bluuebunny/crossref_metadata_2025 huggingface dataset:
SIGWEB annual report
Authors: Bulterman Dick C. A.
Published: July 2019

SIGWEB is a medium-sized special interest group within ACM. Financially, SIGWEB is in an excellent position to develop and experiment with new initiatives to help promote a vibrant scientific community within our domain. This spring, ACM will hold SIG elections. The SIGWEB nominating committee has decided to offer a new slate of candidates for each of the three elected positions at SIGWEB: the Chair, the Vice-Chair and Secretary/Treasurer.
Upcoming SIGWEB supported conferences
Authors: Samuel Hamman
Published: July 2019

The Special Interest Group on Hypertext and the Web, SIGWEB was created in 1989 to support the community participating in the annual ACM Hypertext Conference. Now in its third decade, SIGWEB has grown considerably and now sponsors seven annual conferences of different sizes and covering a wide range of topics. SIGWEB supports several specialized conferences, short courses, and workshops, as well as the Annual Hypertext Conference. SIGWEB sponsored conferences focus on timely topics in applied and computational hypertext and Web disciplines and provide a place for members and the entire applied Hypermedia and Web community to exchange ideas and to meet with and expand their network of colleagues. In this article, we provide a brief overview of SIGWEB sponsored conferences, in addition to events that are in cooperation with SIGWEB.
Statistical Early Termination and Early Skip Models for Fast Mode Decision in HEVC INTRA Coding
Authors: Zhang Yun , Li Na , Kwong Sam , Jiang Gangyi , Zeng Huanqiang
Published: July 2019

In this article, statistical Early Termination (ET) and Early Skip (ES) models are proposed for fast Coding Unit (CU) and prediction mode decision in HEVC INTRA coding, in which three categories of ET and ES sub-algorithms are included. First, the CU ranges of the current CU are recursively predicted based on the texture and CU depth of the spatial neighboring CUs. Second, the statistical model based ET and ES schemes are proposed and applied to optimize the CU and INTRA prediction mode decision, in which the coding complexities over different decision layers are jointly minimized subject to acceptable rate-distortion degradation. Third, the mode correlations among the INTRA prediction modes are exploited to early terminate the full rate-distortion optimization in each CU decision layer. Extensive experiments are performed to evaluate the coding performance of each sub-algorithm and the overall algorithm. Experimental results reveal that the overall proposed algorithm can achieve 45.47% to 74.77%, and 58.09% on average complexity reduction, while the overall Bjøntegaard delta bit rate increase and Bjøntegaard delta peak signal-to-noise ratio degradation are 2.29% and −0.11 dB, respectively.
Interpretable Partitioned Embedding for Intelligent Multi-item Fashion Outfit Composition
Authors: Feng Zunlei , Yu Zhenyun , Jing Yongcheng , Wu Sai , Song Mingli , Yang Yezhou , Jiang Junxiao
Published: July 2019

Intelligent fashion outfit composition has become more popular in recent years. Some deep-learning-based approaches reveal competitive composition. However, the uninterpretable characteristic makes such a deep-learning-based approach fail to meet the businesses’, designers’, and consumers’ urges to comprehend the importance of different attributes in an outfit composition. To realize interpretable and intelligent multi-item fashion outfit compositions, we propose a partitioned embedding network to learn interpretable embeddings from clothing items. The network contains two vital components: attribute partition module and partition adversarial module. In the attribute partition module, multiple attribute labels are adopted to ensure that different parts of the overall embedding correspond to different attributes. In the partition adversarial module, adversarial operations are adopted to achieve the independence of different parts. With the interpretable and partitioned embedding, we then construct an outfit-composition graph and an attribute matching map. Extensive experiments demonstrate that (1) the partitioned embedding have unmingled parts that correspond to different attributes and (2) outfits recommended by our model are more desirable in comparison with the existing methods.
A Unified Simplicial Model for Mixed-Dimensional and Non-Manifold Deformable Elastic Objects
Authors: Chang Jumyung , Da Fang , Grinspun Eitan , Batty Christopher
Published: July 2019

We present a unified method to simulate deformable elastic bodies consisting of mixed-dimensional components represented with potentially non-manifold simplicial meshes. Building on well-known simplicial rod, shell, and solid models for elastic continua, we categorize and define a comprehensive palette expressing all possible constraints and elastic energies for stiff and flexible connections between the 1D, 2D, and 3D components of a single conforming simplicial mesh. This palette consists of three categories: point connections, in which simplices meet at a single vertex around which they may twist and bend; curve connections in which simplices share an edge around which they may rotate (bend) relative to one another; and surface connections, in which a shell is embedded on or into a solid. To define elastic behaviors across non-manifold point connections, we adapt and apply parallel transport concepts from elastic rods. To address discontinuous forces that would otherwise arise when large accumulated relative rotations wrap around in the space of angles, we develop an incremental angle-update strategy. Our method provides a conceptually simple, flexible, and highly expressive framework for designing complex elastic objects, by modeling the geometry with a single simplicial mesh and decorating its elements with appropriate physical models (rod, shell, solid) and connection types (point, curve, surface). We demonstrate a diverse set of possible interactions achievable with our method, through technical and application examples, including scenes featuring complex aquatic creatures, children's toys, and umbrellas.
Efficient Neural Networks for Real-time Motion Style Transfer
Authors: Smith Harrison Jesse , Cao Chen , Neff Michael , Wang Yingying
Published: July 2019

Style is an intrinsic, inescapable part of human motion. It complements the content of motion to convey meaning, mood, and personality. Existing state-of-the-art motion style methods require large quantities of example data and intensive computational resources at runtime. To ensure output quality, such style transfer applications are often run on desktop machine with GPUs and significant memory. In this paper, we present a fast and expressive neural network-based motion style transfer method that generates stylized motion with quality comparable to the state of the art method, but uses much less computational power and a much smaller memory footprint. Our method also allows the output to be adjusted in a latent style space, something not offered in previous approaches. Our style transfer model is implemented using three multi-layered networks: a pose network, a timing network and a foot-contact network. A one-hot style vector serves as an input control knob and determines the stylistic output of these networks. During training, the networks are trained with a large motion capture database containing heterogeneous actions and various styles. Joint information vectors together with one-hot style vectors are extracted from motion data and fed to the networks. Once the network has been trained, the database is no longer needed on the device, thus removing the large memory requirement of previous motion style methods. At runtime, our model takes novel input and allows real-valued numbers to be specified in the style vector, which can be used for interpolation, extrapolation or mixing of styles. With much lower memory and computational requirements, our networks are efficient and fast enough for real-time use on mobile devices. Requiring no information about future states, the style transfer can be performed in an online fashion. We validate our result both quantitatively and perceptually, confirming its effectiveness and improvement over previous approaches.
Linear capabilities for fully abstract compilation of separation-logic-verified code
Authors: Van Strydonck Thomas , Piessens Frank , Devriese Dominique
Published: July 2019

Separation logic is a powerful program logic for the static modular verification of imperative programs. However, dynamic checking of separation logic contracts on the boundaries between verified and untrusted modules is hard, because it requires one to enforce (among other things) that outcalls from a verified to an untrusted module do not access memory resources currently owned by the verified module.

This paper proposes an approach to dynamic contract checking by relying on support for capabilities, a well-studied form of unforgeable memory pointers that enables fine-grained, efficient memory access control. More specifically, we rely on a form of capabilities called linear capabilities for which the hardware enforces that they cannot be copied.

We formalize our approach as a fully abstract compiler from a statically verified source language to an unverified target language with support for linear capabilities. The key insight behind our compiler is that memory resources described by spatial separation logic predicates can be represented at run time by linear capabilities. The compiler is separation-logic-proof-directed: it uses the separation logic proof of the source program to determine how memory accesses in the source program should be compiled to linear capability accesses in the target program.

The full abstraction property of the compiler essentially guarantees that compiled verified modules can interact with untrusted target language modules as if they were compiled from verified code as well.
Dependently typed Haskell in industry (experience report)
Authors: Christiansen David Thrane , Diatchki Iavor S. , Dockins Robert , Hendrix Joe , Ravitch Tristan
Published: July 2019

Recent versions of the Haskell compiler GHC have a number of advanced features that allow many idioms from dependently typed programming to be encoded. We describe our experiences using this "dependently typed Haskell" to construct a performance-critical library that is a key component in a number of verification tools. We have discovered that it can be done, and it brings significant value, but also at a high cost. In this experience report, we describe the ways in which programming at the edge of what is expressible in Haskell's type system has brought us value, the difficulties that it has imposed, and some of the ways we coped with the difficulties.
A predicate transformer semantics for effects (functional pearl)
Authors: Swierstra Wouter , Baanen Tim
Published: July 2019

Reasoning about programs that use effects can be much harder than reasoning about their pure counterparts. This paper presents a predicate transformer semantics for a variety of effects, including exceptions, state, non-determinism, and general recursion. The predicate transformer semantics gives rise to a refinement relation that can be used to relate a program to its specification, or even calculate effectful programs that are correct by construction.
Robust Optimal Selection of Radio Type and Transmission Power for Internet of Things
Authors: Mu Di , Ge Yunpeng , Sha Mo , Paul Steve , Ravichandra Niranjan , Chowdhury Souma
Published: July 2019

Research efforts over the last few decades produced multiple wireless technologies, which are readily available to support communication between devices in various dynamic Internet of Things (IoT) and robotics applications. However, single radio technology can hardly deliver optimal performance across all critical quality of service (QoS) dimensions under the typically varying environmental conditions or under varying distance between communicating nodes. Using a single wireless technology therefore falls short of meeting the demands of varying workloads or changing environmental conditions. Instead of pursuing a one-radio-fits-all approach, we design
ARTPoS
, an
Adaptive Radio and Transmission Power Selection
system, which makes available at runtime multiple wireless technologies (e.g., WiFi and ZigBee) and selects the radio(s) and transmission power(s) most suitable for the current conditions and requirements. The principal components of ARTPoS include new empirical models of power consumption and packet reception ratio (the latter can also be refined online) and online optimization schemes. We have implemented our system and evaluate it on the physical testbed consisting of our new embedded platforms with heterogeneous radios. Experimental results show that ARTPoS can significantly reduce the power consumption, while maintaining desired link reliability, compared to standard baselines.
Synthesis and Properties of Red Mud-Based Nanoferrite Clinker
Authors: Sun Hongfang , Chen Chuyu , Ling Li , Memon Shazim Ali , Ding Zhu , Li Weiwen , Tang Lu-ping , Xing Feng
Published: July 2019

Red mud, an industrial waste obtained from alumina plants, is usually discharged into marine or disposed into a landfill polluting the surrounding water, atmosphere, and soil. Thus, disposal of red mud is an environmental concern and it should be recycled in an effective way. Since red mud consists of iron- and aluminum-rich phases, it can potentially be processed into cementitious material and can be used for a construction purpose. This research investigated the synthesis of nanoferrite (NF) clinker by using red mud as a raw material through chemical combustion technology for potential use in cement-based composite. Before the synthesis of NF, red mud was characterized by using XRF, XRD, and SEM techniques. From characterization results, the stoichiometric ratio of raw materials was calculated and experimentally optimized. The sample was then tested at various temperatures (815, 900, 1000, and 1100°C) to find the optimum synthesis temperature. Finally, the hydraulic activity of NF was verified and the contribution to mechanical properties was determined by replacing cement with NF at various substitution levels (0, 5, 10, and 20 wt%). Test results showed that the optimum condition for the synthesis of NF was found when the ratio of CaCO3/red mud was 1.5 and the sintering temperature was 815°C. The synthesized NF had an average diameter of 300 nm, and the main composition was brownmillerite (C4AF) with distinct hydraulic reaction. When NF was used as a substitute of Portland cement in mortar, the flexural strength with a 5% replacement level improved by 15%. Therefore, it can be concluded that the synthesis of NF provides an alternative approach to recycle red mud and could significantly help in reducing environmental pollution.
Effect of Flexibility Ratio on Seismic Response of Cut‐and‐Cover Box Tunnel
Authors: Sadiq Shamsher , van Nguyen Quang , Jung Hyunil , Park Duhee
Published: July 2019

Equivalent linear time history analyses are conducted to calculate the seismic response of various types of cut‐and‐cover single box tunnels. A finite‐element numerical model is calibrated against the results of centrifuge tests. The calculated tunnel responses compare favourably with the measurements. A validated model is then used to quantify the seismic response of box tunnels. The flexibility ratio (F) is illustrated to have a governing influence on the tunnel response. It is shown that the previously developed relationship between F and the racking ratio (R) is applicable for a wide range of F up to 20. It is also shown that an increase in F accompanies corresponding increase in R, the spectral acceleration in the tunnel lining, and the shear stress along the tunnel lining‐soil interface. The thrust in the tunnel lining is also revealed to increase with F, although the calculated value is significantly lower than the pressure on yielding walls. Additionally, the surface settlement is shown to increase with an increase in F.
Danzhi Jiangtang Capsule Mediates NIT-1 Insulinoma Cell Proliferation and Apoptosis by GLP-1/Akt Signaling Pathway
Authors: Wu Yuan-Jie , Wu Yuan-Bo , Fang Zhao-Hui , Chen Mei-Qiao , Wang Yu-Feng , Wu Chuan-Yun , Lv Ming-An
Published: July 2019

Objective. This study aimed to investigate the effects of Danzhi Jiangtang Capsule (DJC) on the proliferation and apoptosis functions of NIT-1 pancreatic β-cells exposed to high-glucose load through GLP-1 activated Akt/ FoxO1 signaling pathway. Methods. Cellular apoptosis of NIT-1 pancreatic β-cells was induced by culturing in medium with 33.3mmol/L high glucose (HG). Then low-dose DJC (HG +LD), high-dose DJC (HG +HD), high-dose DJC+ GLP-1 inhibition (HG +HD +GI), and high-dose DJC+AKT inhibition (HG +HD+AI) were added, respectively. Cellular proliferation was accessed by cell counting kit (CCK-8) and cellular apoptosis was measured by Annexin V-FITC/PI staining. The protein levels of phosphorylated phosphatidylinositol-3-kinase (p-PI3K), phosphorylated AKT (p-AKT), phosphorylated Forkhead box protein O1 (p-FoxO1), and cleaved caspase-3 were detected by Western blotting. The mRNA expression of pancreatic duodenal homeobox-1 (PDX-1), CyclinD1, Bcl-2, and insulin was tested by Q-PCR. Results. Comparing to HG group, (HG+HD) group showed a significantly increased cellular proliferation. The apoptosis of NIT-1 cells also was obviously reduced, with downregulated cleaved caspase-3 protein level and upregulated PDX-1, CyclinD1, and Bcl-2 mRNA levels (P<0.05). Additionally, (HG+HD) group manifested increased insulin mRNA expression; the protein levels of p-PI3K and p-AKT were markedly increased and p-FoxO1 was decreased. All of the above therapeutic effects by DJC intervention had been reversed by GLP-1 inhibition in (HG+HD+GI) group or AKT inhibition in (HG+HD+AI) group. Conclusion. DJC was able to attenuate the toxicity of high-glucose load in NIT-1 pancreatic β-cells, ascribed to the improvement of cellular proliferation and apoptosis by GLP-1/Akt signaling pathway. This study could supply a new mechanism of DJC effects on type 2 diabetes mellitus (T2DM) treatment.
A Gradient‐Based Interior‐Point Method to Solve the Many‐to‐Many Assignment Problems
Authors: Das Nitish , Priya P. Aruna
Published: July 2019

The many‐to‐many assignment problem (MMAP) is a recent topic of study in the field of combinatorial optimization. In this paper, a gradient‐based interior‐point method is proposed to solve MMAP. It is a deterministic method which assures an optimal solution. In this approach, the relaxation of the constraints is performed initially using the cardinality constraint detection operation. Then, the logarithmic barrier function (LBF) based gradient descent approach is executed to reach an accurate solution. Experiments have been performed to validate the practical implementation of the proposed algorithm. It also illustrates a significant improvement in convergence speed for the large MMAPs (i.e., if group size, α ≥ 80) over state‐of‐the‐art literature.
Nymphaea lotusLinn. (Nymphaeaceae) Alleviates Sexual Disability in L-NAME Hypertensive Male Rats
Authors: Kameni Poumeni Mireille , Dzeufiet Djomeni Paul Desire , Bilanda Danielle Claude , Mballa Marguerite Francine , Mengue Ngadena Yolande Sandrine , Tchoupou Tchinda Huguette , Ouafo Agnes Carolle , Ngoungoure Madeleine Chantal , Dimo Theophile , Kamtchouing Pierre
Published: July 2019

Hypertension (HT) is a risk factor for erectile dysfunction (ED). This study aimed to evaluate the suppressive effect ofNymphaea lotus(N. lotus) on erectile dysfunction induced by NO deficiency in rat. 40 male rats equally divided into 4 groups received an oral treatment with 10 mg/kg/day of L-NAME, a NO blocker, during 4 weeks. Control group composed of 10 male rats received only distilled water (10 mL/kg). Thereafter oral treatments withN. lotus(75 and 200 mg/kg/day) and losartan (10 mg/kg/day) started and continued concomitantly with L-NAME in 3 groups for 4 additional weeks. Normal and negative controls received only distilled water. Sexual behaviour, orientation activities, anxiety, and penile histomorphology were evaluated at the end of treatment. L-NAME administration elevated significantly the blood pressure in male rats and decreased the copulatory rate by enhancing intromission latency and decreasing the numbers of intromission and ejaculation. However, the sexual motivation remains unaltered by chronic NO blockage suggesting that L-NAME induces penile dysfunction mainly by peripheral mechanisms. L-NAME chronic intake also induced anxiety, 4 weeks ofN. lotuscotreatment prevented inhibitory effects of L-NAME on male sexual behaviour by shortening mainly ejaculation latency and postejaculatory interval while losartan does not. Losartan proved to be a more effective drug to decrease the blood pressure compared to the plant extract. Effectively,Nymphea lotuswas able to reverse totally at 75 mg/kg the increment of hemodynamic parameters and the histological damage and exhibit anxiolytic-like effects in hypertensive male rats.Nymphaea lotususes NO pathway to facilitate sexual responses at central and peripheral levels and can have a double medicinal use, against anxiety and erectile dysfunction.
A Systematic Review and Meta-Analysis on Microsurgical Safety and Efficacy of Profunda Artery Perforator Flap in Breast Reconstruction
Authors: Qian Bei , Xiong Lingyun , Li Jialun , Sun Yang , Sun Jiaming , Guo Nengqiang , Wang Zhenxing
Published: July 2019

Background. The profunda artery perforator (PAP) flap was first applied in breast reconstruction in 2010 by Robert J. Allen. It provided an alternative for autologous breast reconstruction in addition to traditional donor sites. Currently, literature reporting its microsurgical safety and efficacy is relatively sparse and heterogeneous. Objective. To clarify the evidence regarding microsurgical safety and efficacy of PAP flap in breast reconstruction, which may contribute to future surgical decision-making. Methods. Multiple databases were systematically searched by two independent reviewers. The result was statistically analyzed with Meta command of R GUI 3.5.1. The proportions with 95% confidence intervals (CIs) were calculated by using random-effect model. Results. There were 12 studies including 516 PAP flaps meeting the inclusion criteria. The pooled surgical success rate was 99% (95% CI: 97%–100%) and overall rate of complications was 23% (95% CI: 18%–27%). The most common individual complication was wound dehiscence with incidence of 6% (95% CI: 4%–9%). The seroma rate was 2% (95%CI: 0%–6%). The hematoma rate was 1% (95% CI: 0%–2%). The partial necrosis rate was 2% (95% CI: 0%–5%). The rate of total flap loss was 1% (95% CI: 0%–3%). Conclusion. To date, this study is the first meta-analysis of microsurgical efficacy and safety evaluation of the PAP flap in breast reconstruction. This present work confirmed that the PAP flap is safe and reliable in breast reconstruction with high success rate, but a relatively low complication rate. Moreover, it might be more than an alternative to the deep inferior epigastric perforator flap (DIEP) in microsurgical breast reconstruction in selected patients.
Numerical Simulation of Dynamic Damage and Stability of a Bedding Rock Slope under Blasting Load
Authors: Chen Yekai , Xu Junhao , Huo Xiaohui , Wang Jinchang
Published: July 2019

Blasting excavation of a bedding rock slope is a common problem in highway construction in mountainous areas. Accurate simulation of damage area caused by blasting excavation is of great significance for the subsequent maintenance of slopes. Based on a highway construction project in Guangdong province of China, a tensile and compressive damage model was used to simulate the whole process of blasting excavation of a typical bedding rock slope. The analysis results show that damage first appears just around the blasting hole and then develops to the both sides and the bottom of the blasting hole, and finally a large range of damage appears in the lower part of the blasting hole, and the damage depth on the right‐side slope is around 2 m, which is in consistent with the scene. Besides, damage also occurs in the middle of the bedding rock mass of the slope. At the same time, the history analysis of vibration velocity also indicates that tensile failure appears on the right‐side slope under the blasting hole. Therefore, the stability of the slope can be assessed by analyzing the distribution of damage factors and the vibration velocity characteristics synthetically. In addition, parameter analysis was also carried out to optimize the blasting design by controlling the blasting load so as to obtain the ideal blasting excavation effect and ensure the stability of the slope under blasting load.
Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer
Authors: Shang Stephen , Yang Jiekun , Jazaeri Amir A. , Duval Alexander James , Tufan Turan , Lopes Fischer Natasha , Benamar Mouadh , Guessous Fadila , Lee Inyoung , Campbell Robert M. , Ebert Philip J. , Abbas Tarek , Landen Charles N. , Difeo Analisa , Scacheri Peter C. , Adli Mazhar
Published: July 2019

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers.

Significance:

Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.
Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia
Authors: Hosseini Mohsen , Rezvani Hamid Reza , Aroua Nesrine , Bosc Claudie , Farge Thomas , Saland Estelle , Guyonnet-Dupérat Véronique , Zaghdoudi Sonia , Jarrou Latifa , Larrue Clément , Sabatier Marie , Mouchel Pierre Luc , Gotanègre Mathilde , Piechaczyk Marc , Bossis Guillaume , Récher Christian , Sarry Jean-Emmanuel
Published: July 2019

Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance.

Significance:

These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.
Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States
Authors: Mahal Brandon A. , Catalano Paul J. , Haddad Robert I. , Hanna Glenn J. , Kass Jason I. , Schoenfeld Jonathan D. , Tishler Roy B. , Margalit Danielle N.
Published: July 2019

Background:

Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed.

Methods:

The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and “other pharynx”), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality.

Results:

From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51–4.73] versus 1.82 (95% CI, 1.75–1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58–0.66) versus 1.38 (95% CI, 1.32–1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P < 0.001], but not non-OPSCC (aHR, 1.08; P = 0.81), Pinteraction = 0.002.

Conclusions:

The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx.

Impact:

This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.
Urinary Metabolites Diagnostic and Prognostic of Intrahepatic Cholangiocarcinoma
Authors: Haznadar Majda , Diehl Christopher M. , Parker Amelia L. , Krausz Kristopher W. , Bowman Elise D. , Rabibhadana Siritida , Forgues Marshonna , Bhudhisawasdi Vajarabhongsa , Gonzalez Frank J. , Mahidol Chulabhorn , Budhu Anuradha , Wang Xin W. , Ruchirawat Mathuros , Harris Curtis C.
Published: July 2019

Background:

Liver cancer is the second leading cause of cancer-related deaths worldwide. With a predicted 2.4-fold rise in liver cancer incidence by 2020, there is an urgent need for early, inexpensive diagnostic biomarkers to deploy in the clinic.

Methods:

We employed ultraperformance liquid chromatography tandem mass-spectrometry (UPLC/MS-MS) for the quantitation of four metabolites, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and a lipid molecule designated as 561+, in urine samples from the NCI-MD cohort comprising 98 hepatocellular carcinoma (HCC) cases, 101 high-risk subjects, and 95 controls. Validation was carried out in the TIGER-LC cohort [n = 370 HCC and intrahepatic cholangiocarcinoma (ICC) cases, 471 high-risk subjects, 251 controls], where ICC, the second most common primary hepatic malignancy, is highly prevalent. Metabolite quantitation was also conducted in TIGER-LC tissue samples (n = 48 ICC; n = 51 HCC).

Results:

All profiled metabolites were significantly increased in liver cancer when compared with high-risk subjects and controls in the NCI-MD study. In the TIGER-LC cohort, the four-metabolite profile was superior at classifying ICC than a clinically utilized marker, CA19-9, and their combination led to a significantly improved model (AUC = 0.88, P = 4E-8). Metabolites CR and NANA were significantly elevated in ICC when compared with HCC cases in both urine and tissue samples. High levels of CR were associated with poorer prognosis in ICC.

Conclusions:

Four metabolites are significantly increased in HCC and ICC and are robust at classifying ICC in combination with the clinically utilized marker CA19-9.

Impact:

Noninvasive urinary metabolite biomarkers hold promise for diagnostic and prognostic evaluation of ICC.
Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab
Authors: Hamid Omid , Molinero Luciana , Bolen Christopher R. , Sosman Jeffrey A. , Muñoz-Couselo Eva , Kluger Harriet M. , McDermott David F. , Powderly John D. , Sarkar Indrani , Ballinger Marcus , Fassò Marcella , O'Hear Carol , Chen Daniel S. , Hegde Priti S. , Hodi F. Stephen
Published: July 2019

Purpose:

Atezolizumab [anti–programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842).

Patients and Methods:

Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored.

Results:

Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35–not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9–66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival.

Conclusions:

Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.
The Covalent CDK7 Inhibitor THZ1 Potently Induces Apoptosis in Multiple Myeloma Cells In Vitro and In Vivo
Authors: Zhang Yu , Zhou Liang , Bandyopadhyay Dipankar , Sharma Kanika , Allen Alexander Joseph , Kmieciak Maciej , Grant Steven
Published: July 2019

Purpose:

The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models.

Experimental Design:

Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model.

Results:

THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2–M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138−/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation.

Conclusions:

THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.
Circulating Tumor Cell Clusters in Patients with Metastatic Breast Cancer: a SWOG S0500 Translational Medicine Study
Authors: Paoletti Costanza , Miao Jieling , Dolce Emily M. , Darga Elizabeth P. , Repollet Madeline I. , Doyle Gerald V. , Gralow Julie R. , Hortobagyi Gabriel N. , Smerage Jeffrey B. , Barlow William E. , Hayes Daniel F.
Published: July 2019

Purpose:

Metastasis requires malignant cell circulation from the primary to a distant tissue. Elevated levels of circulating tumor cells (CTC) portend a poor prognosis in breast and other cancers. Recent studies have suggested that CTC clusters may be a factor in the metastatic process. We conducted a prospective retrospective study of the SWOG0500 clinical trial to test whether CTC clusters are associated with poorer prognosis.

Experimental Design:

CTC CellSearch galleries from SWOG0500 trial were reread using prespecified criteria for CTC clusters, doublets, and enumeration. Survival analysis methods include Kaplan–Meier plots and log-rank tests.

Results:

Patients were classified into three prognostic subgroups based on baseline CTC/7.5 mL whole blood (WB): Arm A: <5CTC; Arm B/C: ≥5CTC and then B (<5CTC) and C (≥5CTC)/7.5 mL WB at first follow-up. At baseline, 19% of patients had CTC doublets or clusters, which were more likely in Arm B/C versus Arm A (38% vs. 1.4%; P < 0.0001). Furthermore, doublets or clusters were significantly more common in patients who were ultimately assigned to Arm C versus B (54% vs. 25%; P < 0.0001). In Arm C, doublets and clusters were associated with worse overall survival than only doublets, clusters, or no doublets nor clusters at baseline (P = 0.008) and first follow-up (P = 0.010). When compared with enumeration alone, doublets, clusters, or both were not prognostic in patients who had 5–19 or ≥20 CTC/7.5 mL WB.

Conclusions:

In patients with metastatic breast cancer starting first-line chemotherapy, mortality is independent of the presence of CTC clusters, but rather depends on the number of CTC/7.5 mL WB.
Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity
Authors: Dagogo-Jack Ibiayi , Rooney Marguerite , Lin Jessica J. , Nagy Rebecca J. , Yeap Beow Y. , Hubbeling Harper , Chin Emily , Ackil Jennifer , Farago Anna F. , Hata Aaron N. , Lennerz Jochen K. , Gainor Justin F. , Lanman Richard B. , Shaw Alice T.
Published: July 2019

Purpose:

Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.

Experimental Design:

We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.

Results:

By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with ≥2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new ALK mutations on lorlatinib.

Conclusions:

ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.
NAFLD-Associated Comorbidities in Advanced Stage HCC Do Not Alter the Safety and Efficacy of Yttrium-90 Radioembolization
Authors: Schotten Clemens , Bechmann Lars P. , Manka Paul , Theysohn Jens , Dechêne Alexander , El Fouly Amr , Barbato Francesco , Neumann Ursula , Radünz Sonia , Sydor Svenja , Heider Dominik , Venerito Marino , Canbay Ali , Gerken Guido , Herrmann Ken , Wedemeyer Heiner , Best Jan
Published: July 2019

Background: Patients with advanced hepatocellular carcinoma (HCC) arising in nonalcoholic fatty liver disease (NAFLD) may not be suitable for systemic therapy due to metabolic syndrome-related diseases. Recent trials did not show a survival benefit of radioembolization (RE) compared to sorafenib in advanced stage HCC but RE may represent an adequate alternative in patients with contraindications to systemic therapy due to its favorable safety profile. Aim: To investigate the impact of NAFLD-related comorbidities on safety and efficacy of RE for HCC treatment in a retrospective monocentric cohort study. Patients and Methods: Safety and efficacy of RE were evaluated in patients with NAFLD-associated HCC. Hepatitis B virus (HBV)-related HCC patients served as controls, exhibiting matching Barcelona Liver Cancer Clinic (BCLC) stages while showing significantly fewer metabolic comorbidities. Results: Overall, 87 HCC patients with NAFLD (mean age 71.3 ± 6.9 years) and 62 HCC patients with HBV (mean age 58.8 ± 10.9 years) not amenable to surgical or conventional locoregional treatments were included. Patients with HBV-related HCC had a comparable liver function to HCC patients with NAFLD. RE treatment-related toxicity did not differ between the two groups (increase in bilirubin Common Terminology Criteria for Adverse Events grade in 29 [38.7%] NAFLD and 20 [39.2%] HBV patients, p = 0.91). Overall survival was similar in HCC patients with NAFLD and HBV (11.1 [interquartile range, IQR, 18.27] vs. 9.3 months [IQR 14.73], p = 0.38), also in the subgroup analyses of BCLC B and C stages. Conclusion: RE showed similar survival outcomes at a comparable toxicity profile in HCC patients with NAFLD and HBV. NAFLD-associated metabolic comorbidities did not exhibit limitations for RE while offering comparable therapeutic efficacy as compared to HBV patients.
Nanomembrane-Based Therapeutic Plasmapheresis after Non-Invasive Ventilation Failure for Treatment of a Patient with Acute Respiratory Distress Syndrome and Myasthenia Gravis: A Case Report
Authors: Yamakova Yordanka , Ilieva Viktoria Asenova , Petkov Rosen , Yankov Georgi
Published: July 2019

Acute respiratory distress syndrome (ARDS) is characterized by a widespread inflammation of the lungs, causing severe hypoxemia. Several mediators have been associated with it and almost all of them are small enough to be filtrated through a nanomembrane. We present a case report of a 41-year-old man with myasthenia gravis in remission; he developed ARDS caused by pneumonia. Although he performed well on both non-invasive and invasive mechanical ventilation, his oxygenation continued to deteriorate. As a last resort of treatment, we decided to apply nanomembrane-based apheresis to cleanse his plasma from the harmful inflammatory mediators. After 3 sessions of plasmapheresis, his condition improved and he was successfully weaned from mechanical ventilation. The obtained results gave us ground to assume that the removal of bioactive molecules can be a useful adjunct to protective mechanical ventilation in ARDS.
Aldosterone Induces Vascular Damage
Authors: Hung Chi-Sheng , Sung Shih-Hsien , Liao Che-Wei , Pan Chien-Ting , Chang Chin-Chen , Chen Zheng-Wei , Wu Vin-Cent , Chen Chen-Huan , Cheng Hao-Min , Lin Yen-Hung ,   TAIPAI Study Group
Published: July 2019

Primary aldosteronism (PA) is hemodynamically independently associated with arterial wall stiffness as assessed by pulse wave velocity (PWV) compared with essential hypertension. Arterial wave reflection parameters derived from pulse wave analysis, such as forward and backward wave amplitudes (Pf and Pb), are promising vascular markers to predict cardiovascular outcomes in addition to PWV. These vascular parameters have never been studied in patients with PA before. In study part A, we prospectively enrolled 67 patients with PA and 132 patients with essential hypertension. In study part B, another 54 patients with PA were enrolled. Heart-carotid PWV was measured, and carotid pressure waveforms were recorded to calculate Pf, Pb, and augmentation index at baseline (part A and B) and 6 months after treatment (part B). The results showed that the patients with PA had significantly higher Pf (
P
=0.001), Pb (
P
=0.01), and PWV (
P
=0.021) than the patients with essential hypertension. In univariate correlation analysis, both log Pf and Pb were significantly correlated with age, office blood pressure, serum potassium level, log PWV, and the presence of PA. However, only Pb was significantly correlated with log plasma renin activity and log aldosterone to renin ratio. In multivariate analysis, log Pf was significantly correlated with the presence of PA (
P
=0.001), male sex, age, and mean arterial blood pressure. Pb was significantly correlated with the presence of PA (
P
=0.031), age, and mean arterial pressure. Six months after treatment, Pf and Pb decreased significantly. In conclusion, the patients with PA had significantly increased wave reflections compared with the patients with essential hypertension. Our results provide clinical evidence of aldosterone-related extensive vascular dysfunction of the arterial system.