bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking the tail
Authors: Friedlaender Alex , Liu Stephen V , Addeo Alfredo
Published: September 2020

Immune-checkpoint inhibitors have deeply changed the therapeutic landscape of advanced non-small cell lung cancer without actionable genomic alterations. Immune-checkpoint inhibitors have become standard front-line therapy, especially among patients with tumours expressing high levels of programmed death ligand-1; yet, many patients do not respond to therapy. This has led to the adoption of front-line combination therapies, administering programmed death-1 inhibitors concomitantly either with other checkpoint inhibitors, chemotherapy or both. Today’s approved standard of care includes options with chemoimmunotherapy or dual checkpoint blockade, but each combination has only been compared to chemotherapy alone and no head-to-head trials exist. In cross-trial comparisons, combinations trials appear to show numerically superior responses to single-agent checkpoint inhibitors but the question is whether they ultimately offer a survival advantage. In this manuscript, we summarize and analyse all currently available front-line immune-checkpoint inhibitor trials in non-small cell lung cancer, whether as monotherapy or in combination with chemotherapy, second immunotherapy agents or both. Should standards of care change given the current data? While we ponder this question, we illustrate current data and conclude that the answer lies in tracking the tail of the survival curves.
Haemodynamic analysis of adult patients with moyamoya disease: CT perfusion and DSA gradings
Authors: Shi Zhiyong , Ma Guofeng , Zhang Dong
Published: September 2020

Object

Moyamoya disease (MMD) is a common and chronic progressive stenotic-occlusive cerebrovascular disease in Eastern Asia. To evaluate the hemispheric haemodynamic status of adult patients with MMD, we explored the potential risk factors of hemispheric perfusion alterations with CT perfusion (CTP) and DSA.

Methods

We retrospectively reviewed 44 male and 44 female (176 hemispheres) adult patients with MMD who had both DSA and CTP. Data on cerebral blood perfusion (CBF), cerebral blood volume (CBV), mean transmit time (MTT), time to peak (TTP) of cerebral hemisphere and cerebellum were gathered and difference of relative haemodynamic parameters between different subgroups were assessed with independent sample t analysis, one-way analysis of variance and general linear regression analysis.

Results

Parameters in regional CBF (rCBF) of frontal, temporal lobe and basal ganglia in female was more superior than male. rCBF, regional MTT (rMTT) and regional TTP (rTTP) in adult MMD patients with haemorrhage were superior than the ischaemic. With the increase of age, significant difference could be seen in rCBF and rCBV of thalamus. However, with progress of arterial stenosis, significant difference could only be obsevrved in rCBV, rMTT and rTTP, whereas rCBF had no significant difference. For increase of moyamoya vessels, significant decrease of rCBF could be seen in temporal and parietal lobe. With the increase of compensatory artery numbers, no significant difference could be seen in rCBF parameters (p>0.05).

Conclusions

In adult MMD patients, age, gender and clinical type were potential risk factors for the change of cerebral perfusion. When arterial stenosis is worsened, moyamoya vessels could alter perfusion of temporal and parietal lobe, but not frontal lobe. Extracranial/intracranial compensatory arteries could maintain microcirculation stability in frontal lobe and basal ganglia, indicating that the protection from extracranial compensatory arteries, a theoretic base for surgery treatment if necessary.
A low-cost three-dimensional reconstruction and monitoring system using digital fringe projection
Authors: Ullah Furqan , Miran Sajjad , Ahmad Furqan , Ullah Irfan
Published: September 2020

In this paper, the design and construction of a low-cost three-dimensional (3D) reconstruction and monitoring system using digital fringe projection (DFP) is proposed, which can perform small- and large-scale measurements in different environments and can be applied to various applications such as intelligent monitoring, 3D online inspection, and obstacle detection for vehicle guidance. The contribution of this paper is threefold: (i) development of a comprehensive 3D measuring system that performs sensors handling, coordinate acquisition, reconstruction, and display process simultaneously and quickly; (ii) proposal of new filters to improve quality and efficiency of the system; and (iii) development of a real-time virtual 3D measurement system to calibrate and analyze the proposed methodologies. Optical and simulation measurement results are presented to verify the feasibility and performance of the developed systems. The observed RMS difference was found to be <0.021 mm in the optical measurement. From measured results, it can be concluded that the proposed systems and adopted methodology are effective in obtaining 3D surface profiles.
Electronic properties of α − 𝒯3 quantum dots in magnetic fields
Authors: Filusch Alexander , Fehske Holger
Published: September 2020

We address the electronic properties of quantum dots in the two-dimensional α − 𝒯3 lattice when subjected to a perpendicular magnetic field. Implementing an infinite mass boundary condition, we first solve the eigenvalue problem for an isolated quantum dot in the low-energy, long-wavelength approximation where the system is described by an effective Dirac-like Hamiltonian that interpolates between the graphene (pseudospin 1/2) and Dice (pseudospin 1) limits. Results are compared to a full numerical (finite-mass) tight-binding lattice calculation. In a second step we analyse charge transport through a contacted α − 𝒯3 quantum dot in a magnetic field by calculating the local density of states and the conductance within the kernel polynomial and Landauer-Büttiker approaches. Thereby the influence of a disordered environment is discussed as well.

Graphical abstract
Listen to Your Fingers
Authors: Chen Huijie , Li Fan , Du Wan , Yang Song , Conn Matthew , Wang Yu
Published: September 2020

Inputting a pattern or PIN code on the touch screen is a popular method to prevent unauthorized access to mobile devices. However, these sensitive tokens are highly susceptible to being inferred by various types of side-channel attacks, which can compromise the security of the private data stored in the device. This paper presents a second-factor authentication method, TouchPrint, which relies on the user's hand posture shape traits (dependent on the individual different posture type and unique hand geometry biometrics) when the user inputs PIN or pattern. It is robust against the behavioral variability of inputting a passcode and places no restrictions on input manner (e.g., number of the finger touching the screen, moving speed, or pressure). To capture the spatial characteristic of the user's hand posture shape when input the PIN or pattern, TouchPrint performs active acoustic sensing to scan the user's hand posture when his/her finger remains static at some reference positions on the screen (e.g., turning points for the pattern and the number buttons for the PIN code), and extracts the multipath effect feature from the echo signals reflected by the hand. Then, TouchPrint fuses with the spatial multipath feature-based identification results generated from the multiple reference positions to facilitate a reliable and secure MFA system. We build a prototype on smartphone and then evaluate the performance of TouchPrint comprehensively in a variety of scenarios. The experiment results demonstrate that TouchPrint can effectively defend against the replay attacks and imitate attacks. Moreover, TouchPrint can achieve an authentication accuracy of about 92% with only ten training samples.
The OnHW Dataset
Authors: Ott Felix , Wehbi Mohamad , Hamann Tim , Barth Jens , Eskofier Björn , Mutschler Christopher
Published: September 2020

This paper presents a handwriting recognition (HWR) system that deals with online character recognition in real-time. Our sensor-enhanced ballpoint pen delivers sensor data streams from triaxial acceleration, gyroscope, magnetometer and force signals at 100 Hz. As most existing datasets do not meet the requirements of online handwriting recognition and as they have been collected using specific equipment under constrained conditions, we propose a novel online handwriting dataset acquired from 119 writers consisting of 31,275 uppercase and lowercase English alphabet character recordings (52 classes) as part of the UbiComp 2020 Time Series Classification Challenge. Our novel OnHW-chars dataset allows for the evaluations of uppercase, lowercase and combined classification tasks, on both writer-dependent (WD) and writer-independent (WI) classes and we show that properly tuned machine learning pipelines as well as deep learning classifiers (such as CNNs, LSTMs, and BiLSTMs) yield accuracies up to 90 % for the WD task and 83 % for the WI task for uppercase characters. Our baseline implementations together with the rich and publicly available OnHW dataset serve as a baseline for future research in that area.
HeartQuake
Authors: Park Jaeyeon , Cho Hyeon , Balan Rajesh Krishna , Ko JeongGil
Published: September 2020

This work presents HeartQuake, a low cost, accurate, non-intrusive, geophone-based sensing system for extracting accurate electrocardiogram (ECG) patterns using heartbeat vibrations that penetrate through a bed mattress. In HeartQuake, cardiac activity-originated vibration patterns are captured on a geophone and sent to a server, where the data is filtered to remove the sensor's internal noise and passed on to a bidirectional long short term memory (Bi-LSTM) deep learning model for ECG waveform estimation. To the best of our knowledge, this is the first solution that can non-intrusively provide accurate ECG waveform characteristics instead of more basic abstract features such as the heart rate using bed-mounted geophone sensors. Our extensive experimental results with a baseline dataset collected from 21 study participants and a longitudinal dataset from 15 study participants suggest that HeartQuake, even when using a general non-personalized model, can detect all five ECG peaks (e.g., P, Q, R, S, T) with an average error of 13 msec when participants are stationary on the bed. Furthermore, clinically used ECG metrics such as the RR interval and QRS segment width can be estimated with errors 3 msec and 10 msec, respectively. When additional noise factors are present (e.g., external vibration and various sleeping habits), the estimation error increases, but can be mitigated by using a personalized model. Finally, a qualitative study with 11 physicians on the clinically perceived quality of HeartQuake-generated ECG signals suggests that HeartQuake can effectively serve as a screening tool for detecting and diagnosing abnormal cardiovascular conditions. In addition, HeartQuake's low-cost and non-intrusive nature allow it to be deployed in larger scales compared to current ECG monitoring solutions.
Finger Gesture Tracking for Interactive Applications
Authors: Liu Yilin , Jiang Fengyang , Gowda Mahanth
Published: September 2020

This paper presents FinGTrAC, a system that shows the feasibility of fine grained finger gesture tracking using low intrusive wearable sensor platform (smart-ring worn on the index finger and a smart-watch worn on the wrist). The key contribution is in scaling up gesture recognition to hundreds of gestures while using only a sparse wearable sensor set where prior works have been able to only detect tens of hand gestures. Such sparse sensors are convenient to wear but cannot track all fingers and hence provide under-constrained information. However application specific context can fill the gap in sparse sensing and improve the accuracy of gesture classification. Rich context exists in a number of applications such as user-interfaces, sports analytics, medical rehabilitation, sign language translation etc. This paper shows the feasibility of exploiting such context in an application of American Sign Language (ASL) translation. Noisy sensor data, variations in gesture performance across users and the inability to capture data from all fingers introduce non-trivial challenges. FinGTrAC exploits a number of opportunities in data preprocessing, filtering, pattern matching, context of an ASL sentence to systematically fuse the available sensory information into a Bayesian filtering framework. Culminating into the design of a Hidden Markov Model, a Viterbi decoding scheme is designed to detect finger gestures and the corresponding ASL sentences in real time. Extensive evaluation on 10 users shows a recognition accuracy of 94.2% for 100 most frequently used ASL finger gestures over different sentences. When the size of the dictionary is extended to 200 words, the accuracy is degrades gracefully to 90% thus indicating the robustness and scalability of the multi-stage optimization framework.
The bad news game
Authors: Golay Diane
Published: September 2020

Given the rising amount of fake news on the web, it is imperative to understand whether people can become immune to fake news and what steps can help achieve this goal. This interview presents insights into the definition of fake news, current research, and the future of fake news education.
Technical Perspective
Authors: Gehrke Johannes
Published: September 2020

Never make a promise - you may have to keep it. - Neil Jordan

Database systems were known to provide strong consistency guarantees. As an example, database textbook defines the ACID guarantees as "four important properties of transactions to maintain data in the face of concurrent access and system failures" [2]. Beyond atomicity, consistency, and durability, the "I" in ACID is loosely defined as "Users should be able to understand a transaction without considering the effects of other concurrently executing transactions, even if the DBMS interleaves the actions of several transactions for performance reasons" [2]. In the resulting model called serializable execution, each transaction operates like it has the database to itself, and the result of running a set of transactions is equivalent to some serial execution of these transactions.
Technical Perspective
Authors: Boehm Matthias
Published: September 2020

From a historical perspective, relational database management systems (RDBMSs) have integrated many specialized systems and data models back into the RDBMS over time. New workloads motivated specialized systems for performance, but over time, general-purpose RDBMSs absorbed this functionality to avoid boundary crossing. We already witnessed this process for object-relational functionality, XML and JSON data types, OLAP/HTAP systems, and RDF/graph processing, while for natural language processing (NLP), time series, and machine learning (ML), the outcomes remain unclear. Interestingly, graph processing, NLP, and time series are largely ML workloads too. For this reason, integrating data management and ML is of high practical relevance and has been addressed by (1) integrating ML into RDBMSs, and (2) specialized ML systems. The paper "Declarative Recursive Computation on an RDBMS" [3] by Jankov et al. makes a very valuable contribution by reconciling these two areas and showing the potential of recursive computations on an RDBMS, as the backend-not necessarily frontend-for large-scale machine learning.
Technical Perspective
Authors: Pichler Reinhard
Published: September 2020

Traditionally, by query answering we mean the problem of finding all answers to a given query over a given database. But what happens if the number of answers is prohibitively big - which may easily occur in a Big Data context? In such situations, it seems preferable to have a mechanism that produces one answer after the other with certain guarantees on the time between any two outputs and to let the user decide when to stop. This leads us to the enumeration problem, which has received a lot of interest recently [1]. However, in order for the user to get a "realistic" picture of the entirety of answers, two crucial questions arise: first, how big is the portion of output answers compared with the total number of answers? And second, do the output answers reflect the variety of the complete set of answers? The first question refers to the counting problem, where we are interested in the total number of answers. The second question leads us to the problem of uniform generation, where we request that the answers be uniformly generated and thus form an unbiased sample of the complete set of answers.
Technical Perspective
Authors: Schelter Sebastian
Published: September 2020

Machine learning (ML) is increasingly used to automate decision making in various domains. In recent years, ML has not only been applied to tasks that use structured input data, but also, tasks that operate on data with less strictly defined structure such as speech, images and videos. Prominent examples are speech recognition for personal assistants or face recognition for boarding airplanes.
Strongly Reciprocally p-Convex Functions and Some Inequalities
Authors: Li Hao , Saleem Muhammad Shoaib , Hussain Ijaz , Imran Muhammad
Published: September 2020

In this paper, we generalize the concept of strong and reciprocal convexity. Some basic properties and results will be presented for the new class of strongly reciprocally p-convex functions. Furthermore, we will discuss the Hermite–Hadamard-type, Jensen-type, and Fejér-type inequalities for the strongly reciprocally p-convex functions.
Effects of Mind‐Body Exercise in Cancer Survivors: A Systematic Review and Meta‐Analysis
Authors: Duan Lining , Xu Yifeng , Li Min
Published: September 2020

Objective. Mind‐body exercise may have potential benefits for cancer survivors according to previous studies. We performed a systematic review and meta‐analysis to summarize the published evidence and evaluate the safety and efficacy of mind‐body exercise on general quality of life (QOL) and symptom management in cancer survivors. Methods. Four English language databases were systematically searched for existing randomized controlled trials (RCTs) of mind‐body exercise in cancer survivors from database inception through October 23, 2019. Methodological quality was appraised with the Cochrane Risk of Bias tool. A meta‐analysis of comparative effects was performed using the Review Manager v.5.3 software. Results. Fifteen studies encompassing 1461 patients were included. Analysis results showed that mind‐body exercise could have a statistically significant effect on the outcomes of physical fitness, fatigue, sleep quality, depression, anxiety, and BMI, while effects on general QOL and stress were not statistically significant (all p > 0.05). No serious adverse events were reported. Conclusions. The current evidence demonstrates that mind‐body exercise is relatively safe and modestly effective for symptom management in cancer survivors. Furthermore, randomized trials with larger sample sizes and of higher methodological quality are needed to confirm these results.
GFD: A Weighted Heterogeneous Graph Embedding Based Approach for Fraud Detection in Mobile Advertising
Authors: Hu Jinlong , Li Tenghui , Zhuang Yi , Huang Song , Dong Shoubin
Published: September 2020

Online mobile advertising plays a vital role in the mobile app ecosystem. The mobile advertising frauds caused by fraudulent clicks or other actions on advertisements are considered one of the most critical issues in mobile advertising systems. To combat the evolving mobile advertising frauds, machine learning methods have been successfully applied to identify advertising frauds in tabular data, distinguishing suspicious advertising fraud operation from normal one. However, such approaches may suffer from labor-intensive feature engineering and robustness of the detection algorithms, since the online advertising big data and complex fraudulent advertising actions generated by malicious codes, botnets, and click-firms are constantly changing. In this paper, we propose a novel weighted heterogeneous graph embedding and deep learning-based fraud detection approach, namely, GFD, to identify fraudulent apps for mobile advertising. In the proposed GFD approach, (i) we construct a weighted heterogeneous graph to represent behavior patterns between users, mobile apps, and mobile ads and design a weighted metapath to vector algorithm to learn node representations (graph-based features) from the graph; (ii) we use a time window based statistical analysis method to extract intrinsic features (attribute-based features) from the tabular sample data; (iii) we propose a hybrid neural network to fuse graph-based features and attribute-based features for classifying the fraudulent apps from normal apps. The GFD approach was applied on a large real-world mobile advertising dataset, and experiment results demonstrate that the approach significantly outperforms well-known learning methods.
Primary Paratesticular Leiomyosarcoma: A Case Report and Literature Review
Authors: Naimi Zeineb , Zarraa Semia , Kammoun Salma , Yahyaoui Safia , Driss Maha , Nasr Chiraz
Published: September 2020

Paratesticular soft tissue sarcomas are very rare malignant mesenchymal tumors. With only few cases reported in the literature, data regarding diagnostic and management of these tumors are limited. We reported a case of primary paratesticular leiomyosarcoma in a 72-year-old man complaining of a progressively growing painless right scrotal mass. The patient underwent radical inguinal right orchiectomy and adjuvant 3D conformal radiotherapy to the tumor bed including the surgical scar. The prescription dose was 54 Gy, and no pelvic irradiation was performed. He remained free of recurrence for the last 16 months.
Rivaroxaban Treatment for Heparin-Induced Thrombocytopenia: A Case Report and a Review of the Current Experience
Authors: Aon Mohamed , Al-Shammari Omar
Published: September 2020

Heparin-induced thrombocytopenia is a life-threatening complication of exposure to heparin. Heparin-induced thrombocytopenia results from an autoantibody directed against platelet factor 4 in complex with heparin. Heparin-induced thrombocytopenia is traditionally treated with bivalirudin, argatroban, danaparoid, or fondaparinux. Recently, direct oral anticoagulants administration to treat heparin-induced thrombocytopenia has been reported. Direct oral anticoagulants do not cause platelet activation in the presence of heparin-platelet factor 4 antibodies, nor do they provoke autoantibody production. Direct oral anticoagulants offer advantages such as consistent and predictable anticoagulation, oral administration with good patient compliance, and a good safety profile. We report a case of heparin-induced thrombocytopenia with deep venous thrombosis successfully treated with rivaroxaban and review the current experience with rivaroxaban for the treatment of heparin-induced thrombocytopenia.
Abstract 1012: Determinants of immune evasion in MET driven lung cancer
Authors: Saigi Maria , Yoshida Ryohei , Knelson Erik H , Mahadevan Navin R , Vajdi Amir , Cañadas Israel , Thai Tran C , Awad Mark M. , Sánchez-Céspedes Montse , Barbie David A
Published: September 2020

PURPOSE: The 5' ectonucleotidase (NT5E) encodes for the CD73 membrane protein that converts the extracellular AMP into adenosine (Ado), an immunosuppressive nucleoside that generates anti-inflammatory responses by stimulating T cell anergy. We aimed to analyze CD73 expression across non-small cell lung cancer (NSCLC) and explore its role in immunomodulation and its predictive value to immunotherapy (ICI).

METHODS: We analyzed CD73 (NT5E) expression across lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) and determined top co-expressed genes or correlations with alterations in lung cancer (LC) driver genes. Correlations were validated in specific cancer cell lines using appropriate treatments to activate or inhibit selected pathways. A CRISPR-Cas9 CD73-knockout cell line model was generated to explore direct regulation of extracellular Ado production, as well as impact on secreted cytokines. Finally, we performed staining of CD73 and other immune-related molecules (CD8+ TILs, PD-L1, STING) in a pilot cohort of NSCLC patients (n=35) treated with first line ICI +/- chemotherapy at the DFCI.

RESULTS: TCGA analysis revealed strong correlation between MET and CD73 expression and identified MET altered tumors, either by MET exon 14 skipping mutations (METex14) or MET amplification, as being enriched for high CD73 expression (p=0.03). Functional assays using LC cell lines showed that MET activation increases CD73 expression at a transcriptional and protein level by using qPCR, western-blot and flow-cytometry. Additional adenosinergic-related molecules, including the adenosine receptor A2BR (ADORA2B), were co-regulated in parallel with CD73, defining a specific phenotype. In our pilot cohort of patients, CD73 high expression (2+) was found in 20% of lung tumors, mostly adenocarcinomas, whereas 50% were negative (0+) for CD73 expression. CD73 was positively associated with high CD8+ (p= 0.02). Clinical outcomes are being evaluated to elucidate the potential role of CD73 as a predictive marker to ICI.

CONCLUSIONS: MET altered tumors and LC cell lines express high levels of CD73 and other adenosinergic-related molecules, representing a potential mechanism of immune evasion and target for immunotherapy. The potential predictive role of CD73 expression in a larger cohort of patients treated with immune checkpoint inhibition (ICI) will be performed.

Citation Format: Maria Saigi, Ryohei Yoshida, Erik H Knelson, Navin R Mahadevan, Amir Vajdi, Israel Cañadas, Tran C Thai, Mark M. Awad, Montse Sánchez-Céspedes, David A Barbie. Determinants of immune evasion in MET driven lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1012.
Abstract 1029: Epigenetic control of tumor-infiltrating lymphocyte metabolic-exhaustion
Authors: Koss Brian , Shields Bradley D. , Taylor Erin M. , Storey Aaron J. , Byrum Stephanie D. , Gies Allen J. , Washam Charity L. , Choudhury Samrat Roy , Ahn Jeong Hyun , Uryu Hidetaka , Krager Kimberly J. , Chiang Tung-Chin , Mackintosh Samuel G. , Edmondson Rick D. , Aykin-Burns Nukhet , Wang Gang Greg , Tackett Alan J.
Published: September 2020

Direct competition between tumor-infiltrating lymphocytes and cancer cells for metabolic resources often renders T cells dysfunctional. It is becoming clearer that T cell metabolic changes can precede functional exhaustion. In the case of solid tumors, the driving force of this dysfunction is thought to be a result of inhibitory metabolism (e.g. glucose deprivation and mitochondrial dysfunction). The mechanisms connecting inhibitory metabolism and T cell metabolic exhaustion are largely unknown. Interestingly, T cells undergo a loss of the histone methyltransferase EZH2 (H3K27me3) during tumor infiltration. Methyltransferases, like EZH2, depend on mitochondria to supply S-Adenosyl-L-Methionine (SAM), the primary methyl donor. We sought to determine if there was a link between EZH2 and mitochondrial function. In this work, we utilized highly specific EZH2 inhibitors to model acute inhibition of EZH2 in CD8+ and CD4+ T cells. Taking an unbiased, multi-omics approach (proteomics, RNAseq, ChIPseq) we fully interrogate the downstream consequences of EZH2 inhibition in T cells. The loss of H3K27me3 does indeed lead to an induction of mitochondrial dysfunction, which in turn, drives a dependency on glycolytic metabolism and sensitivity to glucose withdrawal. The metabolic shift phenotype was confirmed using extracellular metabolic flux analysis. In T cells, we found the loss of H3K27me3 repression of the Cdkn2aArf locus to be a major contributor to mitochondrial dysfunction, independent of the canonical role to stabilize p53. Furthermore, we show Arf-/- mice are resistant to EZH2-inhibition induced mitochondrial dysfunction. Reprogramming tumor-specific T cells to exogenously express a gain-of-function EZH2 mutant (Y641F) resulted in an enhanced ability of T cells to inhibit solid tumor growth. This work demonstrates the potential for manipulation of EZH2 in cellular therapies for solid tumors with harsh metabolic conditions and sheds light on the dynamic interplay of epigenetics and metabolic sufficiency.

Citation Format: Brian Koss, Bradley D. Shields, Erin M. Taylor, Aaron J. Storey, Stephanie D. Byrum, Allen J. Gies, Charity L. Washam, Samrat Roy Choudhury, Jeong Hyun Ahn, Hidetaka Uryu, Kimberly J. Krager, Tung-Chin Chiang, Samuel G. Mackintosh, Rick D. Edmondson, Nukhet Aykin-Burns, Gang Greg Wang, Alan J. Tackett. Epigenetic control of tumor-infiltrating lymphocyte metabolic-exhaustion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1029.
Abstract 1048: Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab
Authors: Stover Elizabeth H. , Tyekucheva Svitlana , Liu Yiwen , Curtis Jennifer D. , Penson Richard T. , Liu Joyce F.
Published: September 2020

We analyzed genomic alterations in patients with relapsed ovarian cancer treated with combined nivolumab and bevacizumab in a phase II clinical trial, in order to identify potential biomarkers of response. Thirty-eight patients were treated with nivolumab and bevacizumab and the previously reported overall response rate was 28.9% (Liu et al, JAMA Oncology, 2019). Formalin-fixed paraffin-embedded patient tumor samples (acquired pre-treatment) underwent whole-exome sequencing, followed by quality control filtering and analysis of mutations, insertions/deletions, copy-number alterations, and mutational signatures using established methods. Differences in genomic event rates were assessed between response groups, as defined by presence or absence of objective response or clinical benefit. We describe the genomic alterations in all patients treated with nivolumab and bevacizumab, including several long-term responders with treatment duration >24 months. The observed alterations in the patient cohort reflected known patterns of common mutations (e.g. TP53) and copy-number alterations (e.g. MYC amplification) in ovarian cancer. Within the limits of sample size, no significant differences in frequency of specific mutations were observed between response groups, with the possible exception of mutations in SETD1B, a histone methyltransferase, which were more frequent in the subset of patients lacking clinical benefit. BRCA1/2 mutation rate was similar between groups. Tumor mutational burden was not significantly different between groups. Initial exploratory analysis for copy-number alterations did not reveal genes with differential copy-number alterations between the response groups, and further analyses of copy-number alterations and mutational signatures are in progress. In summary, we describe genomic biomarker analysis from tumors of patients with relapsed ovarian cancer receiving treatment with nivolumab and bevacizumab. Taken together, we did not identify genomic alterations that clearly distinguish responding and non-responding patients in the data evaluated to date. Analysis of targeted RNA-sequencing data is planned as a next step. Further studies are needed to identify genomic or transcriptomic biomarkers of responses to checkpoint blockade and anti-angiogenic therapy in ovarian cancer.

Citation Format: Elizabeth H. Stover, Svitlana Tyekucheva, Yiwen Liu, Jennifer D. Curtis, Richard T. Penson, Joyce F. Liu. Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1048.
Abstract 106: The inhibitory effects of baicalein on cell proliferation in breast cancer cells
Authors: Monear Nicodemus C. , Kantola Austin L. , Xhabija Besa
Published: September 2020

Baicalein is a naturally occurring substance found in certain herbaceous species such as Scutellaria baicalensis and Oroxylum indicum, as well more well-known species such as Thymus vulgaris (thyme). Classified as a flavonoid derivative, baicalein has been shown to inhibit cell proliferation by signaling apoptotic pathways in cell lines typically resistant to induced cell death. In this analysis, we have assessed cell viability by methylene blue staining and have shown that T47D breast cancer cells exhibit stunted proliferation patterns within 24 hours of exposure to baicalein at concentrations as low as 100 µM. Additionally, we have performed an analysis of the cell cycle by flow cytometry for which we have observed an arrest in the S phase, further indicating inhibited cell proliferation.

Citation Format: Nicodemus C. Monear, Austin L. Kantola, Besa Xhabija. The inhibitory effects of baicalein on cell proliferation in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 106.
Abstract 1061: Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer
Authors: Demeule Michel , Currie Jean-Christophe , Charfi Cyndia , Larocque Alain , Zgheib Alain , Kozelko Sophie , Béliveau Richard , Marsolais Christian , Annabi Borhane
Published: September 2020

Rational : The development of personalized therapies against ovarian cancer remains highly challenging even in current modern oncology. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to peptide ligands that selectively target receptors abundantly and/or exclusively expressed in these tumor cells. Increased expression of Sortilin (SORT1), a scavenging receptor also known as neurotensin receptor-3, has been observed in invasive ovarian cancer biopsies. In addition, increased SORT1 expression correlated with breast tumor grades.

Procedures : In light of these observations, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. As a proof-of-concept, doxorubicin and docetaxel were conjugated to a Sortilin-binding proprietary peptide (TH19P01).

Results : In vitro, significant intracellular delivery of the doxorubicin-TH19P01 conjugate (TH1904) and docetaxel-TH19P01 conjugate (TH1902) were observed in a ES-2 ovarian cancer cell line model while preserving efficient doxorubicin or docetaxel cytotoxic mechanism. TH19P01 and drug conjugate uptake in ovarian cancer cells assays were reduced when SORT1 expression was specifically silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Importantly, drug-TH19P01 conjugates were found to bypass the P-glycoprotein (P-gp) efflux pump in MDCK-MDR1 cells overexpressing P-gp as the uptake of conjugates was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, TH1904 and TH1902 caused a more potent inhibition of human ovarian tumor xenografts grown in mice and were better tolerated than their unconjugated parent drugs.

Conclusion : These results strongly support future clinical development of this targeted technology platform to generate novel personalized therapeutics with specific indications in Sortilin-positive cancers.

Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Sophie Kozelko, Richard Béliveau, Christian Marsolais, Borhane Annabi. Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1061.
Abstract 107: Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients
Authors: Cendon-Florez Ylenia , Pippa Raffaella , Boffo Silvia , Odero Maria D. , Giordano Antonio
Published: September 2020

Breast and prostate cancer are aggressive hormone-dependent diseases that affect thousands of people every year. Despite advances in early detection and the understanding of the molecular bases of both cancers' biology, resistance to therapy frequently occurs. Thus, the identification of novel therapeutic targets and pathways that contribute to breast and prostate cancer lethality is necessary for improving clinical outcomes. Here, we analyzed the gene expression of known inhibitors of the protein phosphatase 2A (PP2A) in both cancer patient samples. Our analysis disclosed a general over-expression of all PP2A negative regulators. Additionally, SET, CIP2A, ANP32E and TIPRL genes are frequently co-expressed, and their expression positively correlates with the ones of the main cyclins and CDKs, suggesting the existence of a feed-forward loop that might contribute to the cancer progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (SET, CIP2A, ANP32E and TIPRL) and cell cycle regulators (Cyclin A, Cyclin E, Cyclin B and CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve breast and prostate cancer patient survival. Keywords: Breast cancer, Prostate Cancer, PP2A, cell cycle

Citation Format: Ylenia Cendon-Florez, Raffaella Pippa, Silvia Boffo, Maria D. Odero, Antonio Giordano. Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 107.
Abstract 1078: The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex
Authors: Xu Ting-Hai , Liu Minmin , Zhou Edward , Liang Gangning , Xu Eric H. , Melcher Karsten , Jones Peter A.
Published: September 2020

CpG methylation by de novo DNA methyltransferases (DNMT) 3A and 3B is essential for mammalian development and differentiation, and is frequently dysregulated in cancer. DNMT3s preferentially bind nucleosomes yet can not methylate the DNA wrapped around the nucleosome core, and favor the methylation of linker DNA at positioned nucleosomes. Here we present the cryo-EM structure of a ternary complex of catalytically active DNMT3A2, the catalytically inactive accessory subunit DNMT3B3, and a nucleosome core particle flanked with linker DNA. We find that the catalytic-like domain (CLD) of the accessory DNMT3B3 binds the acidic patch of the nucleosome core, which orients the binding of the catalyticaly active DNMT3A2 to linker DNA. The sterical constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur.

Citation Format: Ting-Hai Xu, Minmin Liu, Edward Zhou, Gangning Liang, Eric H. Xu, Karsten Melcher, Peter A. Jones. The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1078.
Abstract 1092: A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors
Authors: Barbash Zohar , Haham Dikla , Hafzadi Liat , Zipor Ron , Barth Shaul , Aizenman Arie , Zimmerman Lior , Tarcic Gabi
Published: September 2020

The MAPK-ERK signaling cascade is among the most frequently mutated pathways in human cancer, with the BRAF V600 mutation being the most common alteration. FDA-approved BRAF inhibitors as well as combination therapies of BRAF and MEK inhibitors are available and provide survival benefits to patients with a BRAF V600 mutation in several indications. Yet non-V600 BRAF mutations are found in many cancers and are even more prevalent than V600 mutations in certain tumor types. As the use of NGS profiling in precision oncology is becoming more common, novel alterations in BRAF are being uncovered. This has led to the classification of BRAF mutations, which is dependent on its biochemical properties and affects it sensitivity to inhibitors. Therefore, annotation of these novel variants is crucial for assigning correct treatment. Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. Our results show that from the 151 different BRAF mutations, ~25% were found to activate the MAPK pathway. All of the class 1 and 2 mutations tested were found to be active, providing positive validation for the method. Additionally, many novel activating mutations were identified, some outside of the known domains. When testing the response of the active mutations to different classes of BRAF inhibitors, we show that while vemurafenib efficiently inhibited V600 mutations, other types of mutations and specifically BRAF fusions were not inhibited by this drug. Alternatively, the second-generation experimental inhibitors were effective against both V600 as well as non-V600 mutations. Using this large-scale approach to characterize BRAF mutations, we were able to functionally annotate the largest number of BRAF mutations to date. Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients.

Citation Format: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic. A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1092.
Abstract 1098: Mediators of early immune response in bronchial premalignant lesions
Authors: Merenstein Carter , Breda Julia , Mazzilli Sarah , Burks Eric , Stevenson Christopher , Reid Mary , Spira Avrum , Lenburg Marc , Beane Jennifer
Published: September 2020

Introduction: Bronchial premalignant lesions (PMLs), precursors to lung squamous cell carcinoma, represent a relevant system for studying early tumor development. Some PMLs will progress through increasing grades of dysplasia to become squamous cell carcinoma, while others will regress back to normal airway without intervention. Previous work has identified molecular subtypes of PMLs and identified immune alterations associated with lesion progression/persistence and regression. Here, we used gene expression profiling to identify genes that may be responsible for immune suppression or activation in PMLs.

Methods: We collected endobronchial biopsies (n=295) longitudinally from 50 high-risk smokers in approximately one-year intervals at Roswell Park Comprehensive Cancer Center. Two biopsies were collected from each lesion, one for standard pathological assessment and one for RNA sequencing. We derived eight immune-related gene expression phenotypes based on immune-oncologic gene coexpression signatures taken from literature sources. Mediation analysis was used to identify genes that may be upstream modulators or downstream effectors of the association between immune phenotypes and lesion progression/persistence. Gene-Set Enrichment Analysis (GSEA) and Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) were used to identify specific signaling and transcription pathways that these mediators were acting through.

Results: Predicted immune phenotypes related to B cell activation, interferon signaling, and antigen presentation were significantly associated with lesion progression/persistence within the Proliferative molecular subtype (FDR ≤ 0.01). Via mediation analysis, we identified 15 genes as candidate immune regulators or downstream immune effectors essential for activation/suppression of the immune response in PMLs. One of these genes, GSTP1, is up-regulated in progressing lesions and negatively correlated with several immune activation pathways, thus representing a possible mechanism for immune suppression in these lesions. Further in silico analysis suggests that GSTP1 acts as a repressor of STAT3 signaling and NF-κB pathways, and in vitro experiments are underway to determine if suppression of GSTP1 is sufficient to induce expression of these immune pathways.

Conclusion: Therapies are needed to intercept lung cancer development and these results suggest a targetable pathway to activate the immune system to stimulate PML regression.

Citation Format: Carter Merenstein, Julia Breda, Sarah Mazzilli, Eric Burks, Christopher Stevenson, Mary Reid, Avrum Spira, Marc Lenburg, Jennifer Beane. Mediators of early immune response in bronchial premalignant lesions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1098.