bluuebunny/crossref_metadata_2025 huggingface dataset:
Yarrpbox: Detecting Middleboxes at Internet-Scale
Authors: Hilal Fahad , Gasser Oliver
Published: July 2023

The end-to-end principle is one of the foundations of the original Internet architecture. This principle is put to the test by middleboxes, i.e., devices which change important parts of a packet in transit. Middleboxes can have beneficial effects, such as a lower handshake time, but also make it more difficult to deploy newly developed protocols, such as TLS 1.3 and QUIC. Therefore, it is important to have a good understanding of the middlebox ecosystem in the Internet.

In this paper, we present results from a multi-faceted middlebox analysis study. We develop Yarrpbox, a tool to efficiently perform middlebox detection measurements on an Internet-scale. With Yarrpbox, we perform IPv4-wide middlebox detection and find that nearly 10% of paths are affected by a total of 5.8k middlebox devices. We perform the first IPv6 study to date, uncovering a lower prevalence of middleboxes in IPv6. Moreover, we show that the location of a vantage point can have an effect on the results, leading to up to 600 more detected middleboxes. Additionally, we characterize middleboxes by mapping them to vendors and resolving aliases. Finally, we release Yarrpbox as open-source software and make data and analysis code publicly available.
The Need for Unsupervised Outlier Model Selection: A Review and Evaluation of Internal Evaluation Strategies
Authors: Ma Martin Q. , Zhao Yue , Zhang Xiaorong , Akoglu Leman
Published: July 2023

Given an unsupervised outlier detection task, how should one select i) a detection algorithm, and ii) associated hyperparameter values (jointly called a model)? E ective outlier model selection is essential as di erent algorithms may work well for varying detection tasks, and moreover their performance can be quite sensitive to the values of the hyperparameters (HPs). On the other hand, unsupervised model selection is notoriously difficult, in the absence of hold-out validation data with ground-truth labels. Therefore, the problem is vastly understudied in the outlier mining literature. There exists a body of work that propose internal model evaluation strate- gies for selecting a model. These so-called internal strategies solely rely on the input data (without labels) and the output (outlier scores) of the candidate models. In this paper, we rst survey internal model evaluation strategies including both those proposed speci cally for outlier detection, as well as those that can be adapted from the unsupervised deep representation learning literature. Then, we investigate their e ectiveness empirically in comparison to simple baselines such as random selection and the popular state-of-the-art detector Isolation Forest (iForest) with default HPs. To this end, we set up (and open-source) a large testbed with 39 detection tasks and 297 candidate models comprised of 8 different detectors and various HP con gurations. We evaluate internal strategies from 7 di erent families on their ability to discriminate between models w.r.t. detection performance, without using any labels. Our study reports a striking nding, that none of the existing and adapted strategies would be practically useful: stand-alone ones are not signi cantly di erent from random, and consensus-based ones do not outperform iForest (w/ default HPs) while being more expensive (as all candidate models need to be trained for evaluation). Our survey stresses the importance of and the standing need for e ective unsupervised outlier model selection, and acts as a call for future work on the problem.
Framework for SQL Error Message Design: A Data-Driven Approach
Authors: Taipalus Toni , Grahn Hilkka
Published: July 2023

Software developers use a significant amount of time reading and interpreting error messages. However, error messages have often been based on either anecdotal evidence or expert opinion, disregarding novices, who arguably are the ones who benefit the most from effective error messages. Furthermore, the usability aspects of Structured Query Language (SQL) error messages have not received much scientific attention. In this mixed-methods study, we coded a total of 128 error messages from eight database management systems (DBMS), and using data from 311 participants, analysed 4,796 queries using regression analysis to find out if and how acknowledged error message qualities explain SQL syntax error fixing success rates. Additionally, we performed a conventional content analysis on 1,505 suggestions on how to improve SQL error messages, and based on the analysis, formulated a framework consisting of nine guidelines for SQL error message design. The results indicate that general error message qualities do not necessarily explain query fixing success in the context of SQL syntax errors and that even some novel NewSQL systems fail to account for basic error message design guidelines. The error message design framework and examples of its practical applications shown in this study are applicable in educational contexts as well as by DBMS vendors in understanding novice perspectives in error message design.
AutoDLAR: A Semi-supervised Cross-modal Contact-free Human Activity Recognition System
Authors: Lu Xinxin , Wang Lei , Lin Chi , Fan Xin , Han Bin , Han Xin , Qin Zhenquan
Published: July 2023

WiFi-based human activity recognition (HAR) plays an essential role in various applications such as security surveillance, health monitoring, and smart home. Existing HAR methods, though yielding promising performance in indoor scenarios, highly depend on a massive
labeled
dataset for training which is extremely difficult to acquire in practical applications. In this paper, we present an automatic data labeling and HAR system, termed AutoDLAR. Taking a semi-supervised cross-modal learning framework with a hybrid loss function as the core, AutoDLAR transfers rich visual information to
automatically label
WiFi signals for WiFi-based HAR. Specifically, we devise a lightweight and multi-view WiFi sensing model with a parallel feature embedding method to accurately identify activities and accelerate recognition speed. Then, we exploit the video data to fine-tune a well-established visual HAR model, generating effective pseudo-labels for guiding the WiFi model’s training. We also build a synchronized Video-WiFi dataset with seven types of human activities under different scenarios to enable training and validating the semi-supervised HAR system. Extensive experiments on our collected activity dataset and the emotion recognition benchmark demonstrate that AutoDLAR attains an average accuracy of over 95.89% without manual labeling and only spends the inference time of 3.35 ms, outperforming the state-of-the-art (SOTA) methods.
ITiCSE 2023 Preview
Authors: Laakso Mikko-Jussi , Monga Mattia
Published: July 2023

The 28th annual ACM Conference on Innovation and Technology in Computer Science Education (ITiCSE) will take place in Turku, Finland, hosted by Turku University.
Galactic Dynamos
Authors: Brandenburg Axel , Ntormousi Evangelia
Published: July 2023

Spiral galaxies, including the Milky Way, have large-scale magnetic fields with significant energy densities. The dominant theory attributes these magnetic fields to a large-scale dynamo. We review the current status of dynamo theory and discuss various numerical simulations designed either to explain particular aspects of the problem or to reproduce galactic magnetic fields globally. Our main conclusions can be summarized as follows:
▪Idealized direct numerical simulations produce mean magnetic fields, whose saturation energy density tends to decline with increasing magnetic Reynolds number. This is still an unsolved problem.▪Large-scale galactic magnetic fields of microgauss strengths can probably be explained only if helical magnetic fields of small or moderate length scales can be rapidly ejected or destroyed.▪Small-scale dynamos are important throughout a galaxy's life and probably provide strong seed fields at early stages.▪The circumgalactic medium (CGM) may play an important role in driving dynamo action at small and large length scales. These interactions between the galactic disk and the CGM may provide important insights into our understanding of galactic dynamos.
We expect future research in galactic dynamos to focus on the cosmological history of galaxies and the interaction with the CGM as means of replacing the idealized boundary conditions used in earlier work.
The Portfolio of Economic Policies Needed to Fight Climate Change
Authors: Blanchard Olivier , Gollier Christian , Tirole Jean
Published: July 2023

Climate change poses an existential threat. Theoretical and empirical research suggest that carbon pricing and green R&D support are the right tools, but their implementation can be improved. Other policies, such as standards, bans, and targeted subsidies, also all have a role to play, but they have often been incoherent, and their implementation is delicate.
The Origin of Metazoan Multicellularity: A Potential Microbial Black Swan Event
Authors: Ruiz-Trillo Iñaki , Kin Koryu , Casacuberta Elena
Published: July 2023

The emergence of animals from their unicellular ancestors is a major evolutionary event. Thanks to the study of diverse close unicellular relatives of animals, we now have a better grasp of what the unicellular ancestor of animals was like. However, it is unclear how that unicellular ancestor of animals became the first animals. To explain this transition, two popular theories, the choanoblastaea and the synzoospore, have been proposed. We will revise and expose the flaws in these two theories while showing that, due to the limits of our current knowledge, the origin of animals is a biological black swan event. As such, the origin of animals defies retrospective explanations. Therefore, we should be extra careful not to fall for confirmation biases based on few data and, instead, embrace this uncertainty and be open to alternative scenarios. With the aim to broaden the potential explanations on how animals emerged, we here propose two novel and alternative scenarios. In any case, to find the answer to how animals evolved, additional data will be required, as will the hunt for microscopic creatures that are closely related to animals but have not yet been sampled and studied.
Candida auris Genetics and Emergence
Authors: Chowdhary Anuradha , Jain Kusum , Chauhan Neeraj
Published: July 2023

Candida auris is a multidrug-resistant fungal pathogen that presents a serious threat to global human health. Since the first reported case in 2009 in Japan, C. auris infections have been reported in more than 40 countries, with mortality rates between 30% and 60%. In addition, C. auris has the potential to cause outbreaks in health care settings, especially in nursing homes for elderly patients, owing to its efficient transmission via skin-to-skin contact. Most importantly, C. auris is the first fungal pathogen to show pronounced and sometimes untreatable clinical drug resistance to all known antifungal classes, including azoles, amphotericin B, and echinocandins. In this review, we explore the causes of the rapid spread of C. auris. We also highlight its genome organization and drug resistance mechanisms and propose future research directions that should be undertaken to curb the spread of this multidrug-resistant pathogen.
Mechanisms of Virulence Reprogramming in Bacterial Pathogens
Authors: Zhou Jianuan , Ma Hongmei , Zhang Lianhui
Published: July 2023

Bacteria are single-celled organisms that carry a comparatively small set of genetic information, typically consisting of a few thousand genes that can be selectively activated or repressed in an energy-efficient manner and transcribed to encode various biological functions in accordance with environmental changes. Research over the last few decades has uncovered various ingenious molecular mechanisms that allow bacterial pathogens to sense and respond to different environmental cues or signals to activate or suppress the expression of specific genes in order to suppress host defenses and establish infections. In the setting of infection, pathogenic bacteria have evolved various intelligent mechanisms to reprogram their virulence to adapt to environmental changes and maintain a dominant advantage over host and microbial competitors in new niches. This review summarizes the bacterial virulence programming mechanisms that enable pathogens to switch from acute to chronic infection, from local to systemic infection, and from infection to colonization. It also discusses the implications of these findings for the development of new strategies to combat bacterial infections.
Cross-Kingdom Interactions Between Plant and Fungal Viruses
Authors: Andika Ida Bagus , Tian Mengyuan , Bian Ruiling , Cao Xinran , Luo Ming , Kondo Hideki , Sun Liying
Published: July 2023

The large genetic and structural divergences between plants and fungi may hinder the transmission of viruses between these two kingdoms to some extent. However, recent accumulating evidence from virus phylogenetic analyses and the discovery of naturally occurring virus cross-infection suggest the occurrence of past and current transmissions of viruses between plants and plant-associated fungi. Moreover, artificial virus inoculation experiments showed that diverse plant viruses can multiply in fungi and vice versa. Thus, virus cross-infection between plants and fungi may play an important role in the spread, emergence, and evolution of both plant and fungal viruses and facilitate the interaction between them. In this review, we summarize current knowledge related to cross-kingdom virus infection in plants and fungi and further discuss the relevance of this new virological topic in the context of understanding virus spread and transmission in nature as well as developing control strategies for crop plant diseases.
Effects of Bromide Ions in Anomalous Codeposition of Ni-Co Alloys with a Sulfamate Based Electrolyte
Authors: Jiang Yiming , Chen Chun-Yi , Kurioka Tomoyuki , Luo Xun , Yamane Daisuke , Sone Masato , Chang Tso-Fu Mark
Published: July 2023

Alloy electrodeposition of Ni-Co alloys is known to show an anomalous codeposition behavior, which the concentration of cobalt in the deposited alloy is higher than the concentration of cobalt ions in the electrolyte. In this study, the cobalt content in the alloy is increased from 30 at% to 60 at% through introduction of bromide ions into a sulfamate bath, while addition of chloride ions does not give any significant influences to the alloy. The bromide ions are found to promote the reduction of cobalt ions but inhibit the reduction of nickel ions. Effects of the pH are also investigated to provide possible explanation to the phenomenon observed, and the anomalous codeposition behavior becomes more obvious in a more acidic electrolyte.
Reaction of Oxygen with Uranium (IV) Chloride in Fused Alkali Chlorides
Authors: Volkovich V. A. , Ryzhov A. A.
Published: July 2023

Reaction of oxygen with solutions of uranium(IV) chloride in fused LiCl and three alkali chloride eutectic mixtures (LiCl–KCl, NaCl–KCl–CsCl, NaCl–CsCl) was investigated at 550–750 °C. Bubbling oxygen or oxygen-containing gas mixtures (O2–H2O, O2–Ar, O2–H2O–Ar) through LiCl–UCl4 melts resulted in significant precipitation of uranium (up to 87%) in the form of oxides and alkali uranates. Increasing mean radius of the solvent melt cations decreased the degree of uranium precipitation and uranyl chloride (soluble in the melt) became the main product of the reaction. High temperature spectroscopy measurements were employed to determine the kinetic parameters of the reaction in LiCl–KCl, NaCl–KCl–CsCl and NaCl–CsCl melts. Reaction rates, order, rate constants and activation energy values were estimated. Increasing temperature led to increased reaction rates but the effect of uranium chloride concentration depended on the cationic melt composition. Oxygen reacts with uranium(IV) containing melts much faster than with the melts containing rare earth chlorides and oxygen sparging can be implemented for separating uranium and rare earth fission products in pyrochemical reprocessing of spent nuclear fuels.
Surviving in an Acidifying Ocean: Acid-Base Physiology and Energetics of the Sea Urchin Larva
Authors: Hu Marian Y. , Stumpp Meike
Published: July 2023

The sea urchin larva has been used by biologists for more than a century to study the development and evolution of animals. Surprisingly, very little information has been generated regarding the physiology of this small planktonic organism. However, in the context of anthropogenic CO2-driven ocean acidification (OA), the membrane transport physiology and energetics of this marine model organism have received considerable attention in the past decade. This has led to the discovery of new, exciting physiological systems, including a highly alkaline digestive tract and the calcifying primary mesenchyme cells that generate the larval skeleton. These physiological systems directly relate to the energetics of the organisms when challenged by OA. Here we review the latest membrane transport physiology and energetics in the sea urchin larva, we identify emerging questions, and we point to important future directions in the field of marine physiology in times of rapid climate change.
Effects of In-Situ Drying–Wetting Cycles on the Stress-Dependent Water Retention Behavior of Intact Loess
Authors: Li X. M. , Di S. J. , Shi L. , Zhang Y. , Huang P. , Mu Q. Y.
Published: July 2023

Understanding the effects of in-situ drying–wetting pattern on the stress-dependent water retention curve of intact loess is vital for addressing geotechnical problems in loess regions. The principal objective of this study is to investigate the influence of in-situ drying–wetting on the stress-dependent water retention behavior of intact loess. To meet this objective, six drying–wetting tests were carried out using a suction- and stress-controlled pressure plate extractor. Intact loess was sampled from three different depths: 1.0, 3.0, and 5.0 m. For specimens from each depth, two vertical net stresses (i.e., 0 and 50 kPa) were applied prior to the drying–wetting cycle. Experimental results revealed that the in-situ drying–wetting pattern greatly affected various aspects of the water retention behavior, particularly the hysteresis. The hysteresis of the specimen from 5.0 m is about 82% and 77% larger than that of the specimens from 1.0 and 3.0 m, respectively. This is because the specimen from 5.0 m has some large-size pores (i.e., >400 μm), which were not found in specimens from 1.0 and 3.0 m. These large-size pores enhance pore nonuniformity and hence the hysteresis. Furthermore, specimens from different depths consistently showed a reduction of hysteresis when the stress was increased from 0 to 50 kPa. The reduction is the most significant for a specimen from 5.0 m due to the collapse of large-size pores under compression.
Petrological Characteristics and Rock Nomenclature of Sedimentary Bauxite Gas Reservoir: A Case Study of Bauxite in Taiyuan Formation of Ordos Basin
Authors: Liu Na , Nan Junxiang , Wang Xingying , Yang Yanning , Yin Peng , Zhang Renyan
Published: July 2023

With the great breakthrough in natural gas exploration of Paleozoic Taiyuan formation in Longdong exploratory area in the southwestern part of Ordos Basin, it is urgent to solve the petrological nomenclature of sedimentary bauxite, so as to further study the pore formation mechanism, distribution law, and controlling factors of bauxite reservoirs. In this paper, X-ray diffraction, polarizing microscope, scanning electron microscope, and other methods are used to analyze the mineral composition and structure of bauxite rocks in the study area and give appropriate names. The results show that the sedimentary sequence of bauxite in the study area can be divided into five sections: A, B, C, D, and E. The main mineral components are diaspore (C section content can be more than 90%), illite, kaolinite, and chlorite; accessory mineral include anatase and pyrite; trace components include quartz, feldspar, rutile, hematite, and rock salt; and some of the pores are filled with calcite, siderite, and (iron) dolomite. The rock structure is mainly bedding and massive structure, and some of them have geopetal structure. The texture mainly consists of granular texture, grain (powder crystal) texture, gel texture, and algal bonding texture. Considering the special lithology of section A~C and the lack of existing nomenclature method, based on mineral composition and sedimentary fabric, a triangulation classification nomenclature method is established, which adopts structure+texture as secondary name and the main mineral components diaspore-mud-pyrite of the three end-member mineral components as primary name. It can not only highlight the mineral assemblage characteristics of sedimentary sequence of bauxite but also reflect the lithologic characteristics of reservoir development section and the influencing factors of reservoir formation, effectively reflecting the petrological characteristics of bauxite reservoir. Among them, the diaspore rocks with granular, bean-oolitic, and grain texture are the main lithologies forming the natural gas reservoir space of Taiyuan formation in Longdong area. The naming method is feasible and reliable for sedimentary bauxite rocks, which lays a good foundation for the study of natural gas reservoir, pore formation mechanism, and distribution law in Longdong area, southwest of the basin.
The Protective Effects of Trametes Versicolor on Arsenic-Induced Male Reproductive Toxicity through Regulation of Oxidative Stress: A Biochemical and Histopathological Survey
Authors: Solaimani Fatemeh , Habibi Emran , Ghasemi Maryam , Mahboubi Saba , Zamani Ehsan , Shaki Fatemeh
Published: July 2023

Exposure to arsenic is linked to a wide range of diseases, in particular male reproductive toxicities. Trametes versicolor is a traditional medicinal fungus with a remarkable potential for antioxidant activity. The purpose of this study was to examine the ameliorating effects of water and methanol extracts of T. versicolor on arsenic-induced male reproductive toxicities via the abrogation of oxidative stress. The mice were divided as follows: control: normal saline, As: arsenic (15 mg/kg), WE: water extract (400 mg/kg), ME: methanol extract (400 mg/kg), As + WE: arsenic (15 mg/kg) + water extract (100, 200, 400 mg/kg), As + ME: arsenic (15 mg/kg) + methanol extract (100, 200, 400 mg/kg), and positive control: arsenic (15 mg/kg) + vitamin C (500 mg/kg). Animals were treated via the intraperitoneal route. About 24 hr later, the mice were euthanized, and oxidative stress parameters (reactive oxygen species [ROS], lipid peroxidation, glutathione concentration, protein carbonylation, glutathione peroxidase, and superoxide dismutase activity), histopathological changes and sperm parameters (count, motility, and morphology) were examined in the testicular tissue. Arsenic caused significant pathological changes in the testicular tissue and sperm morphology and significantly reduced sperm count and motility. Moreover, arsenic mediated oxidative stress via significant increases in ROS generation, lipid peroxidation, and protein carbonyl content, as well as significant depletion in glutathione concentration and superoxide dismutase and glutathione peroxidase activities. Although, coadministration of water and methanol extracts of T. versicolor at 200 and 400 mg/kg counteracted arsenic-induced oxidative and histopathological damages and improved sperm parameters. Our study indicated that T. versicolor ameliorated arsenic-induced testis toxicity and sperm dysfunction via attenuation of oxidative damage.
Traditional Uses, Active Ingredients, and Biological Activities of Paris polyphylla Smith: A Comprehensive Review of an Important Himalayan Medicinal Plant
Authors: Rawat Janhvi Mishra , Pandey Shweta , Rawat Balwant , Rai Nishant , Preeti P. , Thakur Ajay , Butola Jitendra Singh , Bachheti Rakesh Kumar
Published: July 2023

Paris polyphylla Smith (family: Melanthiaceae), a high-value medicinal herb endemic to the Himalayan region, has drawn much attention recently due to its immense use in the traditional healthcare system since ancient times. In the present review, an extensive database on P. polyphylla was systematically searched from databases such as Medline/PubMed, Scopus, the Web of Science, and the online service E-library.ru and SCImago (https://www.scimagojr.com/). Information on species, ecology, distribution, trade, ethnopharmacology, pharmacology, biotechnology, and molecular biology was gathered from 1979 to 2023 using 116 research publications. Major steroidal saponins such as Paris saponin I, V, VI, VII, and H have been found substantially effective in anticancer activity, abnormal uterine bleeding, dysfunctional uterine bleeding, and menorrhagia. Traditional breeding and propagation techniques cannot keep up with the world’s growing demand for herbal drugs. Therefore, it is critically necessary to take conservation measures and develop novel techniques for growing and cultivating this economically significant and highly valuable therapeutic herb. The advanced biotechnological approaches like micropropagation and genetic analysis introduced long back are either rare or lacking in the case of P. polyphylla. It contains a wealth of information that will serve as a baseline data source for various stakeholders, researchers working on various research aspects, and policymakers to define appropriate utilization and conservation plans for a high-value commercial medicinal plant called P. polyphylla. The review provides an updated overview and critical assessment of secondary data regarding the past and recent applications and interventions of P. polyphylla.
A Modified Enucleation and Deflation to Treat Large Ameloblastoma in the Mandible
Authors: Budihardja Andi Setiawan , Lutfianto Bakhrul
Published: July 2023

Objective. Treatment of large ameloblastoma with a conservative method. Case Presentation. Ameloblastomas are benign tumors of odontogenic origin. These tumors are locally invasive with a high recurrence rate. This case report will present a conservative approach to treating large ameloblastoma in the mandible using modified enucleation and deflation technique. The patient presents with a recurrence of large unicystic ameloblastoma. The following patient is treated with the two-stage enucleation and deflation technique. One-year post-treatment follow-up shows satisfactory healing, with good bone regeneration in the defected area, showing no signs of recurrence. Conclusion. The technique that will be discussed in this case report provides an alternative treatment for ameloblastomas of the mandible. This approach can avoid radical operative procedures, such as jaw resection and bone reconstruction.
A Safety Huddle Intervention in In-Patient Surgical Units: A Mixed-Methods Study
Authors: Lee Seung Eun , Dahinten V. Susan , Kim Eunkyung , Lee Sang Hwa , Han Soo Young , Kim Phill Ja , Kim Jung Yeon
Published: July 2023

Open communication about patient safety concerns is necessary to enable a learning environment where lessons can be learned to improve patient safety, but nurses often hesitate to speak up even in situations where their patients may be at risk. One way to create a safe environment for speaking up is through the use of unit-level daily huddles. This study aimed to assess the effects of a 12-week huddle intervention on nine unit, nurse and patient care outcomes and describe nurses’ experiences with the intervention. We used a single group, pre- and post-test mixed-methods design, with a dominant quantitative thread, and a final sample of 89 staff nurses. The intervention was conducted in four surgical units in a tertiary teaching hospital in Seoul, Korea. The intervention included two educational workshops for huddle leaders, two workshops for staff nurses, and 12-week huddles with coaching visits. We collected quantitative data on nine outcomes using online surveys before and after the intervention and qualitative data on nurse experiences of the intervention after the intervention. Paired t-tests were used for quantitative data analysis, and content analysis was used for qualitative data. We examined four unit-level outcomes (organizational learning, situation monitoring, mutual support, and speaking-up climate), three nurse-level outcomes (promotive and prohibitive voice behaviors and job satisfaction), and two patient care outcomes (patient safety and quality of care). Significant improvements were found in six of the nine outcomes. Findings from the qualitative data confirmed the benefits of the intervention but also identified challenges to huddle participation. Patient safety huddles can contribute to a learning environment by flattening hierarchies and encouraging nurses to speak up regarding safety issues. Leadership is a key in role modelling and creating the foundation for a more collaborative patient safety culture in healthcare organizations, for example, through the use of daily huddles.
Data from MEN1 Degradation Induced by Neddylation and the CUL4B–DCAF7 Axis Promotes Pancreatic Neuroendocrine Tumor Progression
Authors: Xu Junfeng , Ye Zeng , Zhuo Qifeng , Gao Heli , Qin Yi , Lou Xin , Zhang Wuhu , Wang Fei , Wang Yan , Jing Desheng , Fan Guixiong , Zhang Yue , Chen Xuemin , Chen Jie , Xu Xiaowu , Yu Xianjun , Ji Shunrong
Published: July 2023

Abstract
Pancreatic neuroendocrine tumors (PanNET) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for patients with PanNET. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 was found in PanNET tissues compared with paired-adjacent tissues and was associated with poor prognosis in patients with PanNET. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacologic mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and to inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B–DCAF7 axis and identifies potential therapeutic targets in patients with MEN1-associated PanNET.
Significance:
Identification of neddylation and ubiquitination pathways that regulate MEN1 protein stability provides an opportunity for therapeutic interventions for treating patients with pancreatic neuroendocrine tumors.
Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer
Authors: Marín Arnaldo , Mamun Abdullah Al , Patel Hima , Akamatsu Hiroaki , Ye Dan , Sudhan Dhivya R. , Eli Lisa , Marcelain Katherine , Brown Benjamin P. , Meiler Jens , Arteaga Carlos L. , Hanker Ariella B.
Published: July 2023

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.

Significance:

HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.
Repurposing Two Old Friends to Fight Cancer: Caffeine and Statins
Authors: Stouth Derek W. , Lebeau Paul F. , Austin Richard C.
Published: July 2023

Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Evidence suggests that certain cancers depend on the mevalonate pathway for growth and survival, and thus blocking the mevalonate pathway with statins may offer a viable therapeutic approach for treating cancer, or at least enhance the efficacy of existing cancer drugs. In this issue of Cancer Research, Tran and colleagues showed that caffeine works jointly with FOXM1 inhibition to enhance the antitumor activity of statins in neuroblastoma cells. They found that caffeine synergizes with statins by suppressing statin-induced feedback activation of the mevalonate pathway. Here, we reflect on the potential of combining caffeine and statin drugs as a strategy for potentiating anticancer activity.

See related article by Tran et al., p. 2248
Uncovering the Role of CD4+ CAR T Cells in Cancer Immunotherapy
Authors: Alizadeh Darya , Wang Dongrui , Brown Christine E.
Published: July 2023

Chimeric antigen receptor (CAR) T-cell therapy has transformed clinical care against blood malignancies and is seeing encouraging progress against solid tumors. While scientific advancement has been rapid, our mechanistic understanding of intrinsic features of CAR-engineered T cells is still evolving. CAR products typically consist of CD4+ and CD8+ T-cell subsets at variable ratios, yet a clear understanding of how each subset contributes together and independently to therapeutic response is lacking. CD8+ CAR T cells are well characterized for their perforin-dependent killing effects; however, the role of CD4+ CAR T cells as “helpers” versus “killers” has been variable across models and warrants more in-depth investigation. A recent study by Boulch and colleagues published in Nature Cancer demonstrates that CD4+ CAR T cells, alone, can exert potent antitumor activity through a mechanism involving IFNγ. CD4+ CAR T-cell production of IFNγ creates a cytokine field that can act at a distance to kill both antigen-positive and -negative tumor cells that are sensitive to the proapoptotic effects of IFNγ. These new findings reveal important insights for the antitumor effects mediated by CD4+ CAR T cells, which could have significant clinical implications.
Supplementary Table 1 from Hepatocellular Carcinoma Surveillance among Individuals with Cirrhosis: Trends by Payer, Etiology, and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010–2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Funk Michele Jonsson , Olshan Andrew F. , Gupta Parul , Barritt A. Sidney , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: July 2023

Supplementary Table 1 includes the validated algorithms and ICD-9-CM and ICD-10-CM codes for cirrhosis, decompensated cirrhosis, and cirrhosis etiologies.
Data from Estimated Ovulatory Years Prior to Menopause and Postmenopausal Endogenous Hormone Levels
Authors: Cramer Daniel W. , Vitonis Allison F. , Huang Tianyi , Shafrir Amy L. , Eliassen A. Heather , Barbieri Robert L. , Hankinson Susan E.
Published: July 2023

AbstractBackground:
Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones.
Methods:
Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses’ Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated.
Results:
Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI.
Conclusions:
This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone.
Impact:
A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.
Data from RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer
Authors: Compadre Amanda J. , van Biljon Lillian N. , Valentine Mark C. , Llop-Guevara Alba , Graham Emily , Fashemi Bisiayo , Herencia-Ropero Andrea , Kotnik Emilee N. , Cooper Isaac , Harrington Shariska P. , Kuroki Lindsay M. , McCourt Carolyn K. , Hagemann Andrea R. , Thaker Premal H. , Mutch David G. , Powell Matthew A. , Sun Lulu , Mosammaparast Nima , Serra Violeta , Zhao Peinan , Lomonosova Elena , Khabele Dineo , Mullen Mary M.
Published: July 2023

AbstractPurpose:
To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples.
Experimental Design:
RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated.
Results:
RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status.
Conclusions:
RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.
Data from An Oncolytic Poxvirus Encoding hNIS, Shows Antitumor Efficacy and Allows Tumor Imaging in a Liver Cancer Model
Authors: Chaurasiya Shyambabu , Valencia Hannah , Zhang Zhifang , Kim Sang-In , Yang Annie , Lu Jianming , Woo Yanghee , Warner Susanne G. , Ede Nicholas J. , Fong Yuman
Published: July 2023

Abstract
Oncolytic viruses (OV) are live viruses that can selectively replicate in cancer cells. We have engineered an OV (CF33) to make it cancer-selective through the deletion of its J2R (thymidine kinase) gene. In addition, this virus has been armed with a reporter gene, human sodium iodide symporter (hNIS), to facilitate noninvasive imaging of tumors using PET. In this study, we evaluated the oncolytic properties of the virus (CF33-hNIS) in liver cancer model, and its usefulness in tumor imaging. The virus was found to efficiently kill liver cancer cells and the virus-mediated cell death exhibited characteristics of immunogenic death based on the analysis of 3 damage-associated molecular patterns: calreticulin, ATP, and high mobility group box-1. Furthermore, local or systemic administration of a single dose of the virus showed antitumor efficacy against a liver cancer xenograft model in mice and significantly increased survival of treated mice. Finally, PET scanning was performed following injection of the radioisotope I-124, for imaging of tumors, and a single dose of virus as low as 1E03 pfu, administered intra-tumorally or intravenously, allowed for PET imaging of tumors. In conclusion, CF33-hNIS is safe and effective in controlling human tumor xenografts in nude mice, and it also facilitates noninvasive imaging of tumors.
Data from Arginase 1/2 inhibitor OATD-02: from discovery to first-in-man setup in cancer immunotherapy
Authors: Borek Bartlomiej , Nowicka Julita , Gzik Anna , Dziegielewski Marek , Jedrzejczak Karol , Brzezinska Joanna , Grzybowski Marcin , Stanczak Paulina , Pomper Paulina , Zagozdzon Agnieszka , Rejczak Tomasz , Matyszewski Krzysztof , Golebiowski Adam , Olczak Jacek , Lisiecki Kamil , Tyszkiewicz Magdalena , Kania Magdalena , Piasecka Sylwia , Cabaj Anna , Dera Paulina , Mulewski Krzysztof , Chrzanowski Jacek , Kusmirek Damian , Sobolewska Elzbieta , Magdycz Marta , Mucha Lukasz , Masnyk Marek , Golab Jakub , Nowotny Marcin , Nowak Elzbieta , Napiorkowska-Gromadzka Agnieszka , Pikul Stanislaw , Jazwiec Radoslaw , Dzwonek Karolina , Dobrzanski Pawel , Meyring Michael , Skowronek Krzysztof , Iwanowski Piotr , Zaslona Zbigniew , Blaszczyk Roman
Published: July 2023

Abstract
Pharmacological inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacological properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed non-clinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in cancer patients.
Data from Selective inhibition of ATM-dependent double-strand break repair and checkpoint control synergistically enhances the efficacy of ATR inhibitors
Authors: Turchick Audrey , Zimmermann Astrid , Chiu Li-Ya , Dahmen Heike , Elenbaas Brian , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T.
Published: July 2023

Abstract
Ataxia Telangiectasia and Rad3-Related Protein (ATR) kinase regulates a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell cycle checkpoints controlled by Ataxia Telangiectasia Mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.
Data from EIF4A3 Acts on the PI3K–AKT–ERK1/2–P70S6K Pathway through FLOT1 to Influence the Development of Lung Adenocarcinoma
Authors: Yu Wenhao , Liang Jinghui , Fang Tao , Jiang Jin , Zhao Renchang , Li Rongyang , Han Jingyi , Tian Hui
Published: July 2023

Abstract
Lung adenocarcinoma (LUAD) is a major lung cancer subtype. In this study, we discovered that the eukaryotic translation initiation factor EIF4A3 expression was significantly higher in LUAD tissues and that this higher expression was closely linked to a poor prognosis for LUAD. In addition, we demonstrated that the knockdown of EIF4A3 significantly inhibited the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. The findings of mass spectrometry analysis revealed that EIF4A3 could interact with Flotillin-1 in LUAD cells and that EIF4A3 could positively regulate the expression of FLOT1 at the protein level. Meanwhile, transcriptome sequencing showed that EIF4A3 could influence the development of LUAD by affecting PI3K–AKT–ERK1/2–P70S6K and PI3K class III–mediated autophagy in the Apelin pathway. In addition, we confirmed that Flotillin-1 expression was upregulated in LUAD based on the existing literature, and knockdown of FLOT1 could inhibit the proliferation and migration of LUAD cells. In addition, the knockdown of Flotillin-1 reversed the increase of cell proliferation and migration caused by EIF4A3 overexpression. Furthermore, we found that the activation of PI3K–AKT–ERK1/2–P70S6K signaling pathway and PI3K class III–mediated autophagy caused by EIF4A3 overexpression was rescued by the knockdown of FLOT1. In a word, we proved that EIF4A3 positively regulates the expression of FLOT1 and plays a procancer role in LUAD.
Implications:
Our study revealed the role of EIF4A3 in prognosis and tumor progression in LUAD, indicating that EIF4A3 could be used as the molecular diagnostic and prognostic therapeutic target.