serious complications were found. We also found that the length of optic canal is different and the medial wall of the optic canal was the longest (p<0.05). The middle section of the optic canal is the narrowest, which was significantly different from cranial mouth and orbital mouth (p<0.05). We assumed that decompression may not require removal of all medial wall. If we remove the length of the shortest wall on the medial wall of the optic canal, the compression may be relieved. Thus, ETOCD was a feasible, safe, effective, and less-invasive approach for patients with TON. The CT postprocessing imaging facilitated recognition of the optic canal during surgery. The decompression length of the medial wall may not need to be completely removed, especially near the cranial mouth.
Immune‐Related lncRNA Risk Signatures Predict Survival of IDH Wild‐Type and MGMT Promoter Unmethylated Glioblastoma
Authors: Li Xiaozhi , Meng Yutong
Published: August 2020

Introduction. Glioblastoma is the most malignant grade of glioma, and it is also the most common primary tumor in the brain. Immunotherapy is a kind of precise tumor treatment. However, there are limited studies about immune‐related lncRNA. This study is aimed at analyzing immune‐related lncRNAs in glioblastoma and screening out prognostic factors, providing new potential targets for glioblastoma immunology research. Material and Methods. Gene expression data and clinical data of IDH wild‐type with MGMT promoter unmethylated glioblastoma were acquired from the TCGA and CGGA databases. Immune‐related lncRNAs were identified with the help of data from the InnateDB database. Immune prognostic factors were recognized by Cox regression analysis. GSEA analysis pursued their potential functions. Results. We found 318 immune‐related lncRNAs. Among them, there were 137 immune‐related lncRNAs that were upregulated and 181 that were downregulated. 15 prognostic lncRNAs were identified by Cox regression, and a total of 6 molecules were included in the following risk scoring model. GSEA showed that these lncRNAs participated in functions such as protein digestion and absorption and the PPAR signaling pathway. Conclusion. There are limited studies about immune regulation mechanisms of lncRNA in IDH wild‐type with MGMT promoter unmethylated glioblastoma. The identified immune‐related lncRNAs in glioblastoma might contribute new targets and research directions for immunological molecular studies of glioblastoma.
Finite-Time Stabilization for p-Norm Stochastic Nonlinear Systems with Output Constraints
Authors: Guan Shijun , Fang Liandi
Published: August 2020

This paper investigates the finite-time stability problem of p-norm stochastic nonlinear systems subject to output constraint. To cope with the constraint on system output, a tan-type barrier Lyapunov function (BLF) is constructed. By using the constructed BLF and the backstepping technique, a new control algorithm is proposed with a continuous state-feedback controller being designed, which guarantees not only that the requirement of output constraint is always achieved but also that the origin of the system is finite-time stable. This result is demonstrated by both the rigorous analysis and the simulation example.
Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer
Authors: Senchukova Marina A. , Makarova Elena V. , Shurygina Elena I. , Volchenko Nadezhda N.
Published: August 2020

The determination of factors associated with progression of cervical cancer is important, both for a recurrence risk assessment and for determining optimal treatment tactics. Previously, we showed the prognostic value of different types of tumor microvessels (MVs) in gastric and breast cancer. The object of this research was to study the morphology and clinical significance of different tumor microvessels in early cervical cancer. A total of 65 archived paraffin blocks of patients with I-IIA stages of squamous cervical cancer were investigated. Samples were stained with Mayer hematoxylin and immunohistochemically using antibodies to CD34, podoplanin, HIF-1a, and Snail. The eight types of tumor MVs differed in morphology were identified. It was established that only the dilated capillaries (DСs) with weak expression of CD34, the contact type DCs, the capillaries in tumor solid component, and the lymphatic vessels in the lymphoid and polymorphic cell infiltrates of tumor stroma are associated with clinical and pathological characteristics of early cervical cancer. Preliminary results also suggest that a combination of fragmentation in tumor solid component and the contact type DCs may predict a recurrence of early cervical cancer. Given the small number of cervical cancer recurrences, the predictive significance of the described markers requires a more thorough examination.
Nuclear Data Uncertainty Quantification and Propagation for Safety Analysis of Lead-Cooled Fast Reactors
Authors: Trivedi Ishita , Hou Jason , Grasso Giacomo , Ivanov Kostadin , Franceschini Fausto
Published: August 2020

In this study, the Best Estimate Plus Uncertainty (BEPU) approach is developed for the systematic quantification and propagation of uncertainties in the modelling and simulation of lead-cooled fast reactors (LFRs) and applied to the demonstration LFR (DLFR) initially investigated by Westinghouse. The impact of nuclear data uncertainties based on ENDF/B-VII.0 covariances is quantified on lattice level using the generalized perturbation theory implemented with the Monte Carlo code Serpent and the deterministic code PERSENT of the Argonne Reactor Computational (ARC) suite. The quantities of interest are the main eigenvalue and selected reactivity coefficients such as Doppler, radial expansion, and fuel/clad/coolant density coefficients. These uncertainties are then propagated through safety analysis, carried out using the MiniSAS code, following the stochastic sampling approach in DAKOTA. An unprotected transient overpower (UTOP) scenario is considered to assess the effect of input uncertainties on safety parameters such as peak fuel and clad temperatures. It is found that in steady state, the multiplication factor shows the most sensitivity to perturbations in 235U fission, 235U ν, and 238U capture cross sections. The uncertainties of 239Pu and 238U capture cross sections become more significant as the fuel is irradiated. The covariance of various reactivity feedback coefficients is constructed by tracing back to common uncertainty contributors (i.e., nuclide-reaction pairs), including 238U inelastic, 238U capture, and 239Pu capture cross sections. It is also observed that nuclear data uncertainty propagates to uncertainty on peak clad and fuel temperatures of 28.5 K and 70.0 K, respectively. Such uncertainties do not impose per se threat to the integrity of the fuel rod; however, they sum to other sources of uncertainties in verifying the compliance of the assumed safety margins, suggesting the developed BEPU method necessary to provide one of the required insights on the impact of uncertainties on core safety characteristics.
Xiaotan Jieyu Prescription Alleviates Breast Precancerous Lesions through PI3K/Akt Signaling Pathway
Authors: Zhao Jing , Pang Tao , Jiao Jian-peng , Wang Bin , Liu Xuan , Xiu Li-juan , Sun Da-zhi , Yue Xiao-qiang , Yu Chao-qin
Published: August 2020

Background/Aims. In previous studies, it has been observed that Xiaotan Jieyu (XTJY) prescription may inhibit the proliferation of human breast precancerous lesion MCF‐10AT cells by inhibiting the PI3K/Akt signaling pathway. The purpose of this study is to further verify the therapeutic effect and the possible mechanism of XTJY on precancerous lesions of breast cancer in vivo. Methods. The successfully established breast precancerous lesion rat model and normal healthy rats were randomly assigned into the blank (BLA), model (MOD), XTJY‐low (LD), XTJY‐medium (MD), XTJY‐high (HD), and tamoxifen (TAM) groups. Different concentrations of XTJY and saline were supplied by intragastric administration for 4 consecutive weeks to assess the protective effect of XTJY on the progress of the breast precancerous lesion in rats involving the phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (Akt) signaling pathway. Results. In this study, it determined that 10 mg/each rat DMBA‐combined estrogen and progesterone induction for 10 weeks was the optimal condition for the establishment of the breast precancerous lesion rat model. In vivo administration of XTJY or TAM was found to inhibit the development of the breast precancerous lesion, and the occurrence rate of breast invasive carcinomas was decreased by about 50%. Furthermore, XTJY or TAM markedly reduced protein expressions of PI3K and p‐Akt and increased protein expressions of PTEN. Conclusion. These data indicated that XTJY can significantly alleviate the development of breast precancerous lesions by inhibiting the activation of the PI3K/Akt signaling pathway. XTJY may be a promising drug for the treatment of precancerous lesions in breast cancer.
Mortality among Cancer Patients within 90 Days of Therapy in a Tertiary Hospital, Tanzania: Is Our Pretherapy Screening Effective?
Authors: Changalucha Marygoreth J. , Mushi Martha F. , Kabangila Rodrick , Silago Vitus , Likonda Beda , Mshana Stephen E.
Published: August 2020

Background. A high mortality has been reported during the first ninety days of cancer therapy and is more pronounced in patients with febrile neutropenia. The Bugando Medical Center oncology department offers cancer diagnosis and treatment services to the population of the Lake Zone of Tanzania with limited data on the outcome within 90 days of therapy. Here, we report the 90-day mortality and factors associated with it among cancer patients attending the oncology department of the tertiary hospital in Tanzania. Methodology. Enrolled participants underwent baseline physical examinations, and their functional status was assessed using Karnofsky score. On each clinic visit, full blood picture was taken and patients were investigated for infections. Data were entered in the Microsoft Excel, cleaned and coded and then transferred to STATA version 13 for analysis. Results. A total of 102 participants were included in the final analysis. Their median age was 50 years (38-60). The majority of the study participants were females 76 (75%), and 82 (80.4%) had primary school education. The majority of the patients had solid cancer 96 (94.1%). A total of 12 (11.8%) patients died within 90 days of starting therapy. Low hemoglobin level at the start of cancer therapy, Karnofsky score below 80%, and using 5-fluorouracil-containing therapy were statistically significantly found to be associated with mortality within 90 days of therapy among cancer patients. Conclusion. One tenth of cancer patients at Bugando Medical Center do not survive within 90 days of therapy; the mortality is significantly high among anemic patients, with poor performance status, on 5-fluorouracil regimen, and diagnosed with head and neck cancer, necessitating close follow-up of these patients.
Rosuvastatin Improves Cognitive Function of Chronic Hypertensive Rats by Attenuating White Matter Lesions and Beta‐Amyloid Deposits
Authors: Zheng Lu , Cai Ying , Qiu Baoshan , Lan Linfang , Lin Jing , Fan Yuhua
Published: August 2020

Hypertensive white matter lesion (WML) is one of common causes of vascular cognitive impairment. In this study, we aimed to investigate the effect of rosuvastatin on cognitive impairment and its underlying mechanisms in chronic hypertensive rats. From the 8th week after establishment of stroke‐prone renovascular hypertensive rats (RHRSPs), rosuvastatin (10 mg/kg) or saline as a control was administrated once daily for consecutive 12 weeks by gastric gavage. Cognitive function was assessed with the Morris water maze test and novel object recognition test. WML was observed by Luxol fast blue staining. Aβ deposits, Claudin‐5, Occludin, and ZO‐1 were determined by immunofluorescence. After rosuvastatin treatment, the escape latencies were decreased and the time of crossing the hidden platform was increased in the Morris water maze, compared with the vehicle‐treated RHRSP group. In a novel object recognition test, the recognition index in the rosuvastatin‐treated RHRSP group was significantly larger than that in the vehicle‐treated RHRSP group. Rosuvastatin treatment presented with the effects of lower WML grades, higher expression of tight junction proteins Claudin‐5, Occludin, and ZO‐1 in the corpus callosum, and less Aβ deposits in the cortex and hippocampus. The data suggested that rosuvastatin improved the cognitive function of chronic hypertensive rats partly by attenuating WML and reducing Aβ burden.
Generalized SOR-Like Iteration Method for Linear Complementarity Problem
Authors: Li Cui-Xia , Wu Shi-Liang
Published: August 2020

In this paper, we present a generalized SOR-like iteration method to solve the non-Hermitian positive definite linear complementarity problem (LCP), which is obtained by reformulating equivalently the implicit fixed-point equation of the LCP as a two-by-two block nonlinear equation. The convergence properties of the generalized SOR-like iteration method are discussed under certain conditions. Numerical experiments show that the generalized SOR-like method is efficient, compared with the SOR-like method and the modulus-based SOR method.
Enhanced Expression of ABCB1 and Nrf2 in CD133-Positive Cancer Stem Cells Associates with Doxorubicin Resistance
Authors: Goto Shinji , Kawabata Tsuyoshi , Li Tao-Sheng
Published: August 2020

The precise mechanism about drug resistance of cancer stem cells (CSCs) has not yet been completely understood. Based on the expression of CD44 and CD133, two well-recognized cell surface markers for CSC identification, we tried to separate HCT8 colorectal cancer cells into different subpopulations and then investigated how the expression of CD44 and CD133 associated with doxorubicin (DXR) resistance. Interestingly, DXR resistance was observed in CD44+CD133+ (P<0.01vs. all other subpopulations), but not in CD44+CD133- cells. CD44+CD133+ cells also showed an enhanced expression of ABCB1 and drug efflux ability (P<0.001vs. all other subpopulations), but verapamil, an inhibitor of ABCB1, only partially mitigated the DXR resistance. Independent on the accumulation of DXR, lower level of reactive oxygen species and higher expression of Nrf2 were detected in CD44+CD133+ than CD44+CD133- cells (P<0.05). Unexpectedly, silencing CD133 by siRNA only partially enhanced the cytotoxicity of DXR, but did not obviously change the expression of ABCB1 and the accumulation of DXR in CD44+CD133+ cells. Complex mechanisms, including drug excretion and redox regulation, are likely involved in the DXR resistance of CD133-positive cells, suggesting the difficulty of drug resistance problem in cancer chemotherapy.
Optimal Pricing Strategy of Electric Vehicle Charging Station for Promoting Green Behavior Based on Time and Space Dimensions
Authors: Xu Xiaomin , Niu Dongxiao , Li Yan , Sun Lijie
Published: August 2020

Considering that the charging behaviors of users of electric vehicles (EVs) (including charging time and charging location) are random and uncertain and that the disorderly charging of EVs brings new challenges to the power grid, this paper proposes an optimal electricity pricing strategy for EVs based on region division and time division. Firstly, by comparing the number of EVs and charging stations in different districts of a city, the demand ratio of charging stations per unit is calculated. Secondly, according to the demand price function and the principle of profit maximization, the charging price between different districts of a city is optimized to guide users to charge in districts with more abundant charging stations. Then, based on the results of the zonal pricing strategy, the time-of-use (TOU) pricing strategy in different districts is discussed. In the TOU pricing model, consumer satisfaction, the profit of power grid enterprises, and the load variance of the power grid are considered comprehensively. Taking the optimization of the comprehensive index as the objective function, the TOU pricing optimization model of EVs is constructed. Finally, the nondominated sorting genetic algorithm (NSGA-II) is introduced to solve the above optimization problems. The specific data of EVs in a municipality directly under the Central Government are taken as examples for this analysis. The empirical results demonstrate that the peak-to-valley ratio of a certain day in the city is reduced from 56.8% to 43% by using the optimal pricing strategy, which further smooth the load curve and alleviates the impact of load fluctuation. To a certain extent, the problem caused by the uneven distribution of electric vehicles and charging stations has been optimized. An orderly and reasonable electricity pricing strategy can guide users to adjust charging habits, to ensure grid security, and to ensure the economic benefits of all parties.
Upregulation of FOXO3 in New-Onset Type 1 Diabetes Mellitus
Authors: Zurawek Magdalena , Fichna Marta , Fichna Piotr , Czainska Maria , Rozwadowska Natalia
Published: August 2020

Forkhead box O (FOXO) transcription factors have been implicated in the development and differentiation of the immune cells. FOXO3 plays a crucial role in physiologic and pathologic immune response. FOXO3, cooperatively with FOXO1, control the development and function of Foxp3+ regulatory T cells (Treg). Since the lack of Treg-mediated control has fundamental impact on type 1 diabetes mellitus (T1DM) development, we investigated FOXO3 expression in patients with T1DM. FOXO3 expression was estimated in peripheral blood mononuclear cells (PBMCs) from newly diagnosed T1DM pediatric patients (n=28) and age-matched healthy donors (n=27) by reahavel-time PCR and TaqMan gene expression assays. Expression analysis revealed significant upregulation of FOXO3 in T1DM (P=0.0005). Stratification of the T1DM group according to the presence of initial diabetic ketoacidosis (DKA) did not indicate differences in FOXO3 expression in patients with DKA compared to a mild T1DM onset (P>0.05). In conclusion, overexpression of FOXO3 is correlated with the ongoing islet autoimmune destruction and might suggest a potential role for this gene in the pathogenesis of type 1 diabetes mellitus.
Investment Payback Period Calculating Model for Airport Bridge Facility
Authors: Wan Jian , Xia Zheng-hong , Zhu Xin-ping
Published: August 2020

Due to the uncertainty and difficulty of estimating the investment payback period of the airport bridge facility, a model for calculating the investment payback period of bridge facility is proposed in this paper from the perspective of airport routine operation. Based on the actual operational data of Kunming Changshui Airport, Wuhan Tianhe Airport, and Lijiang Sanyi Airport in 2018, the factors influencing the payback period of bridge facility are the number of bridge facilities and service time, which have been discussed in this paper. According to the simulation, it is concluded that the number of bridge facilities and service time are the key points to the length of the investment payback period, and the annual operating cost of the airline can be saved quite a lot. The research results can be used to assist the leaders’ decision-making of airports and airlines for the promotion of the service of bridge facilities.
Abstract A14: Exploiting DNA damage repair defects to enhance PD-L1 expression in Ewing sarcoma
Authors: Maurer Lisa M. , Venier Rose M. , Julian Claire , Bailey Kelly M.
Published: August 2020

Objective: The purpose of this work is to determine whether PD-L1 expression can be upregulated by PARP inhibitor treatment in Ewing tumor cells harboring DNA damage repair defects. Further, we aimed to determine whether enhanced PD-L1 expression renders Ewing cells more susceptible to T-cell mediated apoptosis following PD-1 inhibition.

Experimental Procedures: Patient-derived tumor organoids and monolayers (named PSaRC-318) were established from a viably cryofrozen metastatic lung lesion from a patient with Ewing sarcoma and a paternally inherited germline BARD1 mutation. A673, CHLA9, and CHLA10 Ewing tumor cell lines were also employed. Sensitivity of PSaRC-318 to the PARP inhibitors olaparib and talazoparib was established by performing IncuCyte apoptosis assays. PD-L1 expression was examined using RT-PCR, Western blot, and flow cytometry. BARD1, BRCA, and RAD51D siRNA were also utilized to test the role of specific DNA damage repair proteins on this effect. T-cell/tumor cell cocultures and tumor-primed T-cells were established. T cell-induced tumor cell apoptosis was monitored in real-time using IncuCyte caspase and annexin assays.

Results: PSaRC-318 organoids demonstrate exquisite sensitivity to PARP inhibitors, with an IC50 for talazoparib of 3.54nM. Treatment of PARP inhibitor-resistant Ewing cell lines, such as CHLA10, with BARD1 siRNA rendered cells sensitive to PARP inhibition. Ewing tumor cells were found to upregulate tumor cell surface expression of the checkpoint protein PD-L1 in response to treatment with PARP inhibitors. The impact of BARD1, BRCA1, and RAD51D on PD-L1 expression in Ewing tumor cells was also determined. Next, Ewing tumor cells were pretreated with PARP inhibitors and then cocultured with tumor-primed T-cells. T cell-mediated tumor cell apoptosis was monitored in real time using caspase IncuCyte assays. PD-1 blocking antibody added to T-cell/tumor cell cocultures resulted in an increase in early tumor cell death compared to IgG controls.

Conclusion: Single-agent PARP inhibitors have not demonstrated significant clinical benefit in relapsed Ewing sarcoma to date, suggesting that combinatorial therapy with PARP inhibitors may be a more effective approach. Here, we have shown that Ewing tumor cells with germline mutations in DNA-damage repair proteins, such as BARD1, can upregulate PD-L1 expression following treatment with PARP inhibitors. Thus, PARP inhibitor/anti-PD-1 therapy may be a logical combination for the treatment of relapsed Ewing sarcoma. Ongoing preclinical studies are continuing to examine this combination.

Citation Format: Lisa M. Maurer, Rose M. Venier, Claire Julian, Kelly M. Bailey. Exploiting DNA damage repair defects to enhance PD-L1 expression in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A14.
Abstract A31: Podxl as therapeutic target for metastasis
Authors: Dhez Anne-Chloe , Paassen Irene , Sorensen Poul
Published: August 2020

Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. Recently, we found that high podocalyxin (gene name PODXL, protein name Podxl) expression is associated with high metastatic profile in OS cell lines. Consistent with this data, we found a significant association between high Podxl expression and poor outcome in pediatric OS patients. Podxl is a cell surface transmembrane glycoprotein belonging to the CD34 family. The functional role of Podxl in tumorigenesis is largely unknown, but it has been demonstrated to promote cancer cell invasion and migration and to enhance metastatic potential. Podxl is upregulated on a variety of human tumors, facilitates disease progression, and is a promising target for immunotherapy as an approach to blocking metastatic disease. Accordingly, in collaboration for the Centre for Drug Research and Development, Kelly McNagny and his collaborators have developed a novel panel of monoclonal antibodies to human Podxl and have explored their utility in suppressing tumor cell growth in vitro and in vivo. To define the relevance of Podxl in the biology of metastasis, we examined Podxl expression in different OS cell lines with different metastatic profiles. Then, we studied the importance of Podxl in migration and invasion processes and in in vitro 3D cell system formation. To assess Podxl’s role in metastatic progression we performed the Pulmonary Metastasis Assay (PuMA). PuMA is an ex vivo lung explant and closed cell culture system that permits to study the biology of lung colonization by fluorescence microscopy. With PuMA model, we assessed the effects of antimetastatic therapeutics over time. In the present study, we found that suppression of Podxl profoundly impairs cell proliferation, migration, invasion properties, and tumorsphere formation in OS cells in vitro. With PuMA model, we found that Podxl is required for the progression of metastasis disease. These data tend to validate podocalyxin as a regulator of tumor progression and a novel therapeutic target in OS. It is necessary to perform in vivo experiments to further explore the functions of Podxl and the effect of the podocalyxin-specific monoclonal antibody (coupled or not to a toxic payload) to suppress the metastasis progression in our model.

Citation Format: Anne-Chloe Dhez, Irene Paassen, Poul Sorensen. Podxl as therapeutic target for metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A31.
Abstract A36: Targeting anaplastic lymphoma kinase in neuroblastoma
Authors: Guan Jikui , Cervantes-Madrid Diana , Siaw Joachim , Alam Wasi , Umapathy Ganesh , Borenäs Marcus , Lind Dan , Szydzik Joanna , Pfeifer Kathrin , Mendoza-Garcia Patricia , Palmer Ruth , Hallberg Bengt
Published: August 2020

Over the last decade Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase (RTK), has been identified as a fusion partner in a diverse variety of translocation events resulting in oncogenic signaling in many different cancer types. In tumors where full-length ALK RTK itself is mutated, such as neuroblastoma, the picture regarding the role of ALK as an oncogenic driver is less clear. Neuroblastoma is a complex and heterogeneous tumor that arises from the neural crest-derived peripheral nervous system. Although high-risk neuroblastoma is rare, it often relapses and becomes refractory to treatment. Thus, neuroblastoma accounts for 10-15% of all childhood cancer deaths. Since most cases are in children under the age of two, understanding the role and regulation of ALK during neural crest development is an important goal in addressing neuroblastoma tumorigenesis. An impressive array of tyrosine kinase inhibitors (TKIs) that act to inhibit ALK have been FDA approved for using in ALK-driven cancers. ALK TKIs bind differently within the ATP-binding pocket of the ALK kinase domain and have been associated with different resistance mutations within ALK itself that arise in response to therapeutic use, particularly in ALK fusion-positive NSCLC. This patient population has highlighted the importance of considering the relevant ALK TKI to be used for a given ALK mutant variant. In this poster we discuss ALK in neuroblastoma, as well as the use of ALK TKIs and other strategies to inhibit tumor growth. Current efforts combining novel approaches and increasing our understanding of the oncogenic role of ALK in neuroblastoma are aimed at improving efficacy of ALK TKIs as precision medicine options in the clinic.

Citation Format: Jikui Guan, Diana Cervantes-Madrid, Joachim Siaw, Wasi Alam, Ganesh Umapathy, Marcus Borenäs, Dan Lind, Joanna Szydzik, Kathrin Pfeifer, Patricia Mendoza-Garcia, Ruth Palmer, Bengt Hallberg. Targeting anaplastic lymphoma kinase in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A36.
Abstract A40: Integration of high-throughput drug screening on patient-derived organdies into pediatric precision medicine programs: The future is now!
Authors: Langenberg Karin , Dolman Emmy , Molenaar Jan
Published: August 2020

Background/Objectives: The most promising option to improve outcomes for pediatric cancer patients with relapsed or refractory disease is through mutation-based targeted therapeutic strategies. However, only 50% of these tumors harbor actionable events. Therefore, compound screening on organoids grown from tumor tissue might reveal additional treatment options.

Design/Methods: The Dutch Childhood Oncology Group-individualized Therapies (DCOG-iTHER) clinical trial in collaboration with INFORM consists of whole-exome sequencing (WES), low-coverage whole-genome sequencing (WGS), RNA profiling using RNAseq and Affymetrix microarrays, and a methylation array. Data are analyzed using the Dutch R2 bioinformatic platform. In addition, tumor-derived organoids are cultured profiled through the same pipeline. Semi-high-throughput screening of a 170-compound library is performed, and effect on cell viability using the CellTiter-Glo® 3D cell viability assay is assessed.

Results: To date, 133 patients with relapsed/refractory pediatric malignancies have been enrolled and analysis has been completed in 80 study subjects. In 47 patients, a total of 128 molecular targets were identified and 29 patients harbored an actionable event with priority score ≥ moderate (46%). In 14% a matched targeted therapy was initiated, and one-third of these patients achieved complete remission. In addition, tumor organoids have been cultured of neuroblastoma tumors and molecular profiling was performed to confirm they reflect the patient’s tumor biology. High-throughput drug screen confirmed existing molecular targets such as ALK and c-kit and in addition revealed increased compound sensitivity to drugs not previously found through sequencing.

Conclusions: Our proof of concept of patient-specific drug testing on tumor organoids within our pediatric precision medicine program might reveal additional treatment options for children who currently have none. Clinical benefit will be evaluated in our upcoming clinical trial iTHER 2.0.

Citation Format: Karin Langenberg, Emmy Dolman, Jan Molenaar. Integration of high-throughput drug screening on patient-derived organdies into pediatric precision medicine programs: The future is now! [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A40.
Abstract A44: Comparative gene expression analysis for identification and prioritization of therapeutic targets in a cohort of childhood cancers
Authors: Sanders Lauren M. , Lyle A. Geoffrey , Beale Holly C. , Kephart Ellen Towle , Learned Katrina , Peralez Jennifer , Lacayo Norman , Rangaswami Arun , Spunt Sheri L. , Bjork Isabel , Haussler David , Salama Sofie R. , Vaske Olena M.
Published: August 2020

Here we describe the utility of comparative RNA sequencing (RNA-seq) analysis in identifying cancer driver pathways and relevant therapeutics in childhood cancer, and we introduce a novel system for prioritizing gene targets based on analytical and published evidence. The purpose of our study was to evaluate the clinical utility of comparative N-of-1 gene expression analysis in identifying therapeutic options for pediatric patients with relapsed or recurrent cancers. The comparative analysis framework and large cancer background cohorts were developed at the Treehouse Childhood Cancer Initiative at UC Santa Cruz. We employed this analysis in a pilot study of 26 patients at the Lucile Packard Children’s Hospital. We analyzed RNA-seq data from 30 biopsied samples from 26 patient donors, including 16 sarcomas, 5 CNS tumors, 3 hematopoietic cancers, 1 liver, and 1 colon cancer. We compared gene expression from each child’s tumor biopsy to a background cohort of RNA-seq data from over 11,000 cancer patients, and also to a smaller cohort defined by molecular and histopathologic similarity to the child’s tumor biopsy. This comparison yielded outlier gene activations in the child’s biopsy compared to those in the background cohorts, reflecting cancer driver pathways in the child’s tumor that are actionable. We stratified each of the resulting therapeutic leads into 5 baskets: RTK activation, JAK/STAT signaling, PI3K/AKT/mTOR signaling, Cell Cycle activation, or Other. Because 27 of the 30 samples had more than one lead, we developed a novel scoring system to prioritize each sample’s therapeutic gene targets based on the analytical strength of the gene expression analysis result, and on published literature evidence for each gene as a biomarker indicative of drug response. We presented the results of our analysis in genomic consensus meetings at Stanford and surveyed the responses of clinicians and families on the utility of our analysis for treatment decisions. Here we report our experience with the method and highlight case studies in which this analysis informed treatment decisions.

Citation Format: Lauren M. Sanders, A. Geoffrey Lyle, Holly C. Beale, Ellen Towle Kephart, Katrina Learned, Jennifer Peralez, Norman Lacayo, Arun Rangaswami, Sheri L. Spunt, Isabel Bjork, David Haussler, Sofie R. Salama, Olena M. Vaske. Comparative gene expression analysis for identification and prioritization of therapeutic targets in a cohort of childhood cancers [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A44.
Abstract A48: YB-1-based oncolytic virotherapy in combination with CDK4/6-inhibitors against Ewing sarcoma
Authors: Schober Sebastian J. , Thiel Uwe , Thiede Melanie , Ehrenfeld Maximilian , Nawroth Roman , Richter Guenther HS , Burdach Stefan E.G. , Holm Per Sonne
Published: August 2020

Oncolytic virotherapy is associated with immunogenic cell death and antitumor inflammatory immune responses. Thereby, a local as well as systemic immunosuppressive microenvironment might be abrogated, resulting in efficient phagocytic and antigen-presenting properties. Consecutively, priming of naive T cells against a multitude of de-repressed tumor and viral antigens is claimed to elicit strong antitumor immune responses accompanied by tumor-infiltrating T cells, especially in combination with immune checkpoint blockade. These features might be beneficial for patients with relapsed and metastatic Ewing sarcoma, who have poor prognosis and lack innovative therapy concepts, and whose tumor biopsies are characterized by low or absent T-cell infiltration. Here, we explore the efficacy of the oncolytic YB-1-selective adenovirus XVir-N-31 in combination with the CDK4/6-inhibitor abemaciclib (LY2835219) in established Ewing sarcoma cell lines. We demonstrate enhanced viral replication, particle formation, and oncolysis when combined with abemaciclib in vitro. Priming of tumor cells with abemaciclib before viral infection leads to cell cycle arrest in G1 phase, with consecutive decrease in Rb, pRb, and E2F1 protein levels. Interestingly, in the Rb-mutated hence CDK4/6-inhibitor-resistant cell line SK-N-MC, the combination with abemaciclib does not result in enhanced viral replication oor oncolysis. However, the same effects as for CDK4/6-inhibitor sensitive cell lines can be induced by siRNA-mediated E2F1 knockdown, indicating the crucial role of E2F1 as a repressor for initiation of viral replication. In summary, our results further support the hypothesis of E2F1 being a repressor of adenoviral replication (Holm et al., manuscript in preparation) and suggest the use of CDK4/6-inhibitors to boost oncolytic adenoviral efficacy. Further in vivo confirmation is planned in order to prepare a clinical phase I study of XVir-N-31 in combination with a CDK4/6-inhibitor and immune checkpoint blockade for treatment-refractory pediatric sarcoma patients.

Citation Format: Sebastian J. Schober, Uwe Thiel, Melanie Thiede, Maximilian Ehrenfeld, Roman Nawroth, Guenther HS Richter, Stefan E.G. Burdach, Per Sonne Holm. YB-1-based oncolytic virotherapy in combination with CDK4/6-inhibitors against Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A48.
Abstract A56: Effect of chemotherapy on gut microbiota and microbiota-derived metabolites in children with cancer
Authors: Benmoussa Abderrahim , Bélanger Véronique , Levy Emile , Laverdière Caroline , Stintzi Alain , Sinnett Daniel , Marcil Valérie
Published: August 2020

Chemotherapy used to treat pediatric cancers often causes significant side effects including vomiting, diarrhea, and severe infections. Bacteria composing the intestinal microbiota play a major role in the health of individuals. The modification of the gut microbiota profile (by nutrition, antibiotics, or other chemical agents) can lead to beneficial or adverse effects on health status. It has been suggested that the gut microbiota may modulate response to treatment, including side effects from chemotherapy. However, studies in the field are lacking to prove this concept. We aim to examine whether the modifications of gut microbiota profiles are associated with negative sides effects of pediatric cancer treatment and lead to higher peripheral inflammation and oxidative stress. To explore this new line of research, we are studying the longitudinal changes in gut microbiota, bacterial-derived metabolites, and state of inflammation and oxidative stress during cancer treatment. A total of 38 children with acute lymphoblastic leukemia and non-Hodgkin lymphoma will be recruited at Sainte-Justine UHC in Montreal. We are collecting clinical data, blood, and fecal samples at different time points during treatment. Nutritional data are gathered with 24-hour recalls assessing diet prior to sample collection. Our methodology includes multiplexed massively parallel sequencing, ELISA, high-performance liquid chromatography, gas chromatography-mass spectrometry, and enzymatic techniques. Our findings will serve as a foundation for mechanistic studies and the development of biomarkers for therapeutic use, and contribute to a better understanding of individual responses to childhood cancer therapy.

Citation Format: Abderrahim Benmoussa, Véronique Bélanger, Emile Levy, Caroline Laverdière, Alain Stintzi, Daniel Sinnett, Valérie Marcil. Effect of chemotherapy on gut microbiota and microbiota-derived metabolites in children with cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A56.
Abstract A60: Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma
Authors: Forconi Catherine S. , Oduor Cliff , Ong’echa John M. , Bailey Jeff , Moormann Ann M.
Published: August 2020

Endemic Burkitt lymphoma (eBL), the most common pediatric cancer in equatorial Africa, has long been associated with two etiologic agents: Epstein-Barr virus (EBV) and Plasmodium falciparum malaria. On the other hand, Natural Killer (NK) cells are essential in the clearance of infected cells as well as play a critical role in tumor immunosurveillance. Despite chronic viral infections as HIV, HCV, which have been found to promote the expansion of a CD56 (negative) NK cell subset with impaired effector function, previous cancer studies have been limited to investigations of CD56dimCD16pos NK cells. We previously published that eBL children had significantly more CD56negCD16pos NK cells compared to age-matched healthy children from a low and high malaria transmission area. Here, we characterized this CD56negCD16pos NK subset using histology staining, multicolor flow cytometry, and RNA-sequencing. We found CD56negCD16pos NK cells to be morphologically similar to CD56dimCD16pos NK cells but had higher expression of FCGR3B (CD16b) (p=0.000008) and MPEG1 (Perforin 2) (p=0.0000007), and lower expression of KLRF1 (NKp80), IL18RAP and IL18R1 (IL18 receptor) (p=0.000003, p=0.000003 and p=0.00005, respectively). Phenotypically, CD56negCD16pos NK cells share characteristics of adaptive NK cells; however, they differ from “memory-like” NK cells, with consistent expression of NKG2C/CD57, lower expression of NKp46 and CD160, and higher expression of KIR3DL1 compared to CD56dimCD16pos NK cells. Finally, higher plasma levels of IL-12p70 and IL-2 (known to help NK cell activation and proliferation) and IL-6 and MIP1a were found in healthy compared to eBL children. Together, these findings suggest that the expansion of CD56negCD16pos NK cells could help explain diminished tumor immunosurveillance and might be a mechanism by which EBV-infected cells evades NK-cell mediated immunity.

Citation Format: Catherine S. Forconi, Cliff Oduor, John M. Ong’echa, Jeff Bailey, Ann M. Moormann. Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A60.
Abstract A64: Functional genomics of metastatic Ewing sarcoma
Authors: Jawhar Wajih , Waterhouse Paul , Khokha Rama , Ishii Takeaki , Turcotte Robert , Jabado Nada , Garzia Livia
Published: August 2020

Ewing sarcoma (ES) is a poorly differentiated bone and soft tissue tumor of high metastatic potential. ES mainly affects children, adolescents, and young adults (AYAs) at a frequency of ~1.5 cases per million globally. Ewing neoplasms strikingly converge on a single recurrent initiating event, which is a chromosomal translocation that generates a fusion transcript between the EWSR1 gene and a gene of the ETS family of transcription factors, most commonly FLi1 (85%). After 20 years since the discovery of the EWS-FLi1 fusion, ES remains a clinical challenge with unacceptably low survival rates, primarily due to metastasis. The bulk of research conducted to date (>95%) being focused on the primary tumor has resulted in a critical knowledge gap. To address this issue and unravel the dysregulated pathways in ES tumor evolution and metastatic dissemination, we harnessed the genome-wide insertional mechanism of transposons and the transduction efficiency of lentiviruses to engineer ES cell models. Human mesenchymal stem cells (hMSC), the putative cells of origin of ES, were engineered to constitutively express EWS-Fli1 accompanied by the inducible expression of a highly active transposase. Upon activation of the former, transposon-mediated mutagenesis will activate oncogenes and inactivate tumor suppressor genes, to mediate transformation of the transduced that can now engraft when implanted in recipient mice. Xenografted tumors are resected and the mice observed for development of distant metastases. Matching primary and metastatic tumors are sequenced to uncover the genes commonly affected by transposition in the two compartments. Pathway-oriented bioinformatic analysis will further reveal candidate metastatic driver genes. Matching of the targeted pathways with drugs will be used to validate the candidates by in vitro and in vivo metastasis assays.

Citation Format: Wajih Jawhar, Paul Waterhouse, Rama Khokha, Takeaki Ishii, Robert Turcotte, Nada Jabado, Livia Garzia. Functional genomics of metastatic Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A64.
Abstract A65: Alveolar soft part sarcoma in children and adolescents: A single-institute retrospective analysis
Authors: Kang Se Na , Choi Jung Yoon , Kim Bo Kyung , Ahn Hong Yul , Hong Kyung Taek , Kang Hyoung Jin , Kim Han Soo , Cheon Jung Eun , Park Sung Hye , Shin Hee Young
Published: August 2020

Background: Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor that typically affects young patients. Because of the rarity of the disease, the standard treatment is not established. The aim of this study is to evaluate the clinical characteristics and treatment outcomes of pediatric ASPS.

Method: A retrospective study was conducted on children and adolescents treated for ASPS at a single center between 2000 and 2018.

Results: A total number of 11 patients were evaluated. Median age at diagnosis was 12.6 (range 3.8-16.3) years. Nine (82%) were female. The most common primary sites were limbs (64%). IRS postsurgical clinical group (IRS CG) was I in 2 (18%), III in 3 (27%), and IV in 6 (55%) patients. Of 9 patients with IRS CG III and IV who received chemotherapy, one had a complete response, two had a partial response, and six had progressive disease. One patient showed SD to sunitinib. The 5-year event-free survival (EFS) and overall survival (OS) rates were 31% and 88%, respectively. The 5-year EFS rate by primary site was 50% for the 7 patients with extremity and 0% for the 4 patients with head and neck (P-value = 0.001). The 5-year OS rate by the primary site was 100% for the 7 patients with extremity and 50% for the 4 patients with head and neck (P-value = 0.027).

Conclusion: Localized ASPS has a good prognosis after total resection. If the primary site is head and neck, the prognosis is poor due to difficulty in surgical resection. Chemotherapy and radiation therapy have limitations in the cure for patients with metastatic disease. Further studies of ASPS need to achieve development in treatment.

Citation Format: Se Na Kang, Jung Yoon Choi, Bo Kyung Kim, Hong Yul Ahn, Kyung Taek Hong, Hyoung Jin Kang, Han Soo Kim, Jung Eun Cheon, Sung Hye Park, Hee Young Shin. Alveolar soft part sarcoma in children and adolescents: A single-institute retrospective analysis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A65.