bluuebunny/crossref_metadata_2025 huggingface dataset:
What the Study of Legal Cynicism and Crime Can Tell Us About Reliability, Validity, and Versatility in Law and Social Science Research
Authors: Hagan John , McCarthy Bill , Herda Daniel
Published: June 2020

We call for a further appreciation of the versatility of concepts and methods that increase the breadth and diversity of work on law and social science. We make our point with a review of legal cynicism. Legal cynicism's value, like other important concepts, lies in its versatility as well as its capacity for replication. Several classic works introduced legal cynicism, but Sampson & Bartusch named it. Kirk & Papachristos used a cultural framework to broaden it and added essential measures of perceived unresponsiveness and incapacity of police to ensure neighborhood safety and security. A structural theory of legal cynicism explains minority residents’ skepticism of, and desperate reliance on, police in the absence of alternative sources of safety. Historical and ethnographic studies play especially important roles in broadening the versatility of legal cynicism for the study of crime and responses to it.
Retinal Image Formation and Sampling in a Three-Dimensional World
Authors: Thibos Larry N.
Published: June 2020

In this review, I develop an empirically based model of optical image formation by the human eye, followed by neural sampling by retinal ganglion cells, to demonstrate the perceptual effects of blur, aliasing, and distortion of visual space in the brain. The optical model takes account of ocular aberrations and their variation across the visual field, in addition to variations of defocus due to variation of target vergence in three-dimensional scenes. Neural sampling by retinal ganglion cells with receptive field size and spacing that increases with eccentricity is used to visualize the neural image carried by the optic nerve to the brain. Anatomical parameters are derived from psychophysical studies of sampling-limited visual resolution of sinusoidal interference fringes. Retinotopic projection of the neural image onto brainstem nuclei reveals features of the neural image in a perceptually uniform brain space where location and size of visual objects may be measured by counting neurons.
Investigating Liquid Water Transport in Different Pore Structure of Gas Diffusion Layers for PEMFC Using Lattice Boltzmann Method
Authors: Sepe M. , Satjaritanun P. , Hirano S. , Zenyuk I. V. , Tippayawong N. , Shimpalee S.
Published: June 2020

Proton exchange membrane fuel cells (PEMFC) require a gas diffusion layer (GDL) to aid in the transport of liquid fuel to the catalyst layer. In this work, direct modeling using the Lattice Boltzmann Method (LBM) was applied to X-ray CT scans of four different carbon gas diffusion layers to understand the mass transport properties through the samples. Three injection orientations were used to study local saturation levels, water evolution through the sample, and mass transport behavior at breakthrough conditions. The LBM, combined with computational fluid dynamic modeling techniques, can accurately predict liquid saturation at the macro and micro scale, which provides more insight into the mass transport phenomena through the GDL. The change of pore structure and orientation in both the in-plane and through-plane determines the path that liquid water must take, which could aid or impact PEMFC performance. The outcomes from this work will also benefit any research that needs knowledge of internal mass transport qualities of gas diffusion media.
Oligomeric collagen as an encapsulation material for islet/β-cell replacement: effect of islet source, dose, implant site, and administration format
Authors: Stephens Clarissa Hernandez , Morrison Rachel A. , McLaughlin Madeline , Orr Kara , Tersey Sarah A. , Scott-Moncrieff J. Catharine , Mirmira Raghavendra G. , Considine Robert V. , Voytik-Harbin Sherry
Published: June 2020

Replacement of islets/β-cells that provide long-lasting glucose-sensing and insulin-releasing functions has the potential to restore extended glycemic control in individuals with type 1 diabetes. Unfortunately, persistent challenges preclude such therapies from widespread clinical use, including cumbersome administration via portal vein infusion, significant loss of functional islet mass upon administration, limited functional longevity, and requirement for systemic immunosuppression. Previously, fibril-forming type I collagen (oligomer) was shown to support subcutaneous injection and in situ encapsulation of syngeneic islets within diabetic mice, with rapid (<24 h) reversal of hyperglycemia and maintenance of euglycemia for beyond 90 days. Here, we further evaluated this macroencapsulation strategy, defining effects of islet source (allogeneic and xenogeneic) and dose (500 and 800 islets), injection microenvironment (subcutaneous and intraperitoneal), and macrocapsule format (injectable and preformed implantable) on islet functional longevity and recipient immune response. We found that xenogeneic rat islets functioned similarly to or better than allogeneic mouse islets, with only modest improvements in longevity noted with dosage. Additionally, subcutaneous injection led to more consistent encapsulation outcomes along with improved islet health and longevity, compared with intraperitoneal administration, whereas no significant differences were observed between subcutaneous injectable and preformed implantable formats. Collectively, these results document the benefits of incorporating natural collagen for islet/β-cell replacement therapies.
Lowering oxidative stress in ghrelin cells stimulates ghrelin secretion
Authors: Mani Bharath K. , Osborne-Lawrence Sherri , Metzger Nathan , Zigman Jeffrey M.
Published: June 2020

Ghrelin is a predominantly stomach-derived peptide hormone with many actions including regulation of food intake, body weight, and blood glucose. Plasma ghrelin levels are robustly regulated by feeding status, with its levels increasing upon caloric restriction and decreasing after food intake. At least some of this regulation might be due to direct responsiveness of ghrelin cells to changes in circulating nutrients, including glucose. Indeed, oral and parental glucose administration to humans and mice lower plasma ghrelin. Also, dissociated mouse gastric mucosal cell preparations, which contain ghrelin cells, decrease ghrelin secretion when cultured in high ambient glucose. Here, we used primary cultures of mouse gastric mucosal cells in combination with an array of pharmacological tools to examine the potential role of changed intracellular oxidative stress in glucose-restricted ghrelin secretion. The antioxidants resveratrol, SRT1720, and curcumin all markedly increased ghrelin secretion. Furthermore, three different selective activators of Nuclear factor erythroid-derived-2-like 2 (Nrf2), a master regulator of the antioxidative cellular response to oxidative stress, increased ghrelin secretion. These antioxidant compounds blocked the inhibitory effects of glucose on ghrelin secretion. Therefore, we conclude that lowering oxidative stress within ghrelin cells stimulates ghrelin secretion and blocks the direct effects of glucose on ghrelin cells to inhibit ghrelin secretion.
Cutaneous Fusariosis in a Patient with Job’s (Hyper-IgE) Syndrome
Authors: Altibi Ahmed M. , Sheth Radhika , Battisha Ayman , Kak Vivek
Published: June 2020

Fusarium is a filamentous fungus that is ubiquitous in nature and can cause severe opportunistic infections in immunocompromised hosts. The association between Fusarium and hyper-IgE syndrome is exceedingly rare and has only been documented in a single report previously. A 44-year-old male, working as marijuana grower, with prior diagnosis of hyper-IgE syndrome and recurrent infections presented with enlarging right knee ulcer that did not respond to antimicrobial treatment. The patient was diagnosed with cutaneous fusariosis, confirmed with punch biopsy and positive wound cultures. The patient was managed with extended antifungal therapy (i.e., posaconazole) and surgical debridement resulting in remarkable improvement with wound healing leaving a pale scar. Fusarium should be considered in differential for cutaneous and invasive fungal infections in presence of cutaneous manifestations. Exposure to Cannabis plants is a noticeable risk factor. Multimodal approach involving systemic antifungals and wound debridement is essential for favorable outcome. Posaconazole was demonstrated to be a highly efficacious antifungal choice.
Predicted Anchor Region Proposal with Balanced Feature Pyramid for License Plate Detection in Traffic Scene Images
Authors: Nguyen Hoanh
Published: June 2020

License plate detection is a key problem in intelligent transportation systems. Recently, many deep learning-based networks have been proposed and achieved incredible success in general object detection, such as faster R-CNN, SSD, and R-FCN. However, directly applying these deep general object detection networks on license plate detection without modifying may not achieve good enough performance. This paper proposes a novel deep learning-based framework for license plate detection in traffic scene images based on predicted anchor region proposal and balanced feature pyramid. In the proposed framework, ResNet-34 architecture is first adopted for generating the base convolution feature maps. A balanced feature pyramid generation module is then used to generate balanced feature pyramid, of which each feature level obtains equal information from other feature levels. Furthermore, this paper designs a multiscale region proposal network with a novel predicted location anchor scheme to generate high-quality proposals. Finally, a detection network which includes a region of interest pooling layer and fully connected layers is adopted to further classify and regress the coordinates of detected license plates. Experimental results on public datasets show that the proposed approach achieves better detection performance compared with other state-of-the-art methods on license plate detection.
Assessment of Factors Affecting Fish Production and Marketing in Gambella Region, Ethiopia
Authors: Deng Gatriay Tut
Published: June 2020

Fish production has been practiced since ancient Egypt and China. It has become a fast-growing agricultural sector that provides animal protein for most people globally. While China is the leading country in the world, Egypt and Nigeria stand on the top in Africa. The overall fishery production potential of Ethiopian water bodies is estimated to be 94,500 tons per year, while the actual production is 38,370 tons. Despite more water bodies and more fish diversity in the region, fish production and marketing is very low. This review is undertaken to assess the main factors affecting fish production and the marketing chain in Gambella region. Despite the known water and fish potential of the region, fish production is very low. Major factors contributing to a reduction in fish production in the region include inefficient fishing gears, poor transportation access, poor postharvest handling, low price at the landing site, and improper market place. Drying is the predominant postharvest technique and fishing methods are of a subsistence basis. All the fishing activities take place in the natural environment, and aquaculture is not yet established. Enough modern and efficient gears need to be made available. Other modern postharvest handling techniques need to be introduced to ensure a longer shelf life of fish after harvest. Infrastructures need to be constructed to access all water bodies in the region. Because the region has such water resource potential and incredible fish species diversity, the aquaculture needs to be established and popularized. Traceability needs to be adopted in the region to prevent food-borne diseases. Based on this paper, the government and other stakeholders could develop policy considering the issue of the fishery status of the region.
Event-Triggered Controller Design for Autopilot with Input Saturation
Authors: Xia Guoqing , Xia Xiaoming , Bo Zhao , Sun Xianxin , Sun Chuang
Published: June 2020

This paper considers the problem of autopilot design for surface ship with environmental disturbances and input saturation. Extended state observer (ESO) is used to reconstruct yaw rate and estimate unknown environmental disturbances. An auxiliary dynamic system is employed to handle the input saturation. By combining with the auxiliary dynamic system and ESO, an event-triggered controller (ETC) is designed, and energy is saved by reduction in the rudder rate. Simulation results illustrate the effectiveness and feasibility of the event-triggered proposed controller.
Prevalence and Characterization ofStreptococcus pyogenesClinical Isolates from Different Hospitals and Clinics in Mansoura
Authors: Helal Zeinab M. , Rizk Dina E. , Adel El-Sokkary Mohamed M. , Hassan Ramadan
Published: June 2020

Streptococcus pyogenesare associated with many bacterial diseases in both humans and animals and are capable of causing a multitude of human diseases.S. pyogenesisolates were identified by their bacitracin sensitivity, positivespy1258detection, and positive GAS latex agglutination. Different isolates were typed serotypically and genotypically by BOX-PCR. Different virulence factors were identified inS. pyogenesisolates. In addition, antimicrobial resistance was tested to eleven different antibiotics. Furthermore, the resistance mechanisms were determined phenotypically by the disc diffusion method. Finally, the correlation between both molecular and serotypes identified and the profile of virulence factors and clinical and geographical sources was determined for all isolates. Thirty-eightS. pyogenesisolates were collected from different clinical sources. Resistance testing indicated high resistance to mostly used antibiotics except amoxicillin/clavulanic acid, amoxicillin, and ampicillin. Serotyping results indicated five different serotypes, M1, M2, M3, M4, and M6, inS. pyogenesisolates, while six isolates were identified as untypeable. In addition, positive PCR results identified most of the tested SAgs genes in whichspeJgene was mostly identified followed byspeI, speC,andssagenes being identified in 81.6%, 63.3%, 60.5%, and 60.5%, respectively. However,speHwas the least detected. In contrast,speL, speM, andsmeZgenes could not be detected in all tested isolates. Finally, BOX-PCR molecular typing was a more effective clustering method when compared to the serotyping method in allS. pyogenes.In conclusion, the isolates in this study were highly resistant to mostly used antibiotics. M1 was the most identified serotype. No significant association was found between serotypes, BOX-PCR cluster groups, and SAgs genes profiles. However, by the application of BOX-PCR, effective molecular typing was obtained.
A Rare Case of Single-Rooted Mandibular Second Molar with Single Canal
Authors: Alfadley Abdulmohsen , Alquraishi Ahmad , Almazrou Yaser , Aljarbou Fahd
Published: June 2020

The root canal anatomy of mandibular second molar teeth is known to be highly variable. Whilst the most frequently seen configuration is two mesial canals and one distal canal, other variations such as four canals, two canals, and C-shaped canal system do also exist. This case report describes the diagnosis and management of unusual root canal configuration of a mandibular second molar, with one canal in a single conical root, using the contemporary advancements in endodontics. Following clinical and radiographic examinations of the case, a diagnosis of symptomatic irreversible pulpitis with symptomatic apical periodontitis of tooth #47 was established, and root canal treatment followed by composite buildup and crown were planned. Clinicians should be aware of the different anatomic variants each tooth may exhibit. Furthermore, clinicians need to possess the proper knowledge and skills that allow them to utilize the diagnostic and therapeutic tools available at their disposal in order to optimize the quality of care provided to their patients.
Performance of Polar-Coded 3D Image Transmission over Fading Channel
Authors: Hao Jianjun , Liu Luyao , Chen Wei
Published: June 2020

Any signal transmitted over an air-to-ground channel is corrupted by fading, noise, and interference. In this paper, a Polar-coded 3D point cloud image transmission system with fading channel is modeled, and also the simulation is performed to verify its performance in terms of 3D point cloud image data transmission over Rician channel with Gaussian white noise and overlap of Gaussian white noise + periodic pulse jamming separately. The comparison of Polar-coded scheme with RS-coded scheme in the same scenario indicates that Polar-coded system gives far better performance against AWGN noise and fading than the RS-coded system does in the case of short block length. But RS-coded scheme shows better performance on antipulse jamming than that of Polar-coded scheme, while there is no interleaving between codewords.
A Methodology for the Zoning Danger Region in Small Arm Firing Range Using Aerial Photogrammetry with Drone
Authors: Baek Jang-Woon , Jang Chang-Su , Park Young-Jun
Published: June 2020

During firing exercises in the military forces, safety accidents have occurred and caused nonbattle loss of human lives. Despite huge impact of the safety accidents in firing ranges on the military forces and civilians, the preventive measures have been limited and inflexible. In this study, to decrease the accident rate in small arm firing ranges, a methodology was presented to determine danger zones in firing ranges that resulted from direct bullets or ricochets during firing exercises. On the basis of ballistic theory and the actual terrain data surveyed by a drone, the danger zone of OO Firing Range was identified by schematizing the trajectories of the direct bullets and ricochets. The Monte Carlo simulation (MCS) with the accuracy of the small arm on the terrain data showed that the danger zone of the current firing range was limited due to topographic advantages. However, when human errors were included in the MCS, the danger zones were significantly enlarged. The methodology of the present study can provide a safety check‐up model that identifies danger zones in the firing ranges used by the Army.
Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows
Authors: Roberts Patrick J. , Kumarasamy Vishnu , Witkiewicz Agnieszka K. , Knudsen Erik S.
Published: June 2020

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the antitumor effects of cytotoxic chemotherapy in tumors that are CDK4/6 dependent. However, there are multiple preclinical studies that illustrate potent cooperation between CDK4/6i and chemotherapy. Furthermore, the combination of CDK4/6i and chemotherapy is being tested in clinical trials to both enhance antitumor efficacy and limit toxicity. Exploitation of the noncanonical effects of CDK4/6i could also provide an impetus for future studies in combination with chemotherapy. Thus, while seemingly mutually exclusive mechanisms are at play, the combination of CDK4/6 inhibition and chemotherapy could exemplify rational medicine.
Abstract A02: Detection of circulating cell-free DNA in renal cancer using renal cancer-specific DNA mutations and methylation changes
Authors: Adamowicz Martyna J. , Thomson John , Warlow Sophie J. , Patra Utsa , Thain Helen , de Proce Sophie Marion , Laird Alexander , Aitman Timothy J.
Published: June 2020

Renal cell cancer (RCC) is the most deadly of urologic malignancies. It is a very invasive and chemoresistant disease that is often treated by surgical resection as it also responds poorly to radiotherapy. Importantly, more than 30% of RCCs recur or metastasize following treatment and in the cases believed to be curable by nephrectomy, distant metastasis can develop even 10 years post-surgery. There is therefore a significant focus on tissue-based biomarkers from the primary kidney tumors to help predict which patients are likely to recur, though there are no biomarkers used in routine clinical practice. Over recent years, much research has aimed at the utilization of blood-based biomarkers, mainly circulating cell-free DNA (cfDNA), as a method of noninvasive disease diagnosis and monitoring. cfDNA is detected through the identification of tumor-specific cfDNA mutations, although cfDNA methylation may be a more specific biomarker as many CpG sites can be tested in parallel. We have collected tumor tissue and pre- and post-surgery blood samples from renal cancer patients and generated exome sequencing and EPIC array data of 20 tumors with matched blood samples to detect tumor-specific DNA mutations and methylation patterns. We have identified well-known driver mutations in renal cancer in VHL in 11 tumors at 0.12-0.51 variant allele fraction (VAF); PBRM1 in 8 tumors at 0.12-0.45 VAF; BAP-1 in 2 tumors at 0.45 and 0.3 VAF; and SETD2 at 0.39 VAF; KDM5C at 0.27 VAF, and CTNNA2 at 0.2 VAF in one out of 20 patients. We aim to validate these changes using droplet digital PCR (ddPCR) in tumor and circulating tumor DNA (ctDNA) pre- and post-surgery. We next plan to combine the result of the exome sequencing with EPIC array data as well in house-developed cfDNA profiles based on publicly available tissue and individual cell type DNA methylation data. This approach will allow us to select the best mutation and methylation diagnostic and prognostic markers to aid the monitoring of early disease and relapse as well as the treatment of renal cell cancer.

Citation Format: Martyna J. Adamowicz, John Thomson, Sophie J. Warlow, Utsa Patra, Helen Thain, Sophie Marion de Proce, Alexander Laird, Timothy J. Aitman. Detection of circulating cell-free DNA in renal cancer using renal cancer-specific DNA mutations and methylation changes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A02.
Abstract A12: DNA methylation-based liquid biopsy detects primary and recurrent meningioma
Authors: Sabedot Thais S. , Malta Tathiane M. , Snyder James , Walbert Tobias , Lee Ian , Kalkanis Steven , Castro Ana Valeria , Noushmehr Houtan
Published: June 2020

Meningiomas are mostly benign CNS tumors; however, a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore, the discovery of noninvasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types; however, limited progress has been made for brain tumors with known biomarkers, possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive marker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers, we used archival serum and matching tissue specimens from primary (n=10) and recurrent (n=4) meningiomas. From isolated cfDNA from meningiomas and epileptic patients (n=5) as a control, we generated epigenetic data using Illumina Human EPIC array. cfDNA fragment size distribution revealed peaks with 150~200bp on average. We identified 482 CpGs (FDR<0.001) differentially methylated between primary meningiomas and controls, of which 294 (61%) show a DNA methylation profile similar to the epigenome of the matched tumor tissue. Overall, we observed that recurrent samples are hypermethylated (56%) compared to primary. From this pilot data, we were able to investigate the LB methylome of meningioma patients and identify potential markers to detect tumor cells in the serum of these patients, which could eventually allow clinicians to monitor impending disease progression and recurrence.

Citation Format: Thais S. Sabedot, Tathiane M. Malta, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. DNA methylation-based liquid biopsy detects primary and recurrent meningioma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A12.
Abstract A14: Detection of a biomarker for B-cell non-Hodgkin lymphomas or leukemias using circulating tumor DNA without the use of PCR or next-gen sequencing
Authors: Stewart Jessica A. , Bhagwat Ashok S.
Published: June 2020

There is a critical need for the development of cheap, safe, and accurate tools for cancer surveillance. Patients diagnosed with cancer require an accurate assessment of tumor burden through the course of their treatment, and the need for tumor surveillance is even more acute for many indolent B-cell malignancies such as follicular lymphoma and chronic lymphocytic leukemia. Over the past several years, we have developed an assay that quantifies a tumor biomarker for many different types of B-cell non-Hodgkin lymphomas or leukemias (B-NHLs). This biomarker, uracils in DNA, originates from the activity of a B-cell maturation enzyme, activation-induced deaminase (AID), which converts cytosines in DNA to uracil. AID is normally not expressed in circulating B cells or any other human tissue and hence this marker is not present in any other types of cells in the human body. We have developed an ELISA-like assay using chemicals with a fluorescence readout that can detect this biomarker in DNA with high sensitivity without PCR or NGS. We will present applications of this technology to genomic DNA from B-NHL tumors and circulating tumor DNA in blood plasma of such patients. Our data show we can detect the presence of this marker in DNA of patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.

Citation Format: Jessica A. Stewart, Ashok S. Bhagwat. Detection of a biomarker for B-cell non-Hodgkin lymphomas or leukemias using circulating tumor DNA without the use of PCR or next-gen sequencing [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A14.
Abstract A16: The potential of circulating cell-free tumor DNA as a diagnostic marker of ovarian cancer
Authors: Yamamoto Misa , Sawada Kenjiro , Shimizu Aasa , Matsumoto Yuri , Kodama Michiko , Hashimoto Kae , Kimura Tadashi
Published: June 2020

Objective: Circulating cell-free tumor DNA (ctDNA) is fragmented DNA released from cancer cells into the circulation. Technological development of digital PCR allows us to detect a small quantity of ctDNA in the circulation, suggesting its possibility for a future noninvasive biomarker. The aim of this study is to pursue its potential as a diagnostic biomarker to detect ovarian cancer using patients’ plasma.

Methods: Twenty-five plasma samples from patients were collected before treatment. The corresponding tumors were also collected, and DNA was extracted. As nonmalignant controls, 10 samples were collected from patients with benign endometrial cysts. Three primers to detect PIK3CA mutations for endometriosis-related carcinoma and three primers to detect TP53 mutations for serous carcinoma were prepared. The presence of these mutations in ctDNA existing in patients’ plasma was confirmed with digital PCR method. PCR data were validated with tumor DNAs.

Results: There were 7 cases of clear cell carcinoma,1 endometrioid carcinoma, and 7 serous carcinoma. Among 8 patients with endometriosis-related cancers (clear cell and endometrioid), PIK3CA mutations in plasma were detected in 6 cases, while mutations were not detected in benign endometrial cysts. Among 7 patients with high-grade serous carcinoma, TP53 mutations in patients’ plasma were detected in all cases. The presence of these mutations was confirmed by tumor DNAs.

Conclusion: PIK3CA mutation in endometriosis-related cancer and p53 mutation in serous carcinoma were successfully detected in patients’ plasma, suggesting the potential of ctDNAs as a future noninvasive biomarker for ovarian cancer.

Citation Format: Misa Yamamoto, Kenjiro Sawada, Aasa Shimizu, Yuri Matsumoto, Michiko Kodama, Kae Hashimoto, Tadashi Kimura. The potential of circulating cell-free tumor DNA as a diagnostic marker of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A16.
Abstract A32: Clinical significance of liquid biopsy in glioblastoma patients through tissue analysis
Authors: Rana Rashmi , Acharya Rajesh , Chhabra Satnam Singh , Jain Sunila
Published: June 2020

Glioblastoma multiforme is the most fatal form of brain tumor, distinguished as an aggressive growth and assists annexing by cell relocation and mortification of extracellular matrix with average survival rate of approximately 6-14 months. The majority of patients suffer recurrence due to molecular heterogeneity of glioblastoma and deregulation of many signaling pathways involved in proliferation, survival, and apoptosis. However, genetic profiling of the tumor is shown to classify disease and therapy response. Although brain surgery is involved for tissue collection, repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease. While the detection of circulating tumor DNA (ctDNA) in the blood of patients with primary brain tumors remains challenging, sequencing of ctDNA from the tissue may provide an alternative way to glioblastoma genotype with morbidity and lower cost. We therefore evaluated the depiction of the glioblastoma genome in tissue from 40 patients with glioblastoma. Here we demonstrated that tumor-derived DNA was detected in tissue from 40 patients and was associated with disease load and adverse effect. The genomic landscape of glioblastoma in the tissue included a broad spectrum of genetic alterations and directly resembled the genomes of tumor biopsies. Alterations that were found during tumorigenesis and mutations in the metabolic pathway gene isocitrate dehydrogenase (IDH1, IDH2) were shared in all matched ctDNA-positive tissue-tumor pairs, whereas growth factor receptor signaling pathways showed significant progress. The ability to monitor the evolution of the glioblastoma genome through an invasive technique could advance the clinical application and use of genotype-directed therapies for glioblastoma, one of the most aggressive human cancers.

Citation Format: Rashmi Rana, Rajesh Acharya, Satnam Singh Chhabra, Sunila Jain. Clinical significance of liquid biopsy in glioblastoma patients through tissue analysis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A32.
Abstract B04: Using PSA dynamics to forecast individual responses to intermittent androgen deprivation
Authors: Brady Renee , Enderling Heiko
Published: June 2020

Intermittent androgen-deprivation therapy (IADT) is an attractive treatment approach for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off has been shown to limit toxicities and reduce cumulative dose. While IADT has been shown to delay the development of treatment resistance, underlying mechanisms and actionable biomarkers are required to accurately predict when resistance will emerge and how to maximally delay time to progression. We developed a quantitative framework to simulate the enrichment of prostate cancer stem cell dynamics during treatment as a plausible mechanism of resistance evolution. Using simulated dynamics of cancer stem cells and nonstem cancer cells, we derive longitudinal blood serum prostate-specific antigen (PSA) concentrations that were calibrated to and validated with data of 70 patients undergoing multiple cycles of IADT. Model analysis suggests that cancer stem cell proliferation patterns correlate with PSA dynamics and patient outcomes. Learning these dynamics adaptively from the earlier treatment cycles in individual patients can predict the evolution of resistance in subsequent IADT cycles with a predictive power of 90%, which warrants prospective evaluation in a clinical setting. The model is used to simulate and predict alternative treatment options. In particular, simulations show that response dynamics from the first IADT cycle can be used to identify patients who would benefit from concurrent docetaxel.

Citation Format: Renee Brady, Heiko Enderling. Using PSA dynamics to forecast individual responses to intermittent androgen deprivation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B04.
Abstract B06: Proteomic biomarker for detection of ovarian cancer using gynecologic liquid biopsy
Authors: Barnabas Georgina D. , Bahar-Shany Keren , Sapoznik Stav , Korach Jacob , Perri Tamar , Friedman Eitan , Stockheim David , Jakobson-Setton Ariella , Eitan Ram , Helpman Limor , Kadan Yfat , Aviel-Ronen Sarit , Harel Michal , Geiger Tamar , Levanon Keren
Published: June 2020

The vast majority of high-grade ovarian cancer (HGOC) patients are diagnosed at a metastatic stage, resulting in exceptionally low cure rates. Current screening options fail to improve mortality due to the absence of early-stage-specific biomarkers and the poor systemic representation of early-stage tumors. We postulated that a gynecologic liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Furthermore, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile may potentially enable earlier detection, as it reveals perturbations in both the tumor compartment as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we isolated microvesicles and performed mass spectrometric proteomic analysis of the UtL samples. Liquid biopsies from HGOC patients (n=85), controls (n=183), and healthy BRCA mutation carriers (n=37), were divided into discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8,578 UtL proteins in total, and on average ~3,000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 63% sensitivity and 73% specificity. The signature correctly identified all Stage I lesions and highlighted increased risk in healthy BRCA carriers. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis but require integration with other biomarker types for improved prediction.

Citation Format: Georgina D. Barnabas, Keren Bahar-Shany, Stav Sapoznik, Jacob Korach, Tamar Perri, Eitan Friedman, David Stockheim, Ariella Jakobson-Setton, Ram Eitan, Limor Helpman, Yfat Kadan, Sarit Aviel-Ronen, Michal Harel, Tamar Geiger, Keren Levanon. Proteomic biomarker for detection of ovarian cancer using gynecologic liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B06.
Abstract B08: Tumor-educated platelets for early prostate cancer diagnosis, and therapy stratification in patients with metastasized castration resistant prostate cancer
Authors: Tjon-Kon-Fat Lee-Ann , Köhn Linda , Best Myron , Lundholm Marie , Wurdinger Thomas , Widmark Anders , Thellenberg-Karlsson Camilla , Wikström Pernilla , Nilsson Jonas
Published: June 2020

One in every ten men diagnosed with prostate cancer will have metastases at some point, causing the high mortality of prostate cancer. Only earlier diagnosis has the chance to save those lives. However, correct therapy stratification may prolong the life of the patients without severely reducing the quality of life, thereby possibly turning a deadly disease into a chronic disease. For this to happen, we need predictive biomarkers that can be employed to longitudinally follow the disease in order to identify vulnerabilities and to monitor acquired resistance for personalized medicine. Using the platelet-enriched fraction of a blood sample, we here show that we can use the ability of platelets to sequester material during circulation to provide information derived from the tumor. This information could be used for early detection of prostate cancer. By using the platelet test in combination with PSA measurements, we may be able to rule out a majority of the false negatives associated with the PSA test. Furthermore, the platelet platform can be used in synergy with other biomarker sources such as circulating tumor DNA or protein biomarkers, providing the possibility to predict and monitor outcome of abiraterone therapy, and providing alternatives to the nonfunctional therapy by guiding therapy switching, in metastatic castration-resistant patients.

Citation Format: Lee-Ann Tjon-Kon-Fat, Linda Köhn, Myron Best, Marie Lundholm, Thomas Wurdinger, Anders Widmark, Camilla Thellenberg-Karlsson, Pernilla Wikström, Jonas Nilsson. Tumor-educated platelets for early prostate cancer diagnosis, and therapy stratification in patients with metastasized castration resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B08.
Abstract B11: Whole-exome sequencing analysis of urine transrenal tumor DNA in metastatic colorectal cancer patients
Authors: Crisafulli Giovanni , Mussolin Benedetta , Cassingena Andrea , Montone Monica , Bartolini Alice , Barault Ludovic , Martinetti Antonio , Morano Federica , Pietrantonio Filippo , Sartore-Bianchi Andrea , Siena Salvatore , Di Nicolatonio Federica , Marsoni Silvia , Bardelli Alberto , Siravegna Giulia
Published: June 2020

Background: The analysis of circulating free tumor DNA (ctDNA) in blood, commonly referred to as liquid biopsy, is being used to characterize patients with solid cancers. Tumor-specific genetic variants can also be present in DNA isolated from other body fluids such as urine. Unlike blood, urine sampling is noninvasive, can be self-performed, and allows recurrent longitudinal monitoring. The features of tumor DNA that clears from the glomerular filtration barrier (transrenal tumor DNA, hereafter trtDNA) are largely unexplored.

Patients and Methods: Specimens were collected from 24 patients with KRAS or BRAF mutant metastatic colorectal cancer (mCRC). Driver mutations were assessed by droplet digital PCR (ddPCR) in ctDNA from plasma and trtDNA from urine. Whole-exome sequencing (WES) was performed in DNA isolated from tissue, plasma, and urine.

Results: Out of the 24 CRC cases, only four had sufficient DNA to allow WES analyses in urine and plasma. We found that tumor alterations reside primarily in low-molecular-weight fragments. In patients where trtDNA was more than 2.69% of the urine-derived DNA, cancer-specific molecular alterations, mutational signatures, and copy number profiles identified in urine DNA are comparable with those detected in plasma ctDNA.

Conclusions: With current technologies, WES analysis of trtDNA is feasible in a small fraction of mCRC patients. Tumor-related genetic information is mainly present in shorter DNA fragments. Although the limited amounts of trtDNA pose analytical challenges, enrichment of low-molecular-weight DNA and optimized computational tools improve detection of tumor-specific genetic information in urine.

Citation Format: Giovanni Crisafulli, Benedetta Mussolin, Andrea Cassingena, Monica Montone, Alice Bartolini, Ludovic Barault, Antonio Martinetti, Federica Morano, Filippo Pietrantonio, Andrea Sartore-Bianchi, Salvatore Siena, Federica Di Nicolatonio, Silvia Marsoni, Alberto Bardelli, Giulia Siravegna. Whole-exome sequencing analysis of urine transrenal tumor DNA in metastatic colorectal cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B11.
Abstract B16: Noninvasive liquid biopsies for guideline-compliant diagnostic assessment in ovarian cancers
Authors: Akolkar Dadasaheb B. , Patil Darshana , Patil Revati , Devhare Pradip , Fulmali Pradip , Fulmali Pooja , Patel Shoeb , Srivastava Navin , Datta Vineet , Sime Cynthe , Srinivasan Ajay , Datar Rajan
Published: June 2020

Diagnosis of ovarian adenocarcinomas is based on histopathologic analysis of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural expenses, sequelae, and risk of complications. Though immunocytochemistry (ICC) profiling of circulating tumor cells (CTCs, defined as EpCAM+, panCK+, CD45-) has been previously considered for diagnosis in some cancers, the attempts have been unsuccessful. We used a novel approach for enrichment of sufficient viable CTCs that permit meaningful ICC profiling for diagnosis of ovarian cancers in suspected cases. We obtained 15 mL of venous blood draw from 248 patients with confirmed diagnosis of ovarian cancer. PMBCs were isolated by centrifugation. CTCs were enriched from PBMC using an epigenetically acting enrichment process that is lethal towards normal (nonmalignant) cells but confers survival privilege on apoptosis-resistant CTCs. Harvested CTCs were confirmed by immunostaining for EpCAM and pan-CK. Deep ICC profiling of these CTCs was performed with organ-specific markers CA125 and WT1 as well as P63 as a nonspecific marker. Viable CTCs could be obtained from 225 samples (90.7%) out of 248. Among the 100 samples characterized by deep ICC profiling, 70 samples (70%) were positive for CA125 and WT1. None of the samples was positive for P63. Our results show that ICC-based characterization of CTCs can provide necessary diagnostic information noninvasively to substitute conventional procedures dependent on tissue extraction.

Citation Format: Dadasaheb B. Akolkar, Darshana Patil, Revati Patil, Pradip Devhare, Pradip Fulmali, Pooja Fulmali, Shoeb Patel, Navin Srivastava, Vineet Datta, Cynthe Sime, Ajay Srinivasan, Rajan Datar. Noninvasive liquid biopsies for guideline-compliant diagnostic assessment in ovarian cancers [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B16.
Abstract B17: An mRNA signature that accurately discerns gliomas from healthy individuals
Authors: Apurwa Sachin , Fulmali Pooja , Akolkar Dadasaheb , Patil Darshana , Pawar Sushant , Puranik Sneha , Todarwal Vipul , Ainwale Akshay , Devhare Pradip , Datta Vineet , Sims Cynthe , Srinivasan Ajay , Datar Rajan
Published: June 2020

Diagnosis of suspected cases of gliomas such as intracranial space-occupying lesions (ICSOLs) is based on histopathologic analysis of tumor tissue obtained by invasive biopsies, which are, however, associated with risk of serious complication, high rates of mortality, procedural expenses, sequelae, and other risks. Liquid biopsy (LB)-based noninvasive approaches for diagnosis of gliomas based on circulating tumor biomarkers in peripheral blood have hence gained considerable interest. We describe the discovery of a unique 20 exosomal mRNA signature that can discern gliomas from healthy individuals. We obtained 15 mL of peripheral blood by venous draw from 222 individuals, among whom 47 had confirmed diagnosis of gliomas and 175 were asymptomatic. Exosomes were enriched from peripheral blood and were used for isolation of mRNAs. Exosomal mRNAs were used for expression analysis of 20,802 gene transcripts, including 18,574 coding genes and 2,228 noncoding genes based on University of California Santa Cruz (UCSC) hg19 annotation. Differentially expressed mRNAs were analyzed using a machine learning algorithm to identify transcripts that were unique to or uniquely absent in known cases of gliomas and in healthy individuals. The machine learning algorithm identified a 20-mRNA signature that discerned gliomas from healthy individuals with high sensitivity (87%) and specificity (95%) with an overall accuracy of 94%. The differentially expressed transcripts included MST4, RARRES3, TARP, IL32, PPP3CC, RSL1D1, RSL24D1, EIF4B, ARHGEF3, DENND2D, EVL, SEC11A, RPL22L1, HIST1H1C, IRF8, SOS2, GLTSCR2, GIMAP7, HIST1H4D, and CDK11. These differentially expressed transcripts are potentially involved in various functions such as tumor suppression, protein phosphorylation-dephosphorylation, signal transduction (ligand binding), and cell cycle regulation. Our data indicate that exosomal mRNA profiling is a viable approach for discerning suspected cases of gliomas from healthy individuals. The noninvasive nature of this approach coupled with high sensitivity and specificity favor potential clinical application.

Citation Format: Sachin Apurwa, Pooja Fulmali, Dadasaheb Akolkar, Darshana Patil, Sushant Pawar, Sneha Puranik, Vipul Todarwal, Akshay Ainwale, Pradip Devhare, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar. An mRNA signature that accurately discerns gliomas from healthy individuals [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B17.