bluuebunny/crossref_metadata_2025 huggingface dataset:
GAN-based Style Transformation to Improve Gesture-recognition Accuracy
Authors: Suzuki Noeru , Watanabe Yuki , Nakazawa Atsushi
Published: December 2020

Gesture recognition and human-activity recognition from multi-channel sensory data are important tasks in wearable and ubiquitous computing. In these tasks, increasing both the number of recognizable activity classes and the recognition accuracy is essential. However, this is usually an ill-posed problem because individual differences in the same gesture class may affect the discrimination of different gesture classes. One promising solution is to use personal classifiers, but this requires personal gesture samples for re-training the classifiers.

We propose a method of solving this issue that obtains personal gesture classifiers using few user gesture samples, thus, achieving accurate gesture recognition for an increased number of gesture classes without requiring extensive user calibration. The novelty of our method is introducing a generative adversarial network (GAN)-based style transformer to 'generate' a user's gesture data. The method synthesizes the gesture examples of the target class of a target user by transforming of a) gesture data into another class of the same user (intra-user transformation) or b) gesture data of the same class of another user (inter-user transformation). The synthesized data are then used to train the personal gesture classifier.

We conducted comprehensive experiments using 1) different classifiers including SVM and CNN, 2) intra- and inter-user transformations, 3) various data-missing patterns, and 4) two different types of sensory data. Results showed that the proposed method had an increased performance. Specially, the CNN-based classifiers increased in average accuracy from 0.747 to 0.822 in the CheekInput dataset and from 0.856 to 0.899 in the USC-HAD dataset. Moreover, the experimental results with various data-missing conditions revealed a relation between the number of missing gesture classes and the accuracy of the existing and proposed methods, and we were able to clarify several advantages of the proposed method. These results indicate the potential of considerably reducing the number of required training samples of target users.
The Effect of Goal Moderation on the Achievement and Satisfaction of Physical Activity Goals
Authors: Alqahtani Deemah , Jay Caroline , Vigo Markel
Published: December 2020

Many self-trackers lose interest in, disengage from and ultimately withdraw from tracking. Reasons for this include poor motivation, unmet expectations and difficulty in attaining daily goals. To support users in reflecting on their goals more realistically, we developed FitReflect, an app that moderates physical activity goals by factoring in users' confidence in achieving the goals. The app also encourages users to reflect on their goals regularly and think about the factors affecting their achievement. We conducted a 4-week field experiment where we trialled the app with fourteen Fitbit users. We found that, compared with a non-moderated goal condition, participants with moderated goals achieved their goals more often, got closer to them, and adjusted them more frequently. Crucially, they were also more satisfied with their physical activity. More frequent goal updates were key to align user goals with their confidence and capabilities in achieving them.
BlinKey
Authors: Zhu Huadi , Jin Wenqiang , Xiao Mingyan , Murali Srinivasan , Li Ming
Published: December 2020

Virtual Reality (VR) has shown promising potentials in many applications, such as e-business, healthcare, and social networking. Rich information regarding user's activities and their online accounts is stored in VR devices. If it is carelessly unattended, then attackers, including insiders, can make use of the stored information to, for example, perform in-app purchases at the legitimate owner's expenses. Current solutions, mostly following schemes designed for general personal devices, have been proved vulnerable to shoulder-surfing attacks due to the sight blocking caused by the headset. Although there have been efforts trying to fill this gap, they either rely on some highly advanced equipment, such as electrodes to read brainwaves, or introduce heavy cognitive load that has users perform a series of cumbersome authentication tasks. Therefore, an authentication method for VR devices that is robust and convenient is in dire need.

In this paper, we present the design, implementation, and evaluation of a two-factor user authentication scheme, BlinKey, for VR devices that are equipped with an eye tracker. A user's secret passcode is a set of recorded rhythms when he/she blinks, together with the unique pupil size variation pattern. We call this passcode as a blinkey, which can be jointly characterized by knowledge-based and biometric features. To examine the performances, BlinKey is implemented on an HTC Vive Pro with a Pupil Labs eye tracker. Through extensive experimental evaluations with 52 participants, we show that our scheme can achieve the average EER as low as 4.0% with only 6 training samples. Besides, it is robust against various types of attacks. BlinKey also exhibits satisfactory usability in terms of login attempts, memorability, and impact of user motions. We also carry out questionnaire-based pre-/post-studies. The survey result indicates that BlinKey is well accepted as a user authentication scheme for VR devices.
Incremental Real-Time Personalization in Human Activity Recognition Using Domain Adaptive Batch Normalization
Authors: Mazankiewicz Alan , Böhm Klemens , Berges Mario
Published: December 2020

Human Activity Recognition (HAR) from devices like smartphone accelerometers is a fundamental problem in ubiquitous computing. Machine learning based recognition models often perform poorly when applied to new users that were not part of the training data. Previous work has addressed this challenge by personalizing general recognition models to the unique motion pattern of a new user in a static batch setting. They require target user data to be available upfront. The more challenging online setting has received less attention. No samples from the target user are available in advance, but they arrive sequentially. Additionally, the motion pattern of users may change over time. Thus, adapting to new and forgetting old information must be traded off. Finally, the target user should not have to do any work to use the recognition system by, say, labeling any activities. Our work addresses all of these challenges by proposing an unsupervised online domain adaptation algorithm. Both classification and personalization happen continuously and incrementally in real time. Our solution works by aligning the feature distributions of all subjects, be they sources or the target, in hidden neural network layers. To this end, we normalize the input of a layer with user-specific mean and variance statistics. During training, these statistics are computed over user-specific batches. In the online phase, they are estimated incrementally for any new target user.
Mapping and Taking Stock of the Personal Informatics Literature
Authors: Epstein Daniel A. , Caldeira Clara , Figueiredo Mayara Costa , Lu Xi , Silva Lucas M. , Williams Lucretia , Lee Jong Ho , Li Qingyang , Ahuja Simran , Chen Qiuer , Dowlatyari Payam , Hilby Craig , Sultana Sazeda , Eikey Elizabeth V. , Chen Yunan
Published: December 2020

The research community on the study and design of systems for personal informatics has grown over the past decade. To take stock of what the topics the field has studied and methods the field has used, we map and label 523 publications from ACM's library, IEEE Xplore, and PubMed. We surface that the literature has focused on studying and designing for health and wellness domains, an emphasis on understanding and overcoming barriers to data collection and reflection, and progressively fewer contributions involving artifacts being made. Our mapping review suggests directions future research could explore, such as identifying and resolving barriers to tracking stages beyond collection and reflection, engaging more with domain experts, and further discussing the privacy and ethical concerns around tracked data.
MorphingCircuit
Authors: Wang Guanyun , Qin Fang , Liu Haolin , Tao Ye , Zhang Yang , Zhang Yongjie Jessica , Yao Lining
Published: December 2020

Manufacturing nonplanar electronics often requires the integration of functions and forms through embedding circuit boards into three-dimensional (3D) shapes. While most popular solutions rely on cavities where electronics reside in forms of rigid circuit boards, other alternative approaches leverage 3D printing or layer lamination to create 3D electronics that often require expensive manufacturing processes and materials. Furthermore, many conventional methods are incompatible with complex geometries (e.g., surfaces that twist or have local minima). In response, we introduce MorphingCircuit, an integrated design, simulation, and fabrication workflow that combines electronic functions with forms through four-dimensional (4D) printing, which effectively reduces cost, production time, and e-waste. Specifically, we start by printing a flat substrate and assembling functional electronics on top of it. The flat structure will then self-morph into a preprogrammed 3D shape when triggered by external heating. Overall, our comprehensive 3D electronics fabrication pipeline encompasses the design, simulation, fabrication, and transformation, with which we hope to inspire designers, researchers, and makers to create conformal electronics on complex substrate geometries that were previously difficult or impossible to design or manufacture.
From the Editor: Welcome to Day 196
Authors: Kelly Rob
Published: December 2020

I think I speak for everyone when I say that I have serious virus fatigue. Everybody is getting a bit grumpy at times. (Of course, no one in my house.) The times in which we are living seem to be conspiring to tax everyone’s patience and better angels. At least here in the U.S., some appear to interpret the wearing of a mask as an in-your-face political statement as opposed to an on-your-face public health action.
From the President: O Tempora! O Mores!
Authors: De Gendt Stefan
Published: December 2020

This Latin phrase, spoken by Cicero around 70 BC, translates to “Oh the times, oh the customs.” These words are more than appropriate for the current worldwide crisis and how we react to it. When I wrote the summer Interface editorial, I hoped that society could look forward to resuming life as usual.
TNF-α-induced sympathetic excitation requires EGFR and ERK1/2 signaling in cardiovascular regulatory regions of the forebrain
Authors: Wei Shun-Guang , Yu Yang , Felder Robert B.
Published: December 2020

Proinflammatory cytokines contribute to the augmented sympathetic nerve activity in hypertension and heart failure, but the central mechanisms involved are largely unknown. The present study reveals that TNF-α transactivates EGFR in the subfornical organ and the hypothalamic paraventricular nucleus to initiate ERK1/2 signaling, upregulate the gene expression of excitatory mediators, and increase sympathetic nerve activity. These findings identify EGFR as a gateway to sympathetic excitation and a potential target for intervention in cardiovascular disease states.
Obesity-induced cognitive impairment in older adults: a microvascular perspective
Authors: Balasubramanian Priya , Kiss Tamas , Tarantini Stefano , Nyúl-Tóth Ádám , Ahire Chetan , Yabluchanskiy Andriy , Csipo Tamas , Lipecz Agnes , Tabak Adam , Institoris Adam , Csiszar Anna , Ungvari Zoltan
Published: December 2020

Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.
Rapid vasodilation within contracted skeletal muscle in humans: new insight from concurrent use of diffuse correlation spectroscopy and Doppler ultrasound
Authors: Ichinose Masashi , Nakabayashi Mikie , Ono Yumie
Published: December 2020

Through the concurrent use of diffuse correlation spectroscopy and Doppler ultrasound, we provide the first evidence in humans that a single brief muscle contraction evokes rapid, intensity-dependent hyperemia within the contracted skeletal muscle microvasculature and the upstream conduit artery. We also show that the magnitude and time course of the contraction-induced rapid hyperemia and vasodilatory responses within skeletal muscle microvessels significantly differ from those in the conduit artery.
Secreted frizzled protein 3 is a novel cardioprotective mechanism unique to the clinically relevant fourth window of ischemic preconditioning
Authors: Vatner Dorothy E. , Zhang Jie , Zhao Xin , Yan Lin , Kudej Raymond , Vatner Stephen F.
Published: December 2020

1) This investigation identifies the novel fourth window of ischemic preconditioning. 2) sFRP3 was identified as the most significantly upregulated gene in the fourth window and was shown to induce cardioprotection when administered to the hearts of wild-type mice.
Airway closure is the predominant physiological mechanism of low ventilation seen on hyperpolarized helium-3 MRI lung scans
Authors: Nilsen Kris , Thompson Bruce R. , Zajakovski Natalie , Kean Michael , Harris Benjamin , Cowin Gary , Robinson Phil , Prisk G. Kim , Thien Francis
Published: December 2020

This study introduces a novel technique of generating high-resolution 3D ventilation maps from hyperpolarized helium-3 MRI. It is the first study to demonstrate that regions of poor or absent ventilation seen on 3He MRI are primarily the result of airway closure.
The cardioprotective effect persisting during recovery from cold acclimation is mediated by the β2-adrenoceptor pathway and Akt activation
Authors: Tibenska Veronika , Marvanova Aneta , Elsnicova Barbara , Hejnova Lucie , Vebr Pavel , Novotný Jiri , Kolar Frantisek , Novakova Olga , M. Zurmanova Jitka
Published: December 2020

Cardioprotective effect of cold acclimation and that persisting for 2 wk after recovery engage in different mechanisms. The β2-adrenoceptor/Gi pathway and Akt are involved only in the mechanism of infarct size-limiting effect occurring during the recovery phase. GSK-3β translocated from the Z-line to the H-zone of sarcomeres by cold acclimation returns back to the original position after the recovery phase. The results provide new insights potentially useful for the development of cardiac therapies.
Unified Framework of Approximating and Interpolatory Subdivision Schemes for Construction of Class of Binary Subdivision Schemes
Authors: Ashraf Pakeeza , Mustafa Ghulam , Ghaffar Abdul , Zahra Rida , Nisar Kottakkaran Sooppy , Mahmoud Emad E. , Alharbi Wedad R.
Published: December 2020

In this paper, a generalized algorithm to develop a class of approximating binary subdivision schemes is presented. The proposed algorithm is based on three-point approximating binary and four-point interpolating binary subdivision schemes. It contains a parameter which classifies members of the new class of subdivision schemes. A set of efficient properties, for instance, polynomial generation and reproduction, support, continuity, and Hölder continuity, is discussed. Moreover, applications of the proposed subdivision schemes are given in order to demonstrate their variety, flexibility, and visual performance.
Metastasis of Uterine Leiomyosarcoma to the Breast: Medical and Histopathological Criteria
Authors: Colón Eugenia
Published: December 2020

It is uncommon for extramammary tumors to metastasize to the breast, and very few cases describing metastasis of primary uterine leiomyosarcoma to the breast have been reported. We present the case of a 51-year-old woman diagnosed with metastasis of uterine leiomyosarcoma to the breast diagnosed 10 years ago after hysterectomy. Ultrasonography, mammography, and cytology were used to establish a preliminary diagnosis that was confirmed upon examination of the excised tumor that show a rare soft tissue tumor composed of atypical spindle cells and increased proliferation rate. We discuss the importance of distinguishing between various primary mesenchymal tumors of the breast because of phenotypic overlap and some guidance of the histological criteria for metastasis of leiomyosarcoma, as well as differential diagnosis and surgical treatment.
Single‐ versus Multiple‐Tract Percutaneous Nephrolithotomy in the Surgical Management of Staghorn Stones or Complex Caliceal Calculi: A Systematic Review and Meta‐analysis
Authors: Jiao Binbin , Ding Zhenshan , Luo Zhenkai , Lai Shicong , Xu Xin , Chen Xing , Zhang Guan
Published: December 2020

Objective. To assess current evidence on the effectiveness and safety of single‐ versus multiple‐tract percutaneous nephrolithotomy in the surgical management of complex caliceal calculi or staghorn stones through a comprehensive literature review. Methods. A comprehensive literature review of articles investigating the clinical efficacy and safety of single‐ versus multiple‐tract percutaneous nephrolithotomy was performed. Relevant literature was obtained by systematically searching PubMed, EMBASE, and the Cochrane Library through May 2020. We followed the search strategy based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. The primary outcomes, including the stone‐free rate (SFR), and secondary outcomes (peri‐ and postoperative complications and operative data) were evaluated using RevMan 5.3 statistical software. Results. Ten studies involving 1844 patients with complex caliceal calculi or staghorn stones met the inclusion criteria. Single‐tract percutaneous nephrolithotomy (STPCNL) had noninferior clinical efficacy with respect to the immediate SFR (odds ratio (OR) = 0.80, 95% confidence interval (CI) (0.46 to 1.38), p = 0.42) and 3‐month SFR (OR = 1.22, 95% CI (0.38 to 3.92), p = 0.74) compared with multiple‐tract percutaneous nephrolithotomy (MTPCNL). In addition, pooled analyses showed that STPCNL resulted in significantly lower hemoglobin decreases (MD = −0.46, 95% CI (‐0.68 to ‐0.25), p < 0.0001), fewer blood transfusions (OR = 0.48, 95% CI (0.34 to 0.67), p < 0.0001), and fewer pulmonary complications (OR = 0.28, 95% CI (0.09 to 0.83), p = 0.02) than MTPCNL. However, the overall evidence was insufficient to suggest a statistically significant difference for other adverse events. Conclusion. This meta‐analysis indicated that STPCNL is an effective method for treating complex caliceal calculi or staghorn stones. Compared with MTPCNL, STPCNL not only yields similarly high SFRs but also is associated with many advantages, less blood loss, fewer blood transfusions, and fewer pulmonary complications without an increase in other complications. However, the findings of this study should be further confirmed by well‐designed prospective randomized controlled trials (RCTs) with a larger patient series.
Olaquindox-Induced Liver Damage Involved the Crosstalk of Oxidative Stress and p53 In Vivo and In Vitro
Authors: Li Daowen , Pei Xingyao , Qin Xiaoling , Liu Xinyu , Li Cun , Li Liuan , Dai Chongshan , Xiao Xilong , Tang Shusheng
Published: December 2020

Olaquindox (OLA), a member of the quinoxaline-N,N-dioxide family, has been widely used as a growth-promoting feed additive and treatment for bacterial infections. The toxicity has been a major concern, and the precise molecular mechanism remains poorly understood. The present study was aimed at investigating the roles of oxidative stress and p53 in OLA-caused liver damage. In a mouse model, OLA administration could markedly cause liver injury as well as the induction of oxidative stress and activation of p53. Antioxidant N-acetylcysteine (NAC) inhibited OLA-induced oxidative stress and p53 activation in vivo. Furthermore, knockout of the p53 gene could significantly inhibit OLA-induced liver damage by inhibiting oxidative stress and the mitochondria apoptotic pathway, compared to the p53 wild-type liver tissue. The cell model in vitro further demonstrated that p53 knockout or knockdown in the HCT116 cell and L02 cell significantly inhibited cell apoptosis and increased cell viability, presented by suppressing ROS production, oxidative stress, and the Nrf2/HO-1 pathway. Moreover, loss of p53 decreased OLA-induced mitochondrial dysfunction and caspase activations, with the evidence of inhibited activation of phosphorylation- (p-) p38 and p-JNK and upregulated cell autophagy via activation of the LC3 and Beclin1 pathway in HCT116 and L02 cells. Taken together, our findings provided a support that p53 primarily played a proapoptotic role in OLA-induced liver damage against oxidative stress and mitochondrial dysfunction, which were largely dependent on suppression of the JNK/p38 pathway and upregulation of the autophagy pathway via activation of LC3 and Beclin1.
Flowchart-Based Cross-Language Source Code Similarity Detection
Authors: Zhang Feng , Li Guofan , Liu Cong , Song Qian
Published: December 2020

Source code similarity detection has various applications in code plagiarism detection and software intellectual property protection. In computer programming teaching, students may convert the source code written in one programming language into another language for their code assignment submission. Existing similarity measures of source code written in the same language are not applicable for the cross-language code similarity detection because of syntactic differences among different programming languages. Meanwhile, existing cross-language source similarity detection approaches are susceptible to complex code obfuscation techniques, such as replacing equivalent control structure and adding redundant statements. To solve this problem, we propose a cross-language code similarity detection (CLCSD) approach based on code flowcharts. In general, two source code fragments written in different programming languages are transformed into standardized code flowcharts (SCFC), and their similarity is obtained by measuring their corresponding SCFC. More specifically, we first introduce the standardized code flowchart (SCFC) model to be the uniform flowcharts representation of source code written in different languages. SCFC is language-independent, and therefore, it can be used as the intermediate structure for source code similarity detection. Meanwhile, transformation techniques are given to transform source code written in a specific programming language into an SCFC. Second, we propose the SCFC-SPGK algorithm based on the shortest path graph kernel to measure the similarity between two SCFCs. Thus, the similarity between two pieces of source code in different programming languages is given by the similarity between SCFCs. Experimental results show that compared with existing approaches, CLCSD has higher accuracy in cross-language source code similarity detection. Furthermore, CLCSD cannot only handle common source code obfuscation techniques used by students in computer programming teaching but also obtain nearly 90% accuracy in dealing with some complex obfuscation techniques.
Chlamydia muridarum Alleviates Colitis via the IL‐22/Occludin Signal Pathway
Authors: Wang Xin , Zeng Huai-cai , Huang Yan-ru , He Qing-zhi
Published: December 2020

Ulcerative colitis (UC) is the most common inflammatory bowel disease, and its incidence has increased in recent years. Recent clinical and experimental data indicate that gut microbiota plays a pivotal role in the pathogenesis of UC. Chlamydia establishes a stable and persistent colonization in the gastrointestinal tract without apparent pathogenicity to gastrointestinal or extragastrointestinal tissues. However, the detailed effects of Chlamydia on the gastrointestinal tissue remain unknown. The primary aim of this study is to investigate the effects of Chlamydia muridarum (C. muridarum) on development of colitis induced by dextran sodium sulfate (DSS) and the underlying molecular mechanism. The results suggested that C. muridarum significantly improved colitis symptoms—including weight loss, disease activity index, colon length, and histopathological changes in the colon caused by DSS—and alleviated the reduced expression of interleukin‐22 and occludin in the colonic tissue due to DSS administration. Furthermore, the absence of IL‐22 completely prevented C. muridarum from alleviating colitis and significantly decreased the levels of occludin, an important downstream effector protein of IL‐22. These findings suggest that C. muridarum ameliorates ulcerative colitis induced by DSS via the IL‐22/occludin signal pathway.
Abstract A02: SYK kinase inhibition causes autophagy pathway activation via suppression of mTORC1 in KRAS-mutant pancreatic cancer cells
Authors: Hua Kevin L. , Pan Michelle , Rafati Minoo , Singh Anurag
Published: December 2020

The spleen tyrosine kinase (SYK) is highly expressed in a subset of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines. This prompted our interest in investigating SYK as a candidate therapeutic target in PDAC cell lines. Here, we use a selective SYK kinase inhibitor (PRT-062607) in pharmacologic and mechanistic studies of SYK kinase signaling in PDAC cell lines. SYK kinase inhibition causes dose-dependent decreases in cell proliferation of “SYK-high” PDAC cell lines YAPC and DAN-G. Furthermore, combined SYK and MEK inhibition causes additive effects on reducing cell proliferation. Mechanistically, SYK inhibition causes reduced S6K and rpS6 phosphorylation, which is independent of MEK/ERK and PI3K/AKT signaling. Therefore, SYK activates mTORC1 activity through an unknown mechanism. The mTORC1 complex is a key activator of the macroautophagy pathway (autophagy), which is implicated as a driver of PDAC progression. However, autophagy can cause tumor suppression in some contexts. We demonstrate that SYK inhibition or shRNA-mediated depletion results in increased autolysosomal biogenesis and autophagic flux that occur with latency following treatment of cells with the SYK inhibitor. These effects are partly mediated by the nuclear localization and activation of MITF, which is a key transcriptional regulator of genes that control lysosomal biogenesis and autophagy. Taken together, our results demonstrate that SYK is a positive regulator of mTORC1 activity in a subset of PDAC cell lines. SYK kinase inhibition or shRNA-mediated depletion causes a strong reduction in mTORC1 activity and subsequent MITF activation and nuclear localization. The net effect is increased autolysosomal biogenesis and autophagic flux in YAPC and DAN-G PDAC cell lines. Therefore, SYK inhibition in combination with KRAS pathway inhibitors may serve as a potential therapeutic strategy to perturb autophagy pathway homeostasis and pancreatic cancer cell survival.

Citation Format: Kevin L. Hua, Michelle Pan, Minoo Rafati, Anurag Singh. SYK kinase inhibition causes autophagy pathway activation via suppression of mTORC1 in KRAS-mutant pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A02.
Abstract A09: Phosphorylation of mSin1-CRIM domain regulates protein stability and substrate selectivity
Authors: Chiu Yueh-Ho , Cui Wei
Published: December 2020

The mechanistic target of rapamycin (mTOR) signaling plays critical roles in controlling mammalian cell behavior and function in response to environmental changes, and thereby it is important for maintaining tissue homeostasis and organism health. Dysregulation of mTOR signaling leads to a variety of human diseases, such as cancer, obesity, type II diabetes, and neurodegeneration. The mTOR signaling functions through two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which differ in their composition, structures, and functions. Considerable knowledge has been obtained regarding mTORC1 in recent years, while, in comparison, much less is known about mTORC2. Rictor and mSin1 are key mTORC2-specific proteins and essential for mTORC2 functions. Rictor is a scaffold protein in mTORC2 as Raptor in mTORC1, while mSin1 is considered to function for recruiting the substrate to the mTORC2 and its expression appears to be Rictor-dependent. However, exact mechanisms remain elusive. To explore the relationship between Rictor and mSin1 and their functions in mTORC2, we have generated RICTOR-knockout HEK293T cells by using the CRISPR-Cas9 system and revealed that mSin1 protein expression was substantially diminished in these cells and so was the mTORC2 activity, whereas mSin1 mRNA expression did not show any changes in the absence of RICTOR. Further analyses demonstrated that Rictor/mTORC2 is crucial for mSin1 protein stability, which may be attributed, at least partly, to the mTORC2-associated phosphorylation of mSin1-CRIM domain. More interestingly, this phosphorylation may also affect substrate recognition of mTORC2. The detailed mechanistic study regarding the influence of phosphorylated mSin1 on mTORC2 activity has been carried out and will be presented at the meeting. Our results suggest that mTORC2 may have an autoregulatory function and affect its substrate selection. Our findings thus advance our understanding in both regulation and function of Rictor/mTORC2, and also provide a potential insight for new therapies development in a number of human diseases.

Citation Format: Yueh-Ho Chiu, Wei Cui. Phosphorylation of mSin1-CRIM domain regulates protein stability and substrate selectivity [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A09.
Abstract A13: Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration
Authors: Nguyen Joe T. , Ray Connor , Fox Alexandra L , Mendonca Daniela B , Kim Jin Koo , Krebsbach Paul H.
Published: December 2020

Nematode EAK-7 (enhancer-of-akt-1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome. This phenomenon is distinguished by S6 and 4E-BP1 activity in response to nutrient stimulation. Conventional S6K1 phosphorylation is uncoupled from S6 phosphorylation in response to mEAK-7 knockdown. mEAK-7 recruits mTOR to the lysosome, a crucial compartment for mTOR activation. Loss of mEAK-7 results in a marked decrease in lysosomal localization of mTOR, whereas overexpression of mEAK-7 results in enhanced lysosomal localization of mTOR. Deletion of the carboxyl terminus of mEAK-7 significantly decreases mTOR interaction. mEAK-7 knockdown decreases cell proliferation and migration, whereas overexpression of mEAK-7 enhances these cellular effects. Constitutively activated S6K rescues mTOR signaling in mEAK-7–knocked down cells. Thus, mEAK-7 activates an alternative mTOR signaling pathway through S6K2 and 4E-BP1 to regulate cell proliferation and migration.

Citation Format: Joe T. Nguyen, Connor Ray, Alexandra L Fox, Daniela B Mendonca, Jin Koo Kim, Paul H. Krebsbach. Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A13.
Abstract A17: Targeting PI3K/Akt-mediated MADD phosphorylation improves TRAIL sensitivity in anaplastic thyroid cancer
Authors: Saini Shikha , Mathur Aditi , Yue Fei , Maker Ajay , Prabhakar Bellur S.
Published: December 2020

Anaplastic thyroid cancer is an extremely hard-to-treat malignancy due to its aggressiveness, metastasis and inherent therapeutic resistance. Despite using all available armamentaria, the median survival of ATC patients remains dismal. In this regard, TNF-related apoptosis-inducing ligand (TRAIL) is known to induce cancer-specific apoptosis without affecting nontumor cells. However, development of resistance to TRAIL hampers its clinical use. One of the mechanisms of TRAIL resistance is mediated through phosphorylation of Map kinase Activating Death Domain-containing protein (MADD) by Akt. In light of this, preventing MADD phosphorylation might be a rational approach to overcome TRAIL resistance. To test this, we examined MADD expression and TRAIL sensitivity by Western blotting and active caspase-3 staining in several ATC cell lines harboring mutations in cancer driver genes including BRAF, Akt, and PTEN. MADD phosphorylation was inhibited by introducing site-directed mutations in Akt phosphorylation sites of MADD and exogenously expressing the mutant constructs to determine the effect on TRAIL-induced apoptosis. Our results showed that MADD was differentially overexpressed in all ATC cells compared to the normal thyroid tissues irrespective of their mutational landscape. Further, exogenous expression of non-phosphorylatable MADD resulted in a significantly increased TRAIL-induced apoptosis accompanied by the activation of both intrinsic and extrinsic apoptotic pathways. Thus, this study establishes a concept of prevention of MADD phosphorylation to improve TRAIL susceptibility of ATC cells as it can yield similar results as that of blocking PI3k/Akt pathway without any off-target effects. Further studies are warranted to explore specific inhibitors to target MADD phosphorylation.

Note: This abstract was not presented at the conference.

Citation Format: Shikha Saini, Aditi Mathur, Fei Yue, Ajay Maker, Bellur S. Prabhakar. Targeting PI3K/Akt-mediated MADD phosphorylation improves TRAIL sensitivity in anaplastic thyroid cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A17.
Abstract A30: Targeting of the mTOR pathway in human acute myeloid leukemia cells using functionalized gold nanoparticles
Authors: Yasinska Inna M. , Gibbs Bernhard F. , Varani Luca , Hussain Rohanah , Siligardi Giuliano , Fasler-Kan Elizaveta , Calzolai Luigi , Sumbayev Vadim V.
Published: December 2020

Specific targeting of fundamental biochemical/signaling pathways in human malignant cells with the purpose of recognition and delivery of cytotoxic drugs into them is a very promising but not well-developed strategic approach. It is a major focus of current molecular cancer research, nanomedicine, biotechnology, and synthetic biology. mTOR pathway is a master regulator of metabolism and cell growth in the majority of malignant cells. Especially this applies to cancerous myeloid cells where it determines the ability of the cells to survive and evade the host immune surveillance. Therefore, specific targeting of this pathway could be a novel strategy for treatment of acute myeloid leukemia (AML), a blood/bone marrow cancer that can rapidly progress into a systemic and often fatal malignancy. In this study we demonstrated for the first time a fundamentally novel approach for specific targeting of human AML cells by functionalized gold nanoparticles. The immune receptor Tim-3 is highly expressed in human AML cells. It is one of the key members of the Tim-3/galectin-9 autocrine pathway that plays a pivotal role in AML cell survival and immune evasion (1). Rapamycin inhibits the mTOR activity, thus affecting translational pathways in AML cells. Inhibition of the mTOR leads to a rapid killing of AML cells. Using these nanomaterials, we managed to successfully deliver rapamycin into AML cells, reaching attenuation of the mTOR activity. Concentration of rapamycin required to reach such a strong effect was at least 50 times lower compared to that of free rapamycin required to achieve the similar result. We therefore concluded that our technology is of potential use for specific targeting of AML cells for the purpose of diagnosis and possibly therapy (2). The nanoconjugates developed in our work can be used to specifically identify malignant blood cells, thus allowing rapid and robust AML diagnosis.

Citation Format: Inna M. Yasinska, Bernhard F. Gibbs, Luca Varani, Rohanah Hussain, Giuliano Siligardi, Elizaveta Fasler-Kan, Luigi Calzolai, Vadim V. Sumbayev. Targeting of the mTOR pathway in human acute myeloid leukemia cells using functionalized gold nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A30.
Abstract B01: Simultaneous targeting of mTOR and mLST8 in human breast cancer cells
Authors: Coyle Melissa , Nabiee Romina , Lamboy Robert , Mahdipoor Parvin , Parang Keykavous , Aliabadi Hamidreza Montazeri
Published: December 2020

Despite our continually increasing knowledge of cancer biology and intracellular mechanisms, identifying targets for cancer treatment remains a challenge. Cancer cells are heterogeneous and plastic, which are involved in innate and acquired resistance to molecularly targeted anticancer drugs, respectively. This project focuses on the PI3K/Akt cell signaling pathway, specifically mammalian target of rapamycin (mTOR) and GβL (mLST8), to halt cell proliferation. The breast cancer cell lines MDA-MB-231, MDA-MB-468, and AU565 were exposed to small interfering RNAs (siRNAs) targeting mTOR or mLST8, as well as a combination of both. The cell protein expression profile was studied to investigate the efficiency of protein silencing, and potential synergistic effect on downstream effectors of the pathway. Due to poor cellular internalization of siRNA, we also investigated the efficiency of small cell-penetrating peptides specifically designed as siRNA carriers. Three cyclic peptides (WR5, [R5K]W5 and [R6K]W6) incorporating ring-forming arginines (as a cationic moiety for inter-ionic interaction with nucleic acids), tryptophan (as a hydrophobic chain to enhance interaction with cell membrane, and lysine as the conjugation site for tryptophan chain were studied for in vitro siRNA delivery. The siRNA complexes formed with these amphiphilic peptides were delivered to the same breast cancer cell lines, and the efficiency of cellular internalization and mTOR and mLST8 silencing was investigated. Our findings confirm the efficiency of siRNAs in interrupting formation of mTOR complexes, and the activation of downstream proteins. Further studies are required to confirm these findings in patient cells and to evaluate the efficacy of this approach in vivo.

Citation Format: Melissa Coyle, Romina Nabiee, Robert Lamboy, Parvin Mahdipoor, Keykavous Parang, Hamidreza Montazeri Aliabadi. Simultaneous targeting of mTOR and mLST8 in human breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B01.
Abstract B02: Combined inhibition of mTOR and Src family kinases enhances treatment effects in prostate cancer cells
Authors: Dai Yao , Siemann Dietmar W
Published: December 2020

Hyperactivated Akt/mTOR pathway and Src family kinases (SFKs) pathway commonly occur in prostate cancer that is highly associated with disease progression and poor prognosis. Therefore, small-molecule inhibitors targeting these pathways have been studied extensively for the treatment of advanced prostate cancer. Nevertheless, clinical observation suggests that individual treatment with either inhibitor only yields limited antitumor effects in patients. One possible interpretation is that these signaling pathways are redundant, such that blocking one pathway is not sufficient to yield considerable efficacies. In this regard, we combined mTOR inhibitor rapamycin and Src inhibitor dasatinib to detect functional behaviors in prostate cancer cells. Cell proliferation was detected by MTT, and clonogenic survival was tested by colony formation assay. Cell migration was assessed by “wound-healing” scratch assay. Protein expression was detected by Western blot analysis. We found that rapamycin plus dasatinib showed greater inhibition on cell proliferation and clonogenic survival than either single agent. Such combination effects were additive in PC-3 and synergistic in DU145 cells, respectively, as reflected by combination index calculation. In addition, cell migration was suppressed to a greater extent by combination treatment than either treatment alone. At the molecular level, co-targeting mTOR and SFKs leads to strong inhibition of not only phosphorylation of these two proteins but also their downstream components such as Akt, focal adhesion kinase (FAK), S6K and 4E-BP1. These data indicate that co-targeting mTOR and Src pathways is able to achieve enhanced tumor-suppressing effects in prostate cancer cells with overexpression of both kinases, suggesting that this combinative intervention modality may serve as a potential anticancer strategy that could be further tested in advanced prostate cancer models in vivo.

Note: This abstract was not presented at the conference.

Citation Format: Yao Dai, Dietmar W Siemann. Combined inhibition of mTOR and Src family kinases enhances treatment effects in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B02.
Abstract B28: Estrogen receptor alpha (ERa) promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f)
Authors: Cuesta Rafael , Holz Marina K.
Published: December 2020

Approximately two-thirds of all breast cancer cases are estrogen receptor (ER) positive. The treatment of this breast cancer subtype with endocrine therapies is effective in the adjuvant and recurrent settings. However, their effectiveness is compromised by the emergence of intrinsic or acquired resistance. Thus, identification of new molecular targets can significantly contribute to the development of novel therapeutic strategies. In recent years, many studies have implicated aberrant levels of translation initiation factors in cancer etiology and provided evidence that identifies these factors as promising therapeutic targets. Accordingly, we observed reduced levels of the eukaryotic translation initiation factor 3 (eIF3) subunit eIF3f in ER-positive breast cancer cells compared to ER-negative cells and determined that low eIF3f levels are required for proper proliferation and survival of ER-positive MCF7 cells. The expression of eIF3f is tightly controlled by ERa at transcriptional (genomic pathway) and translational (non-genomic pathway) level. Specifically, estrogen-bound ERa represses transcription of the EIF3F gene, while promoting eIF3f mRNA translation. In regulation of translation, estrogen activates the mTORC1 pathway, which enhances the binding of eIF3 to the eIF4F complex and, consequently, the assembly of 48S preinitiation complexes and protein synthesis. We observed preferential translation of mRNAs with highly structured 5' untranslated regions (UTRs) that usually encode factors involved in cell proliferation and survival (e.g., cyclin D1 and survivin). Our results underscore the importance of estrogen-ERa-mediated control of eIF3f expression for the proliferation and survival of ER-positive breast cancer cells. These findings may provide rationale for the development of new therapies to treat ER-positive breast cancer.

Citation Format: Rafael Cuesta, Marina K. Holz. Estrogen receptor alpha (ERa) promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f) [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B28.
Abstract IA04: Stroma-driven resistance to PI3K/mTOR inhibition
Authors: Muranen Taru
Published: December 2020

PI3/mTOR pathway, a major regulator of cellular growth and metabolism, is mutated in ~70% of breast cancers and conveys resistance towards estrogen receptor- and HER2-targeted therapies. Unfortunately, targeting the PI3K pathway in the clinic has been hampered by emergence of drug resistance, often through rewiring of their signaling pathways rather than through mutations, a phenomenon called adaptive resistance that is often observed with targeted therapies. Our previous data have shown that adaptive resistance requires input from the tumor microenvironment. Cancer cells require the presence of extracellular matrix proteins to elicit drug resistance; without matrix contact the tumor cells died. Our data also show that fibroblasts secrete matrix proteins that increase cellular survival of epithelial cells under starvation and PI3K and mTOR inhibition. To investigate the identity and role of the secreted proteins that drive resistance, we performed mass-spectrometry and cytokine analysis of fibroblast secretomes treated with PI3K inhibitors. These data have identified several candidate proteins as potential drivers of stroma-mediated drug resistance, and we will discuss how targeting these proteins can increase the efficacy of PI3K- and mTOR-targeted therapies.

Citation Format: Taru Muranen. Stroma-driven resistance to PI3K/mTOR inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA04.