bluuebunny/crossref_metadata_2025 huggingface dataset:
Vagally‐mediated HRV as a marker of trait rumination in healthy individuals? A large cross‐sectional analysis
Authors: Li Zefeng , Pulopulos Matias , Allaert Jens , De Smet Stefanie , De Wandel Linde , Kappen Mitchel , Puttevils Louise , Razza Lais B. , Schoonjans Emmanuelle , Vanhollebeke Gert , Baeken Chris , De Raedt Rudi , Vanderhasselt Marie‐Anne
Published: October 2023

The tendency to ruminate (i.e., repetitive, self‐referential, negative thoughts) is a maladaptive form of emotional regulation and represents a transdiagnostic vulnerability factor for stress‐related psychopathology. Vagally‐mediated heart rate variability (vmHRV) provides a non‐invasive, surrogate measure of vagal modulation of the heart, and higher HRV is considered an indicator of susceptibility, or ability to respond to stress. Past research has suggested a link between trait rumination and vmHRV; however, inconsistent results exist in healthy individuals. In this study, we investigated the association between the tendency to ruminate, brooding, and reflection (using the Ruminative Response Scale) with vmHRV measured at baseline in a healthy population using a large cross‐sectional dataset (N = 1189, 88% female; mean age = 21.55, ranging from 17 to 48 years old), which was obtained by combining samples of healthy individuals from different studies from our laboratory. The results showed no cross‐sectional correlation between vmHRV and trait rumination (confirmed by Bayesian analysis), even after controlling for important confounders such as gender, age, and depressive symptoms. Also, a non‐linear relationship was rejected. In summary, based on our results in a large sample of healthy individuals, vmHRV is not a marker of trait rumination (as measured by the Ruminative Response Scale).
Facing the human capital crisis: A systematic review and research agenda on recruitment and selection in the public sector
Authors: Jakobsen Mette , Løkke Ann‐Kristina , Keppeler Florian
Published: October 2023

As a human capital crisis poses urgent challenges across multiple countries, public administration scholars and practitioners are concerned with recruitment and selection questions. Literature evolves with an increasing pace whereby clarity over the state‐of‐the‐art and gaps in recruitment and selection research in the public sector is needed to direct future research and practice. We conducted a review of 59 studies to systematize and reorient research on recruitment and selection. Summarizing the state‐of‐the‐art, we identify a strong focus on individual‐level research of attraction, revealing several blind spots of research on other levels and process stages of hiring. Based on the synthesis of existing knowledge, we provide a research agenda that extends the predominant focus on attraction. By bridging public administration concepts with generic recruitment and selection research, the agenda aims at advancing the research on hiring in the public sector, offering a framework for levels, concepts/theories, processes, and key variables.
Interactive word walls for 3D learning: Visually representing the NGSS in elementary science methods courses
Authors: Reinhart Meredith
Published: October 2023

Even though the Next Generation Science Standards (NGSS) were released over a decade ago, science is still infrequently taught in early childhood and elementary classrooms. A lack of teacher confidence due to inadequate content knowledge may be a contributing factor, making access to high‐quality elementary science methods courses even more imperative. This article highlights preservice elementary teachers’ use of an interactive word wall, an instructional strategy that explicitly documented their experiences with disciplinary core ideas, scientific and engineering practices, and crosscutting concepts. Students enrolled in four undergraduate elementary science methods sections participated in the creation, implementation, and evaluation of their classroom's interactive word wall. Through written assignments, classroom discussions, and photographic documentation, students helped to identify seven benefits of using this strategy while collaboratively building their interactive word walls. This article describes the process of setting up the word walls, the students’ choices during the construction of the walls, and their reflections on the benefits and challenges associated with using an interactive word wall at the university level. This article provides teacher educators with a strategy to strengthen students’ understanding of the NGSS framework and encourages preservice teachers to reflect upon how to use this strategy in their future classrooms.
Non-operative management of high-grade splenic injury: a systematic review protocol
Authors: Nann Silas , Clarke Molly , Jog Shivangi , Aromataris Edoardo
Published: October 2023

Objective:

The objective of this review is to establish whether embolization is more effective than clinical observation for adult patients with grade III–V splenic injuries. The findings will be used to guide future practice and, if necessary, inform future research design and conduct.

Introduction:

The spleen is one of the most frequently injured intra-abdominal organs, with a reported adult mortality of 7% to 18% following trauma. Non-operative management has become a standard of care for hemodynamically stable patients. In clinical practice, the decision whether to prophylactically embolize or manage high-grade injuries with observation alone remains controversial.

Inclusion criteria:

Sources including adult patients with grade III–V splenic injuries secondary to blunt trauma will be included in this review. Eligible studies must include comparisons between 2 cohorts of patients undergoing either prophylactic embolization or clinical observation only. Outcomes will include mortality rate, failure of treatment, intensive care unit admission, length of hospital stay, blood transfusion requirements, and patient satisfaction.

Methods:

A systematic review with meta-analysis will be conducted. PubMed, Embase, and CINAHL will be searched for eligible studies, as will trial registries and sources of gray literature. Study selection, quality appraisal, and data extraction of outcomes will be performed in duplicate. Methodological quality will be evaluated using JBI critical appraisal tools. Studies will, where possible, be pooled in statistical meta-analysis. A random effects model will be used and statistical analysis will be performed. The certainty of the findings will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Review registration:

PROSPERO CRD42023420220
Capacidad dinámica de innovación en las empresas: un análisis bibliométrico
Authors: Penagos Guzmán Fernando , García Solarte Mónica , Hernández Castorena Octavio
Published: October 2023

En este artículo se presentan los resultados de un estudio bibliométrico descriptivo dirigido a identificar investigaciones publicadas entre 2018 y marzo del 2023, disponibles en la base de datos Scopus, relacionadas con el tema de capacidad dinámica de innovación. El propósito fue realizar un análisis bibliométrico como parte del proyecto de investigación denominado “Habilidades gerenciales, capacidad dinámica de innovación y desempeño organizacional de las Mipymes del departamento del Caquetá”. Se analizaron diversos documentos con elementos de búsqueda a partir de palabras clave, áreas de conocimiento, países, autores y años de publicación con un análisis de datos y análisis de coocurrencia usando la herramienta VOS Viewer. Los resultados sugieren un amplio campo de estudio y publicación sobre la temática de capacidad dinámica de innovación, aplicada con mayor fuerza en áreas negocios, gestión y contabilidad. Estas publicaciones han aumentado durante los años de selección para el desarrollo del análisis bibliométrico, en países como China, Estados Unidos, Reino Unido, y países latinoamericanos como Colombia, México, Argentina, Chile, Ecuador y Perú.
Discomfort estimation for aircraft cabin noise using linear regression and modified psychoacoustic annoyance approaches
Authors: Huang Yu , Lv Bingcong , Ni Ke , Jiang Weikang
Published: October 2023

Appropriate sound quality models for noise-induced discomfort are necessary for a better acoustic comfort design in the aircraft cabin. This study investigates the acoustic discomfort in two large passenger aeroplanes (i.e., planes A and B). We recorded the noise at 21 positions in each aircraft cabin and selected 42 stimuli ranging from 72 to 81 dB(A) during the cruising flights. Twenty-four participants rated the noise discomfort by the absolute magnitude estimation method. The discomfort values in the middle section of the aircraft cabin are 10% points higher than in the front or rear section. The discomfort magnitude was dominated by loudness and influenced by roughness and sharpness. A multiple linear (MA) discomfort model was established, accounting for the relationship between the discomfort and sound quality metrics (i.e., loudness, sharpness, and roughness). The MA model estimated noise discomfort better than the Zwicker and other (i.e., More and Di) psychoacoustic annoyance (PA) models. We modified the coefficients of independent variables in the formulations of Zwicker, Di, and More PA models, respectively, according to the present experimental results. The correlation coefficients between the estimated and measured values of the modified models were at least 20% points higher than the original ones.
A simple model for the spatial correlation of turbulence-induced pressures
Authors: Shepherd Micah R.
Published: October 2023

The Reflections series takes a look back on historical articles from The Journal of the Acoustical Society of America that have had a significant impact on the science and practice of acoustics.
Sound and sturgeon: Bioacoustics and anthropogenic sound
Authors: Popper Arthur N. , Calfee Robin D.
Published: October 2023

Sturgeons are basal bony fishes, most species of which are considered threatened and/or endangered. Like all fishes, sturgeons use hearing to learn about their environment and perhaps communicate with conspecifics, as in mating. Thus, anything that impacts the ability of sturgeon to hear biologically important sounds could impact fitness and survival of individuals and populations. There is growing concern that the sounds produced by human activities (anthropogenic sound), such as from shipping, commercial barge navigation on rivers, offshore windfarms, and oil and gas exploration, could impact hearing by aquatic organisms. Thus, it is critical to understand how sturgeon hear, what they hear, and how they use sound. Such data are needed to set regulatory criteria for anthropogenic sound to protect these animals. However, very little is known about sturgeon behavioral responses to sound and their use of sound. To help understand the issues related to sturgeon and anthropogenic sound, this review first examines what is known about sturgeon bioacoustics. It then considers the potential effects of anthropogenic sound on sturgeon and, finally identifies areas of research that could substantially improve knowledge of sturgeon bioacoustics and effects of anthropogenic sound. Filling these gaps will help regulators establish appropriate protection for sturgeon.
A multiscale residual U-net architecture for super-resolution ultrasonic phased array imaging from full matrix capture data
Authors: Liu Lishuai , Liu Wen , Teng Da , Xiang Yanxun , Xuan Fu-Zhen
Published: October 2023

Ultrasonic phased array imaging using full-matrix capture (FMC) has raised great interest among various communities, including the nondestructive testing community, as it makes full use of the echo space to provide preferable visualization performance of inhomogeneities. The conventional way of FMC data postprocessing for imaging is through beamforming approaches, such as delay-and-sum, which suffers from limited imaging resolution and contrast-to-noise ratio. To tackle these difficulties, we propose a deep learning (DL)-based image forming approach, termed FMC-Net, to reconstruct high-quality ultrasonic images directly from FMC data. Benefitting from the remarkable capability of DL to approximate nonlinear mapping, the developed FMC-Net automatically models the underlying nonlinear wave-matter interactions; thus, it is trained end-to-end to link the FMC data to the spatial distribution of the acoustic scattering coefficient of the inspected object. Specifically, the FMC-Net is an encoder-decoder architecture composed of multiscale residual modules that make local perception at different scales for the transmitter-receiver pair combinations in the FMC data. We numerically and experimentally compared the DL imaging results to the total focusing method and wavenumber algorithm and demonstrated that the proposed FMC-Net remarkably outperforms conventional methods in terms of exceeding resolution limit and visualizing subwavelength defects. It is expected that the proposed DL approach can benefit a variety of ultrasonic array imaging applications.
Data-driven rheological characterization of stress buildup and relaxation in thermal greases
Authors: Nagrani Pranay P. , Kulkarni Ritwik V. , Kelkar Parth U. , Corder Ria D. , Erk Kendra A. , Marconnet Amy M. , Christov Ivan C.
Published: October 2023

Thermal greases, often used as thermal interface materials, are complex paste-like mixtures composed of a base polymer in which dense metallic (or ceramic) filler particles are dispersed to improve the heat transfer properties of the material. They have complex rheological properties that impact the performance of the thermal interface material over its lifetime. We perform rheological experiments on thermal greases and observe both stress relaxation and stress buildup regimes. This time-dependent rheological behavior of such complex fluid-like materials is not captured by steady shear-thinning models often used to describe these materials. We find that thixo-elasto-visco-plastic (TEVP) and nonlinear-elasto-visco-plastic (NEVP) constitutive models characterize the observed stress relaxation and buildup regimes, respectively. Specifically, we use the models within a data-driven approach based on physics-informed neural networks (PINNs). PINNs are used to solve the inverse problem of determining the rheological model parameters from the dynamic response in experiments. These training data are generated by startup flow experiments at different (constant) shear rates using a shear rheometer. We validate the “learned” models by comparing their predicted shear stress evolution to experiments under shear rates not used in the training datasets. We further validate the learned TEVP model by solving a forward problem numerically to determine the shear stress evolution for an input step-strain profile. Meanwhile, the NEVP model is further validated by comparison to a steady Herschel–Bulkley fit of the material’s flow curve.
Search for Signs of Sublimation-Driven Dust Activity of Primitive-Type Asteroids Near Perihelion
Authors: Busarev V. V. , Petrova E. V. , Shcherbina M. P. , Kuznetsov S. Yu. , Burlak M. A. , Ikonnikova N. P. , Savelova A. A. , Belinskii A. A.
Published: October 2023

Abstract—

In December 2021 to February 2022, the UBVRI photometry of 29 primitive-type asteroids of the Main Belt, being near the perihelion distances, was carried out at the 0.6-meter RC600 semiautomatic telescope of the Caucasus Mountain Observatory (CMO) of the Sternberg Astronomical Institute, Moscow State University. These observations, as well as the data processing and analysis, were aimed at searching for supposed sublimation-driven dust activity on asteroids under maximal subsolar temperatures. Among the tasks to be accomplished was the comparison of the physical and dynamic parameters of active and inactive asteroids. The main result is that substantial spectral signs of quasi-simultaneous sublimation-driven dust activity were detected on six primitive-type asteroids of the Main Belt—145 Adeona, 302 Clarissa, 322 Phaeo, 435 Ella, 690 Wratislavia, and 779 Nina (on 302 Clarissa, 322 Phaeo, 435 Ella, and 690 Wratislavia—for the first time). These six asteroids represent ~21% of all bodies included in the observation program. Probable spectral manifestations of activity at a lower intensity level were detected for the first time on five more asteroids—424 Gratia, 751 Faina, 762 Pulcova, 778 Theobalda, and 859 Bouzaréah. On 145 Adeona and 779 Nina, sublimation-driven dust activity near perihelion was registered for the third time for the last ten years; this time interval corresponds to about three orbital periods of these asteroids around the Sun. We consider the circumstances due to which five of the listed asteroids possess families. General processes and conditions that could and/or can influence the portion of primitive-type asteroids that quasi-simultaneously show signs of sublimation-driven dust activity are discussed.
Higher-derivative quantum gravity with purely virtual particles: renormalizability and unitarity
Authors: Piva Marco
Published: October 2023

We review the formulation of quantum field theories with purely virtual particles, a new type of degrees of freedom that can mediate interactions without ever appear as external on-shell states. This property allows to solve the problem of ghosts in higher-derivative quantum gravity, leading to a renormalizable and unitary theory. The main steps for the BRST quantization of gravity are recalled and renormalizability is discussed. Then, we introduce purely virtual particles in a general quantum field theory and show the derivation of the so-called spectral identities, which are a key ingredient to prove unitarity. Finally, phenomenological consequences and predictions in inflationary cosmology are presented.
Efficient Task-driven Video Data Privacy Protection for Smart Camera Surveillance System
Authors: Wang Zhiqiang , Hou Jiahui , Wu Guangyu , Liu Suyuan , Luo Puhan , Li Xiangyang
Published: October 2023

As one of the most commonly used AIoT sensors, smart cameras and their supporting services, namely cloud video surveillance (CVS) systems, have brought great convenience to people’s lives. Recent CVS providers use different machine learning techniques to improve their services (regarded as tasks) based on the uploaded video. However, uploading data to the CVS providers may cause severe privacy issues. Existing works that remove privacy information could not achieve a high tradeoff between data usability and privacy, because the importance of information varies with the task. In addition, it is challenging to design a real-time privacy protection mechanism, especially in resource-constrained smart cameras. In this work, we design a task-driven and efficient video privacy protection mechanism for a better tradeoff between privacy and data usability. We use Class Activation Mapping to protect privacy while preserving data usability. To improve the efficiency, we utilize the motion vector and residual matrix produced during video codec. Our work outperforms the region of interest–based methods in data protection while preserving data usability. The attack accuracy drops 70%, while the task accuracy is comparable to those without protection (within ± 4%). The average protection frame rate of the High Definition video can exceed 16 fps+ even on a CPU.
NIR-Prompt: A Multi-task Generalized Neural Information Retrieval Training Framework
Authors: Xu Shicheng , Pang Liang , Shen Huawei , Cheng Xueqi
Published: October 2023

Information retrieval aims to find information that meets users’ needs from the corpus. Different needs correspond to different IR tasks such as document retrieval, open-domain question answering, retrieval-based dialogue, and so on, while they share the same schema to estimate the relationship between texts. It indicates that a good IR model can generalize to different tasks and domains. However, previous studies indicate that state-of-the-art neural information retrieval (NIR) models, e.g., pre-trained language models (PLMs) are hard to generalize. It is mainly because the end-to-end fine-tuning paradigm makes the model overemphasize task-specific signals and domain biases but loses the ability to capture generalized essential signals. To address this problem, we propose a novel NIR training framework named NIR-Prompt for retrieval and reranking stages based on the idea of decoupling signal capturing and combination. NIR-Prompt exploits Essential Matching Module (EMM) to capture the essential matching signals and gets the description of tasks by Matching Description Module (MDM). The description is used as task-adaptation information to combine the essential matching signals to adapt to different tasks. Experiments under in-domain multi-task, out-of-domain multi-task, and new task adaptation settings show that NIR-Prompt can improve the generalization of PLMs in NIR for both retrieval and reranking stages compared with baselines.
Synchronised Shared Memory and Model Checking
Authors: Aguado Joaquín , Duenas Alejandra
Published: October 2023

In this article, a formal generic framework for defining and reasoning about deterministic concurrency in synchronous systems is implemented in the
Spin
model checker. Concretely, the work implements the
clock-synchronised shared memory
(
csm
) theory, which extends synchronous programming with more and higher-level
csm
 data types. These
csm
 data types are equipped with a synchronisation
policy
prescribing how concurrent calls to objects methods must be organised. In a policy constructive system, all methods of every object can be scheduled in a policy-conformant manner without deadlocking. In our framework, synchronous policies get codified as
Promela
never-claims. In this form, the model checker can search for executions (interleavings) that satisfy the synchronous product of all the never-claims, namely policy-conformant schedules for all the
csm
 objects. The existence of such policy-conformant schedules verifies that the concurrent synchronous system is deterministic. The approach of this article extends beyond a single semantics since it can handle the synchronous programming model as well as the various forms of the sequentially constructive model found in the literature.
GHZ distillation protocols in the presence of decoherence
Authors: de Bone S´ebastian , Elkouss David
Published: October 2023

In this paper, we introduce a novel heuristic approach designed to optimize the performance of Greenberger-Horne- Zeilinger (GHZ) creation and distillation protocols under decoherence. Our methodology converts these protocols into a practical set of instructions, demonstrating, through simulations, the production of higher-quality GHZ states than previously known protocols. This advancement contributes to the field of distributed quantum computing by addressing the need for high-quality entanglement required for operations between different quantum computers.
Cobalt-H3BTC Metal Organic Framework-Based Electrochemical Nanosensor for Hydrogen Peroxide
Authors: Hesari Mahdi , Jia Rui , Wu Shu , Mirkin Michael V.
Published: October 2023

Metal organic frameworks (MOFs) have found diverse applications in electrocatalysis and electrochemical sensing, owing to the presence of both metallic nodes and organic networks. Here, we electrosynthesized cobalt benzene tricarboxylate MOF inside an open carbon nanopipette (CNP) to produce a CNP-CoMOF nanoelectrode whose response is determined by Co(II)/Co(III) nodes attached to its porous nanostructure. Steady-state voltammograms of ferrocenemethanol at CNP-CoMOF nanoelectrodes exhibit a sigmoidal shape with a well-defined plateau current. A linear calibration curve obtained for the hydrogen peroxide oxidation suggests that CNP–CoMOF nanoelectrodes are potentially useful as nanosensors for peroxide free from interference of dissolved dioxygen.
Python for Electrochemistry: A Free and All-In-One Toolset
Authors: Zheng Weiran
Published: October 2023

Python, an open-source, interpreted programming language, has emerged as a transformative force within the scientific community, captivating researchers with its rich ecosystem of packages and syntax that prioritizes readability and simplicity. In the rapidly evolving field of electrochemistry, where the analysis of complex data sets, custom analysis routines, and theoretical simulations are indispensable, Python’s capabilities have garnered significant attention. This review serves as a general introduction to the utilization of Python in electrochemistry, focusing on beginners who are new to programming concepts.
The methylome of buccal epithelial cells is influenced by age, sex, and physiological properties
Authors: Protti Giulia , Rubbi Liudmilla , Gören Tarik , Sabirli Ramazan , Civlan Serkan , Kurt Özgür , Türkçüer İbrahim , Köseler Aylin , Pellegrini Matteo
Published: October 2023

We have developed a quantitative model to assess how the human methylome is associated with several factors and to identify the genomic loci significantly impacted by each trait. We reported novel health-related factors driving DNA methylation patterns and new site-specific regulations that further elucidate methylome dynamics. Our study contributes to a better understanding of the plasticity of the human methylome and unveils novel physiological traits with a potential role in future medical epigenomic investigations.
Data from Intraperitoneal paclitaxel is a safe and effective therapeutic strategy for treating mucinous appendiceal adenocarcinoma
Authors: Ito Ichiaki , Yousef Abdelrahman M.G. , Chowdhury Saikat , Dickson Princess N. , Naini Zahra Alavi. , White Michael G. , Fleten Karianne Giller. , Flatmark Kjersti , Fournier Keith F. , Fowlkes Natalie W. , Shen John Paul.
Published: October 2023

Abstract
Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy of paclitaxel given by IP administration using three orthotopic patient-derived xenograft (PDX) models of AA established in immunodeficient NSG mice. Weekly IP paclitaxel treatment dramatically reduced AA tumor growth in all three PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration, IP delivery of paclitaxel was more effective with reduced systemic side effects in mice. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.
Data from Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity
Authors: Smith Alison E. , Chan Stacia , Wang Zhiyong , McCloskey Asako , Reilly Quinn , Wang Jayden Z. , Patel Hetika Vora. , Koshizuka Keiichi , Soifer Harris S. , Kessler Linda , Dayoub Ashley , Villaflor Victoria , Adkins Douglas R. , Bruce Justine Y. , Ho Alan L. , Perez Cesar A. , Hanna Glenn J. , Gasco Hernandez Amaya , Saunders Andrew , Dale Stephen , Gutkind J. Silvio , Burrows Francis , Malik Shivani
Published: October 2023

Abstract
Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. Based on these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.
Data from Galectin-1 mediates chronic STING activation in tumors to promote metastasis through MDSC recruitment
Authors: Nambiar Dhanya K. , Viswanathan Vignesh , Cao Hongbin , Zhang Weiruo , Guan Li , Chamoli Manish , Holmes Brittany , Kong Christina , Hildebrand Rachel , Koong Amanda Jeanette. , von Eyben Rie , Plevritis Sylvia , Li Lingyin , Giaccia Amato , Engleman Edgar , Le Quynh-Thu
Published: October 2023

Abstract
The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral Galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a pre-metastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from pre-metastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the pre-metastatic compartment. Gal1 promoted MDSC accumulation in the pre-metastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing STING protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected pro-tumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous positive regulator of STING in advanced-stage cancers.
Data from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment
Authors: Nambiar Dhanya K. , Viswanathan Vignesh , Cao Hongbin , Zhang Weiruo , Guan Li , Chamoli Manish , Holmes Brittany , Kong Christina , Hildebrand Rachel , Koong Amanda Jeanette , von Eyben Rie , Plevritis Sylvia , Li Lingyin , Giaccia Amato , Engleman Edgar , Le Quynh Thu
Published: October 2023

Abstract
The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers.
Significance:
Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.
The NCI-60 Human Tumor Cell Line Screen: A Catalyst for Progressive Evolution of Models for Discovery and Development of Cancer Drugs
Authors: Workman Paul
Published: October 2023

Following three decades of systematic primary empirical screening against mice bearing two transplantable murine leukemias, the NCI took the bold step of switching to a radically different approach—initial screening of 10,000 diverse compounds/year against a panel of 60 human tumor cell lines in vitro. The establishment of the “NCI-60” screen was announced in the landmark Cancer Research article by Alley and colleagues, published in 1988, which exemplified the technological basis for the new microculture screen, operating at unprecedented scale. The underlying concept was that NCI-60 might expedite the discovery of innovative cancer drugs, especially those with predicted activity against particular solid cancers—not then possible. We discuss how NCI-60 provided a major technological advance and delivered a successful legacy for cancer research and development. While not immediately cracking the thorny problem of model-to-human tumor type prediction, NCI-60 nevertheless provided the conceptual and methodologic foundation for subsequent, much larger-scale human cancer cell panel screens with detailed molecular annotation and sophisticated informatics. Now used in modern molecular target–based drug discovery, these panels help enable the implementation of contemporary biomarker-led precision oncology.

See related article by Alley and colleagues, Cancer Res 1988;48:589–601
Data from A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder
Authors: Li Roger , Sexton Wade J. , Dhillon Jasreman , Berglund Anders , Naidu Shreyas , Borjas Gustavo , Rose Kyle , Kim Youngchul , Wang Xuefeng , Conejo-Garcia Jose R. , Jain Rohit K. , Poch Michael A. , Spiess Philippe E. , Pow-Sang Julio , Gilbert Scott M. , Zhang Jingsong
Published: October 2023

Abstract
Purpose: Immune checkpoint blockade holds promise for treating BCG-unresponsive non-muscle invasive bladder cancer. In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive CIS. Patients and Methods: Patients with BCG-unresponsive CIS containing non-muscle invasive bladder cancer received durvalumab IV at 1500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response rate at month 6, defined by negative cystoscopy, urine cytology and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a complete response rate of 18% and alternative hypothesis 40%. According to the Simon 2-stage design, if ≤3/13 patients achieved complete response during stage 1, the trial is stopped due to futility. Results: Between 03/8/2017 and 1/24/2020, 17 patients were accrued while 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. 2 of 17 (12%) achieved a complete response at month 6, with duration of response of 10 and 18 months, respectively. A single Grade 3 lipase elevation was attributed to durvalumab, and immune related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high PD-L1 expression pre-treatment. On RNAseq, complement activation genes were elevated post-treatment, along with enrichment of tumor associated macrophage signature. Conclusions: Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6mo complete response of 12%. Complement activation is a potential mechanism behind treatment resistance.
Data from ILUSTRO: Phase 2 Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Klempner Samuel J. , Lee Keun-Wook , Shitara Kohei , Metges Jean-Phillippe , Lonardi Sara , Ilson David H. , Fazio Nicola , Kim Tae Yong , Bai Li-Yuan , Moran Diarmuid , Yang Jianning , Arozullah Ahsan , Park Jung Wook , Raizer Jeffrey J. , Bang Yung-Jue , Shah Manish A.
Published: October 2023

Abstract
Background: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive human epidermal growth factor receptor 2–negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients and methods: This phase 2 study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n=30), with mFOLFOX6 in first-line (Cohort 2, n=21), or with pembrolizumab in third/later-line (Cohort 3A, n=3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). Results: ORR was 0% in Cohorts 1A and 3A, and 71.4% (95% CI, 47.82–88.72) in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31–2.56) in Cohort 1A, 2.96 months (95% CI, 1.48–4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05–25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27–11.53). Gastrointestinal adverse events occurred across cohorts (nausea, 63%–90% [grade ≥3, 4.8%–6.7%] and vomiting, 33%–67% [grade ≥3, 6.7%–9.5%]). Conclusions: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2 positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.
Data from ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2–Positive Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Klempner Samuel J. , Lee Keun-Wook , Shitara Kohei , Metges Jean-Phillippe , Lonardi Sara , Ilson David H. , Fazio Nicola , Kim Tae Yong , Bai Li-Yuan , Moran Diarmuid , Yang Jianning , Arozullah Ahsan , Park Jung Wook , Raizer Jeffrey J. , Bang Yung-Jue , Shah Manish A.
Published: October 2023

AbstractPurpose:
Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma.
Patients and Methods:
This phase II study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n = 30), with mFOLFOX6 in first-line (Cohort 2, n = 21), or with pembrolizumab in third/later-line (Cohort 3A, n = 3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts).
Results:
ORR was 0% in Cohorts 1A and 3A, and 71.4% [95% confidence interval (CI), 47.82–88.72] in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31–2.56) in Cohort 1A, 2.96 months (95% CI, 1.48–4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05–25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27–11.53). Gastrointestinal adverse events occurred across cohorts [nausea, 63%–90% (grade ≥ 3, 4.8%–6.7%) and vomiting, 33%–67% (grade ≥ 3, 6.7%–9.5%)].
Conclusions:
Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2-positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.
Data from Learning Individual Survival Models from PanCancer Whole Transcriptome Data
Authors: Kumar Neeraj , Skubleny Daniel , Parkes Michael , Verma Ruchika , Davis Sacha , Kumar Luke , Aissiou Amira , Greiner Russell
Published: October 2023

AbstractPurpose:
Personalized medicine attempts to predict survival time for each patient, based on their individual tumor molecular profile. We investigate whether our survival learner in combination with a dimension reduction method can produce useful survival estimates for a variety of patients with cancer.
Experimental Design:
This article provides a method that learns a model for predicting the survival time for individual patients with cancer from the PanCancer Atlas: given the (16,335 dimensional) gene expression profiles from 10,173 patients, each having one of 33 cancers, this method uses unsupervised nonnegative matrix factorization (NMF) to reexpress the gene expression data for each patient in terms of 100 learned NMF factors. It then feeds these 100 factors into the Multi-Task Logistic Regression (MTLR) learner to produce cancer-specific models for each of 20 cancers (with >50 uncensored instances); this produces “individual survival distributions” (ISD), which provide survival probabilities at each future time for each individual patient, which provides a patient's risk score and estimated survival time.
Results:
Our NMF-MTLR concordance indices outperformed the VAECox benchmark by 14.9% overall. We achieved optimal survival prediction using pan-cancer NMF in combination with cancer-specific MTLR models. We provide biological interpretation of the NMF model and clinical implications of ISDs for prognosis and therapeutic response prediction.
Conclusions:
NMF-MTLR provides many benefits over other models: superior model discrimination, superior calibration, meaningful survival time estimates, and accurate probabilistic estimates of survival over time for each individual patient. We advocate for the adoption of these cancer survival models in clinical and research settings.
Data from Liquid biopsies with circulating plasma HPV–DNA measurements – a clinically applicable surveillance tool for HPV-positive oropharyngeal cancer patients
Authors: Jakobsen Kathrine K. , Bendtsen Simone K. , Pallisgaard Niels , Friborg Jeppe , Lelkaitis Giedrius , Grønhøj Christian , von Buchwald Christian
Published: October 2023

Abstract
Purpose: To evaluate the accuracy of cell-free human papillomavirus-DNA (cfHPV-DNA) measurements in liquid biopsies in predicting disease in HPV+/p16+ oropharyngeal squamous cell carcinoma (OPSCC) patients. Experimental Design: This is a prospective cohort study. Plasma samples were collected before treatment, and serially after curative intended therapy at follow-up visits 2 weeks, and 6, 9, 12, 18, 24, and 30 months after treatment. A Droplet Digital (dd)PCR assay comprising eight HPV genotypes was used. HPV genotypes found in plasma and tumour tissue were compared. We correlated biopsy- or imaging-verified tumour progression to cfHPV-DNA in follow-up samples. Results: We enrolled 72 HPV+/p16+ OPSCC patients. Baseline sensitivity for cfHPV-DNA detection was 97.2% (95% CI 90.3%–99.6). CfHPV-DNA copy number/millilitre plasma correlated with tumour stage. We found a 100% concordance between HPV genotype in tumour tissue and plasma. Fifty-four patients were followed with serial blood samples for a median of 19.7 months (Interquartile Range: 13.5–25.5 months). Forty-one patients had undetectable plasma cfHPV-DNA in all follow-up samples, and none developed recurrences. Thirteen patients were classified as cfHPV-DNA positive in a follow-up plasma sample. Of these, five patients developed a recurrence, and three had residual cancer. It was possible to detect cfHPV-DNA in plasma 97–166 days prior to the proven recurrence. Conclusion: Our study, comprising the largest study of HPV+/p16+ OPSCC patients, using an ultrasensitive multiplex HPV gene panel, revealed a high sensitivity of cfHPV-DNA detection in the liquid biopsies. We recommend serial plasma HPV samples for clinical monitoring of HPV+/p16+ OPSCC patients.
Data from Liquid Biopsies with Circulating Plasma HPV–DNA Measurements—A Clinically Applicable Surveillance Tool for Patients with HPV-Positive Oropharyngeal Cancer
Authors: Jakobsen Kathrine K. , Bendtsen Simone K. , Pallisgaard Niels , Friborg Jeppe , Lelkaitis Giedrius , Grønhøj Christian , von Buchwald Christian
Published: October 2023

AbstractPurpose:
To evaluate the accuracy of cell-free human papillomavirus-DNA (cfHPV-DNA) measurements in liquid biopsies in predicting disease in patients with HPV-positive/p16-positive (HPV+/p16+) oropharyngeal squamous cell carcinoma (OPSCC).
Experimental Design:
This was a prospective cohort study. Plasma samples were collected before treatment, serially after curative intended therapy at follow-up visits 2 weeks, and 6, 9, 12, 18, 24, and 30 months after treatment. A droplet digital PCR assay comprising eight HPV genotypes was used. HPV genotypes found in plasma and tumor tissue were compared. We correlated biopsy- or imaging-verified tumor progression to cfHPV-DNA in follow-up samples.
Results:
We enrolled 72 patients with HPV+/p16+ OPSCC. Baseline sensitivity for cfHPV-DNA detection was 97.2% (95% confidence interval, 90.3%–99.6%). CfHPV-DNA copy number/milliliter plasma correlated with tumor stage. We found a 100% concordance between HPV genotype in tumor tissue and plasma. Fifty-four patients were followed with serial blood samples for a median of 19.7 months (interquartile range, 13.5–25.5 months). Forty-one patients had undetectable plasma cfHPV-DNA in all follow-up samples, and none developed recurrences. Thirteen patients were classified as cfHPV-DNA–positive in a follow-up plasma sample. Of these, five patients developed a recurrence, and three had residual cancer. It was possible to detect cfHPV-DNA in plasma 97 to 166 days prior to the proven recurrence.
Conclusions:
To our knowledge, to date, our study, comprising the largest study of patients with HPV+/p16+ OPSCC, using an ultrasensitive multiplex HPV gene panel, revealed a high sensitivity of cfHPV-DNA detection in the liquid biopsies. We recommend serial plasma HPV samples for clinical monitoring of patients with HPV+/p16+ OPSCC.