bluuebunny/crossref_metadata_2025 huggingface dataset:
Including supramaximal verification reduced uncertainty in VO2peak response rate
Authors: Renwick John R.M. , Preobrazenski Nicholas , Giudice Michael D. , Swinton Paul A. , Gurd Brendon J.
Published: August 2023

Many reports describe using a supramaximal verification phase—exercising at a power output higher than the highest power output recorded during an incremental cardiopulmonary test—to validate VO2max. The impact of verification phases on estimating the proportion of individuals who increased VO2peak in response to high-intensity interval training (HIIT) remains an underexplored area in the individual response literature. This analysis investigated the influence of same-day and separate-day verification phases during repeated measurements (incremental tests—INCR1 and INCR2; incremental tests + supramaximal verification phases—INCR1+ and INCR2+) of VO2peak on typical error (TE) and the proportion of individuals classified as responders (i.e., the response rate) following 4 weeks of HIIT ( n = 25) or a no-exercise control period ( n = 9). Incorporation of supramaximal verification consistently reduced the standard deviation of individual response, TE, and confidence interval (CI) widths. However, variances were statistically similar across all groups ( p > 0.05). Response rates increased when incorporating either one (INCR1 to INCR1+; 24%–48%, p = 0.07) or two (INCR2 to INCR2+; 28%–48%, p = 0.063) supramaximal verification phases. However, response rates remained unchanged when either zero-based thresholds or smallest worthwhile difference response thresholds were used (50% and 90% CIs, all p > 0.05). Supramaximal verification phases reduced random variability in VO2peak response to HIIT. Compared with separate-day testing (INCR2 and INCR2+), the incorporation of a same-day verification (INCR1+) reduced CI widths the most. Researchers should consider using a same-day verification phase to reduce uncertainty and better estimate VO2peak response rate to HIIT.
Framework for thaw consolidation of fine-grained soils
Authors: Dumais Simon , Konrad Jean-Marie
Published: August 2023

A framework for thaw consolidation of fine-grained soils is proposed. The development of the framework is based on the general definition of large-strain consolidation and on the general behaviour of soils upon thawing. The residual stress and the residual stress curve are used in the framework to define the initial thawed state. The concept of the residual stress is generalized to ice-rich soils by specifying that the residual stress is the effective stress within the soil elements upon thawing rather than the effective stress in the bulk soil. The framework is formulated in terms of [Formula: see text] relationships. The volume change behaviour of ice-poor soils is described by a semi-logarithmic linear [Formula: see text] relationship. The slope of the [Formula: see text] relationship is given by the compression index of the thawed soil. For ice-rich soils, a bilinear [Formula: see text] relationship is adopted. First, drainage of the excess water occurs with no compression of the soil skeleton. Then, water is drained out of the soil upon compression of the soil skeleton in an ice-poor equivalent manner. The e− k v relationship of thawed fine-grained soils is defined by a semi-logarithmic linear curve with a slope defined by the hydraulic conductivity change index of the thawed soil.
Pressure infiltration behavior and fluid loss of bentonite slurry: a comparative study of two bentonite slurries
Authors: Qin Su , Cheng Yang , Huang He , Zhou Wan-Huan
Published: August 2023

Bentonite slurry is frequently used to temporarily stabilize the excavation for slurry tunnel boring machines (TBMs) driving in permeable soils, such as sand and gravel. In this study, two types of bentonite slurries (BS1 and BS2) were subjected to a series of infiltration column tests and modified fluid-loss tests under various pressure levels. Monitoring of water discharge and pore pressures at different depths of the sand bed enabled the identification of two effective sealing patterns during infiltration: the formation of a filter cake and rheological blocking. BS1 exhibited a tendency to form a filter cake, which played a vital role in effectively transferring the applied pressure to the underlying soil skeleton. The application of higher pressure facilitated the rapid formation of a filter cake, resulting in a shorter time span for slurry invasion and minimizing fluid loss. On the other hand, rheological blocking was dominant when using BS2, and the maximum infiltration distance was found to linearly increase with the applied pressure. A comparison between the measurement and a simple prediction model derived from Darcy's law revealed an overestimation of the infiltration distance during slurry invasion. Furthermore, based on the modified fluid-loss test, higher pressure was found to densify the filter cake and result in lower hydraulic conductivity.
A language framework for modeling social media account behavior
Authors: Nwala Alexander C. , Flammini Alessandro , Menczer Filippo
Published: August 2023

Malicious actors exploit social media to inflate stock prices, sway elections, spread misinformation, and sow discord. To these ends, they employ tactics that include the use of inauthentic accounts and campaigns. Methods to detect these abuses currently rely on features specifically designed to target suspicious behaviors. However, the effectiveness of these methods decays as malicious behaviors evolve. To address this challenge, we propose a language framework for modeling social media account behaviors. Words in this framework, called BLOC, consist of symbols drawn from distinct alphabets representing user actions and content. Languages from the framework are highly flexible and can be applied to model a broad spectrum of legitimate and suspicious online behaviors without extensive fine-tuning. Using BLOC to represent the behaviors of Twitter accounts, we achieve performance comparable to or better than state-of-the-art methods in the detection of social bots and coordinated inauthentic behavior.
Mineral and whole-rock geochemistry of high-Al podiform chromitites in the Fizh Massif of the Cretaceous Oman ophiolite: origin of hydrous N-MORB melts in a nascent forearc setting
Authors: Bo Rong-Zhong , Dilek Yildirim , Nasir Sobhi , Wu Wei-Wei , Cai Peng-Jie , Lu Yu-Xiao , Lian Dong-Yang , Yang Jing-Sui
Published: August 2023

The Oman ophiolite is one of the largest and best exposed ophiolites in the world and has >450 chromitite deposits. We report here a newly identified chromitite deposit in the Wadi Rajmi, Oman. This deposit occurs within a dunitic envelope, which is surrounded by harzburgite, and consists of both massive and disseminated chromitite types. The Rajmi peridotites represent depleted upper mantle rocks that underwent >20% partial melting and experienced metasomatism by melts and fluids derived from a subducting slab. They demonstrate geochemical affinities similar to those of the Izu–Bonin–Mariana forearc peridotites, supporting their formation in a forearc environment. The Rajmi chromitites have low Cr# values and are classified as high-Al chromitites. They have geochemical compositions comparable with those of chromitites crystallized from mid-ocean ridge basalt (MORB)-type melts. However, the chromites in these high-Al chromitites contain various silicate inclusions (e.g. amphiboles and micas), indicating the hydrous and atypical MORB nature of their parental magmas. Combined with the mineralogical and geochemical characteristics of the country rocks, we posit that the parental melts of the Rajmi high-Al chromitites have a MORB-like affinity derived from partial melting of a nascent forearc mantle.

Supplementary material:
The whole-rock and mineral data of the Rajmi harzburgites, dunites and chromitites are available at
https://doi.org/10.6084/m9.figshare.c.6795689

Thematic collection:
This article is part of the Ophiolites, melanges and blueschists collection available at:
https://www.lyellcollection.org/topic/collections/ophiolites-melanges-and-blueschists
Humble AI
Authors: Knowles Bran , D'Cruz Jason , Richards John T. , Varshney Kush R.
Published: August 2023

An effort to bring artificial intelligence into better alignment with our moral aims and finally realize the vision of superior decision making through AI.
Model Counting Meets Distinct Elements
Authors: Pavan A. , Vinodchandran N. V. , Bhattacharyya Arnab , Meel Kuldeep S.
Published: August 2023

Constraint satisfaction problems (CSPs) and data stream models are two powerful abstractions to capture a wide variety of problems arising in different domains of computer science. Developments in the two communities have mostly occurred independently and with little interaction between them. In this work, we seek to investigate whether bridging the seeming communication gap between the two communities may pave the way to richer fundamental insights. To this end, we focus on two foundational problems: model counting for CSPs and the computation of the number of distinct elements in a data stream, also known as the zeroth frequency moment (
F
0
) of a data stream.

Our investigations lead us to observe striking similarity in the core techniques employed in the algorithmic frameworks that have evolved separately for model counting and distinct elements computation. We design a recipe for the translation of algorithms developed for distinct elements estimation to that of model counting, resulting in new algorithms for model counting. We then observe that algorithms in the context of distributed streaming can be transformed into distributed algorithms for model counting. We next turn our attention to viewing streaming from the lens of counting and show that framing distinct elements estimation as a special case of #DNF counting allows us to obtain a general recipe for a rich class of streaming problems, which had been subjected to case-specific analysis in prior works.
Real-Time Guarantees in Routerless Networks-on-Chip
Authors: Soares Indrusiak Leandro , Burns Alan
Published: August 2023

This article considers the use of routerless networks-on-chip as an alternative on-chip interconnect for multi-processor systems requiring hard real-time guarantees for inter-processor communication. It presents a novel analytical framework that can provide latency upper bounds to real-time packet flows sent over routerless networks-on-chip, and it uses that framework to evaluate the ability of such networks to provide real-time guarantees. Extensive comparative analysis is provided, considering different architectures for routerless networks and a state-of-the-art wormhole network based on priority-preemptive routers as a baseline.
Online Partial Service Hosting at the Edge
Authors: Borusu V. S. Ch Lakshmi Narayana , Agarwala Mohit , R Sri Prakash , Karamchandani Nikhil , Moharir Sharayu
Published: August 2023

We consider the problem of service hosting where an application provider can dynamically rent edge computing resources and serve user requests from the edge to deliver a better quality of service. A key novelty of this work is that we allow the service to be hosted partially at the edge that enables a fraction of the user query to be served by the edge. We model the total cost for (partially) hosting a service at the edge as a combination of the latency in serving requests, the bandwidth consumption, and the time-varying cost for renting edge resources. We propose an online policy called α-RetroRenting (α-RR) that dynamically determines the fraction of the service to be hosted at the edge in any time-slot, based on the history of the request arrivals and the rent cost sequence. As our main result, we derive an upper bound on α-RR’s competitive ratio with respect to the offline optimal policy that knows the entire request arrival and rent cost sequence in advance. In addition, we provide performance guarantees for our policy in the setting where the request arrival process is stochastic. We conduct extensive numerical evaluations to compare the performance of α-RR with various benchmarks for synthetic and trace-based request arrival and rent cost processes and find several parameter regimes where α-RR’s ability to store the service partially greatly improves cost-efficiency.
A Reconfigurable 7T SRAM Bit Cell for High Speed, Power Saving and Low Voltage Application
Authors: Rawat Bhawna , Mittal Poornima
Published: August 2023

The decreasing operational voltage and scaled technology node for memory designing has widened the gap between two crucial parameters for an SRAM – delay and power. As the demand for internet of things is increasing, the need for round the clock connectivity is increasing. This mandates designing a cell with a capability to switch between low power and high speed operation. Thus, this paper presents the design of dual mode operational 7T cell that can switch between single port and dual port configuration. The proposed reconfigurable cell can operate as single port or dual port cell single ended 7T cell. The reconfigurability in the cell is realized using control signals. The noise stability of the bit cell is obtained to be 333, 333, and 470 mV for read, hold, and write modes, respectively. The robustness of the cell against temperature variation, process variation and voltage variation is also analyzed. The performance variation in each parameter will not have a dramatic impact as it is within manageable limit. Its write time is 0.14 ns, while 5 ps are required for a successful read operation. The dual port configuration of the cell supports pipelining and thus operates faster than its single port configuration.
Don’t Accept All and Continue: Exploring Nudges for More Deliberate Interaction with Tracking Consent Notices
Authors: Gerber Nina , Stöver Alina , Peschke Justin , Zimmermann Verena
Published: August 2023

Legal frameworks rely on users to make an informed decision about data collection, e.g., by accepting or declining the use of tracking technologies. In practice, however, users hardly interact with tracking consent notices on a deliberate website per website level, but usually accept or decline optional tracking technologies altogether in a habituated behavior. We explored the potential of three different nudge types (color highlighting, social cue, timer) and default settings to interrupt this auto-response in an experimental between-subject design with 167 participants. We did not find statistically significant differences regarding the buttons clicked. Our results showed that opt-in default settings significantly decrease tracking technology use acceptance rates. These results are a first step towards understanding the effects of different nudging concepts on users’ interaction with tracking consent notices.
Collaborative Hotspot Data Collection with Drones and 5G Edge Computing in Smart City
Authors: Song Pei-Cheng , Pan Jeng-Shyang , Chao Han-Chieh , Chu Shu-Chuan
Published: August 2023

The construction and governance of smart cities require the collaboration of different systems and different regions. How to realize the monitoring of abnormal hot spots through the collaboration of subsystems with limited resources is related to the stability and efficiency of the city. This work constructs a hot data processing framework for drones and 5G edge computing infrastructure, as well as an Ensemble Multi-Objective Cooperative Learning method to process three different types of hot data. The data collection phase combines set operations with the 0-1 multi-knapsack model, and the cooperative learning phase realizes the degree of cooperation control while retaining the ability of independent optimization of the subsystem. Finally, the advantages of the framework are verified by hot data coverage and collaborative processing efficiency, resource use cost, and balance.
A Clique-Querying Mining Framework for Discovering High Utility Co-Location Patterns without Generating Candidates
Authors: Wang Lizhen , Tran Vanha , Do Thanhcong
Published: August 2023

Groups of spatial features whose instances frequently appear together in nearby areas are regarded as prevalent co-location patterns (PCPs). Traditional PCP mining ignores the significance of instances and features. However, in reality, these instances and features have different significance, the traditional PCPs may not sufficiently expose knowledge from spatial data. This study focuses on discovering high utility co-location patterns (HUCPs) in which each instance is assigned a utility to reflect its significance. To filter HUCPs, an adaptive utility participation index (UPI) is designed. Unfortunately, the UPI does not hold the downward closure property. The performance of mining HUCPs is very inefficient since unnecessary candidates cannot be early pruned. Thus, an efficient clique-querying mining framework is devised without generating candidates. This framework first divides neighboring instances into cliques, then compacts these cliques into a hash table structure. Next, the adaptive UPI of any patterns can be quickly calculated based on their participating instances that are obtained by executing a querying scheme on the hash table. Finally, HUCPs are filtered efficiently. The effectiveness and efficiency of the proposed method are proved in both theory and experiments to make a promise that the patterns mined are more meaningful and the mining performance is significantly improved compared to the previous methods.
Investigations on Piezoelectric, Dielectric and Mechanical Properties of PVDF/PVC/GO Nanocomposites
Authors: Sagar Rohan , Kumar Akash , Raghav Rajesh Kumar , Gaur M. S.
Published: August 2023

In this study, the hardness of polyvinylidene fluoride (PVDF), PVC and PVDF/PVC/GO (2.0 wt%) was estimated using piezoelectric and dielectric properties. The structure morphology was analyzed by Fourier transform infrared spectroscopy (FTIR). With the help of the solution casting technique, GO nanofiller were incorporated into PVDF/PVC matrix to prepare nanocomposites. In the case of PVDF/PVC/GO nanocomposites (2.0 wt%), the d33 coefficient is comparatively higher. PVDF have lower dielectric constant, however, may be due to interfacial polarization occurring at the spherulites and at the polymer/filler interfaces. The achieved lower loss tangent (tanδ) for PVDF compared to PVDF/PVC and PVDF/PVC/GO (2.0 wt%) nanocomposites is attributed to PVDF highly insulating nature. The PVDF/PVC/GO (2.0 wt%) nanocomposite exhibited a d33 value of ∼26 pm V−1, which was significantly higher than pure PVDF and PVDF/PVC.
Gradients of response latencies and temporal precision of auditory neurons extend across the whole inferior colliculus
Authors: Offutt Sarah J. , Rose Jessica E. , Crawford Kellie J. , Harris Megan L. , Lim Hubert H.
Published: August 2023

Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.
Enhancement of phase-locking in rodents. II. An axonal recording study in chinchilla
Authors: Wei Liting , Verschooten Eric , Joris Philip X.
Published: August 2023

The sensitivity of neurons to small time differences in sustained sounds to both ears is important for binaural hearing, and this sensitivity is critically dependent on phase-locking in the monaural pathways. Although studies in cat showed a marked improvement in phase-locking from the peripheral to the central auditory nervous system, the evidence in rodents is mixed. Here, we recorded from AN and TB of chinchilla and found temporal enhancement, though more limited than in cat.
A Semantic-Based Cognitive Training Programme on Everyday Activities: A Feasibility and Acceptability Study among Cognitively Healthy Older Adults
Authors: Tulliani Nikki , Bye Rosalind , Bissett Michelle , Coutts Samantha , Liu Karen P. Y.
Published: August 2023

Background. During the normal ageing process, a person’s cognitive functions and memory gradually decline, which can affect their ability to perform everyday activities including cooking, cleaning, managing finances, and shopping. Semantic memory encoding strategies benefit older adults’ cognitive and functional performance. Such strategies can be taught by an accessible, cost-effective, and flexible app-based programme. Currently, no studies examine such an app-based programme focussed on everyday activities. Objectives. To determine if an app-based programme constructed on the principles of semantic memory encoding strategies, targeted towards older adults, called Enhancing Memory in Daily Life (E-MinD Life) is (1) feasible by examining acceptance, engagement, and attendance and (2) acceptable by examining the perceived effectiveness, relevancy, clarity, and convenience. Methods. Eleven participants were recruited to a nine-week (18 sessions) programme using E-MinD Life. Feasibility was measured by collecting data on recruitment and retention rates, attendance, and duration of sessions. Acceptability was measured via a Likert scale questionnaire and free comments. Likert scale responses were analysed using descriptive statistics; open-ended responses were categorised qualitatively via constant comparative approach. Results. Nine participants completed the programme. Overall, most participants found the programme relevant, convenient, logical, and easy to understand and perceived it to be effective to address functional cognitive problems impacting performance of everyday activities. The results from the qualitative analysis showed that participants found the programme enjoyable and the interaction with the research team throughout the intervention beneficial. Conclusion. E-MinD Life shows promise as the focus of further research to determine the effectiveness of the programme and sematic-based cognitive strategies in maintaining cognition and performance in everyday activities among older adults with and without cognitive impairment.
Gilteritinib as Bridging and Posttransplant Maintenance for Relapsed Acute Myeloid Leukemia with FLT3-ITD Mutation Accompanied by Extramedullary Disease in Elderly
Authors: Saburi Masuho , Sakata Masanori , Maruyama Rika , Kodama Yosuke , Takata Hiroyuki , Miyazaki Yasuhiko , Kawano Katsuya , Wada Junpei , Urabe Shogo , Ohtsuka Eiichi
Published: August 2023

A 69-year-old woman was diagnosed with acute myeloid leukemia (AML) with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation. Complete remission (CR) was achieved after induction therapy, but AML resulted in a hematological relapse two months after the consolidation chemotherapy. Relapse was accompanied by multiple skin lesions that demonstrated leukemic cell infiltration as well as a drooping right eyelid with extroversion of the eye due to right oculomotor palsy. Gilteritinib was started as salvage therapy, and bone marrow blasts decreased to 0.8% after one month. Two months later, the eye symptoms improved, and the patient underwent cord blood transplantation (CBT). The skin lesions disappeared after the conditioning regimen, and the patient achieved CR status with complete donor chimerism at day 28. Gilteritinib was restarted as posttransplant maintenance therapy on day 53 of CBT. No adverse events other than mild hepatotoxicity were observed, and the patient was alive and in CR status, while continuing gilteritinib at one year and seven months after CBT. Bridging and posttransplant maintenance therapy with gilteritinib may be a promising therapeutic option for relapsed AML with the FLT3-ITD mutation in elderly patients.
Event-Triggered Quantized Stabilization of Markov Jump Systems under Deception Attacks
Authors: Yan Jingjing , Zhao Shuaibing , Feng Xiaoliang
Published: August 2023

This paper focuses on the event-triggered quantized control for Markov jump systems with deception attacks. First, we design an event-triggered scheme relying on dwell time and end instants of attacks. It can limit the number of switches within the triggered intervals and the lower bound of triggered instants. Second, the quantization rules and the increasing/decreasing rate of Lyapunov function are obtained for different cases. Next, combined with the increasing/decreasing rate, the lower bound of triggered instants, and the probability of switches occurring, the upper bound of Lyapunov function at the triggered instants is provided. On this basis, sufficient conditions ensuring the exponential convergence in the mean sense of the closed-loop system are given. Finally, atwo-tank system is provided to verify the effectiveness of the proposed stability analysis framework for Markov jump systems.
Design of Torsion Plate Energy-Absorbing Member and Analysis of Energy-Absorbing and Anti-Impact Characteristics
Authors: Zhang Jianzhuo , Guo Hao , Xiao Yonghui , Pan Yishan , Jiang Biao , Su Shijie , Ni Baojun
Published: August 2023

In order to effectively improve the impact resistance performance of the roadway anti-impact hydraulic support and reduce the loss caused by rock burst to a certain extent, a torsion plate energy-absorbing member was designed for using with the hydraulic column. By using theoretical analysis and numerical simulation methods and combining them with the parameters of the energy-absorbing characteristics evaluation index, single-factor tests were designed. Under the premise of constant impact velocity, the influence law of torsion angle, plate thickness, and fillet radius of the pressure plate on the energy-absorbing and anti-impact characteristics of energy-absorbing members were analysed. The results show that the deformation process and resistance trend of the torsion plate correspond to energy absorption. The resistance stability is high in the reaction force platform stage, and the energy increases linearly. With the increase of the torsion angle, the mean value of the reaction force increases, the fluctuation of the reaction force platform stage becomes more obvious, the specific energy absorption increases linearly, and the standard deviation reaches the minimum at 480°. Both the tensile length and the length of the reaction force platform stage increase continuously. With the increase of the plate thickness, the flatness of the torsion plate shows a trend of bad-good-bad, the mean value of the reaction force gradually increases, the specific energy absorption grows faster and then slower, and the tensile length and the length of the reaction force platform stage increase accordingly. With the increase of the fillet radius, the flatness of the torsion plate is better and the reaction force has a small improvement. The fluctuation of reaction force is most significant when the fillet radius is 2 mm, and the energy-absorbing member has the largest swing. The specific energy absorption is highest when the fillet radius is 2.5 mm, the standard deviation shows a tendency to develop firstly decreasing and then stabilising, the tensile length of the torsion plate decreases slightly, and the length of the reaction force platform firstly increases and then tends to stabilise. The torsion plate energy-absorbing member is a more ideal energy-absorbing and anti-impact member, which plays a positive role in the energy-absorbing and anti-impact of the hydraulic support.
Time-Dependent Anabolic Response of hMSC-Derived Cartilage Grafts to Hydrostatic Pressure
Authors: Chariyev-Prinz Farhad , Neto Nuno , Monaghan Michael G. , Kelly Daniel J.
Published: August 2023

It is generally accepted that the application of hydrostatic pressure (HP) is beneficial for MSC chondrogenesis. There is, however, evidence to suggest that the timing of application might determine its impact on cell fate and tissue development. Furthermore, understanding how the maturity of engineered cartilage affects its response to the application of HP can provide critical insight into determining when such a graft is ready for in vivo implantation into a mechanically loaded environment. In this study, we systematically examined chondrogenic maturation of hMSCs over 35 days in the presence of TGF-β3 in vitro. At specific timepoints, the response of hMSCs to the application of HP following the removal of TGF-β3 was assessed; this partially models conditions such grafts will experience in vivo upon implantation. In free swelling culture, the expression of chondrogenic (COL2A1 and ACAN) and hypertrophic (COL10A1) markers increased with time. At early timepoints, the expression of such markers continued to increase following TGF-β3 withdrawal; however, this was not observed after prolonged periods of chondrogenic priming (35 days). Interestingly, the application of HP was only beneficial after 35 days of chondrogenic priming, where it enhanced sGAG synthesis and improved key chondrogenic gene ratios. It was also found that HP can facilitate a metabolic shift towards oxidative phosphorylation, which can be viewed as a hallmark of successfully differentiating MSCs. These results point to the importance of mechanical loading as a key stimulus for maintaining a chondrogenic phenotype once MSCs are removed from chemically defined culture conditions.
Fatty Acids Support the Fitness and Functionality of Tumor-Resident CD8+ T Cells by Maintaining SCML4 Expression
Authors: Feng Maoxiao , Liu Xiaoyan , Hao Xiaodong , Ren Yidan , Dong Guoying , Tian Jie , Wang Yuli , Du Lutao , Wang Yunshan , Wang Chuanxin
Published: August 2023

CD8+ tissue-resident memory T (Trm) cells and tumor-infiltrating lymphocytes (TIL) regulate tumor immunity and immune surveillance. Characterization of Trm cells and TILs could help identify potential strategies to boost antitumor immunity. Here, we found that the transcription factor SCML4 was required for the progression and polyfunctionality of Trm cells and was associated with a better prognosis in patients with cancer. Moreover, SCML4 maintained multiple functions of TILs. Increased expression of SCML4 in CD8+ cells significantly reduced the growth of multiple types of tumors in mice, while deletion of SCML4 reduced antitumor immunity and promoted CD8+ T-cell exhaustion. Mechanistically, SCML4 recruited the HBO1–BRPF2–ING4 complex to reprogram the expression of T cell–specific genes, thereby enhancing the survival and effector functions of Trm cells and TILs. SCML4 expression was promoted by fatty acid metabolism through mTOR–IRF4–PRDM1 signaling, and fatty acid metabolism–induced epigenetic modifications that promoted tissue-resident and multifunctional gene expression in Trm cells and TILs. SCML4 increased the therapeutic effect of anti–PD-1 treatment by elevating the expression of effector molecules in TILs and inhibiting the apoptosis of TILs, which could be further enhanced by adding an inhibitor of H3K14ac deacetylation. These results provide a mechanistic perspective of functional regulation of tumor-localized Trm cells and TILs and identify an important activation target for tumor immunotherapy.

Significance:

SCML4 upregulation in CD8+ Trm cells and tumor-infiltrating lymphocytes induced by fatty acid metabolism enhances antitumor immune responses, providing an immunometabolic axis to target for cancer treatment.

See related commentary by Chakraborty et al., p. 3321
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Authors: Nayyar Naema , de Sauvage Magali A. , Chuprin Jane , Sullivan Emily M. , Singh Mohini , Torrini Consuelo , Zhang Britney S. , Bandyopadhyay Sushobhana , Daniels Keith A. , Alvarez-Breckenridge Christopher , Dahal Ashish , Brehm Michael A. , Brastianos Priscilla K.
Published: August 2023

Purpose:

Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.

Experimental Design:

Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor–immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development.

Results:

We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti–PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells.

Conclusions:

Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases.

See related commentary by Margolin, p. 257
Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study
Authors: Randon Giovanni , Nakamura Yoshiaki , Yaeger Rona , Lonardi Sara , Cremolini Chiara , Elez Elena , Nichetti Federico , Ghelardi Filippo , Nasca Vincenzo , Bergamo Francesca , Conca Veronica , Ros Javier , Bando Hideaki , Maddalena Giulia , Oldani Simone , Prisciandaro Michele , Raimondi Alessandra , Schrock Alexa B. , Agnelli Luca , Walch Henry , Yoshino Takayuki , Pietrantonio Filippo
Published: August 2023

Purpose:

To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade.

Experimental Design:

The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case–control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group.

Results:

PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%.

Conclusions:

PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting.

See related commentary by Raghav et al., p. 260
FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation–Positive Low-Grade Glioma
Authors: Barbato Michael I. , Nashed Jeannette , Bradford Diana , Ren Yi , Khasar Sachia , Miller Claudia P. , Zolnik Banu S. , Zhao Hong , Li Yangbing , Bi Youwei , Shord Stacy S. , Amatya Anup K. , Mishra-Kalyani Pallavi S. , Scepura Barbara , Al-Matari Raniya A. , Pazdur Richard , Kluetz Paul G. , Donoghue Martha , Singh Harpreet , Drezner Nicole
Published: August 2023

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35–59] in the D+T arm and 11% (95% CI, 3.0–25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5–NE) in the D+T arm and not estimable (95% CI, 6.6– NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6– 11.8) [HR, 0.31 (95% CI, 0.17–0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.
Apátridas: percursos da memória em sob céus estranhos, de Ilse Losa
Authors: Félix Roseane Oliveira de Araújo , Cardoso João Batista
Published: August 2023

Propomos no presente estudo analisar questões relacionadas à memória de expatriados. O fio que conduz nossa discussão está centrado na obra Sob céus estranhos (1962), de Ilse Losa, que relata o testemunho de sobreviventes judeus que resistiram ao sofrimento que lhes impôs os nazistas durante a Segunda Guerra Mundial. A literatura tem apresentado questões que elucidam e documentam momentos específicos na história, com significativa participação no processo de resgate de memórias, como se deu com obras de autores que testemunharam tragédias, perseguições e massacres por parte dos mais fortes sobre os mais fracos. Trazer ao lume reflexões sobre o passado, seja por meio da ficção, do testemunho ou da historiografia, possibilita uma reorganização da sociedade e, sobretudo, da memória. Significa apoderar-se de uma lembrança tal como ela transparece em momentos ameaçadores, como ocorreu num determinado momento histórico o extermínio massificado dos judeus. O problema, em particular, foi adensado pelo antissemitismo, que daí desencadeou as diásporas forçadas e as dificuldades na busca por territórios que servissem de exílio. Tais fatos levaram os judeus a se afastarem de suas origens. A saída para terras desconhecidas se deu mesmo sem saber, de antemão, sobre as possibilidades de sobrevivência em outros territórios que não estivessem sob o domínio da Alemanha. Nesse novo território, o expatriado sobrevive, principalmente, através de memórias de um passado em que pertencera a uma pátria.
Short-Term DAPT and DAPT De-Escalation Strategies for Patients With Acute Coronary Syndromes: A Systematic Review and Network Meta-Analysis
Authors: Kuno Toshiki , Watanabe Atsuyuki , Shoji Satoshi , Fujisaki Tomohiro , Ueyama Hiroki , Takagi Hisato , Deharo Pierre , Cuisset Thomas , Bangalore Sripal , Mehran Roxana , Stone Gregg W. , Kohsaka Shun , Bhatt Deepak L.
Published: August 2023

BACKGROUND:

Short-term (≤6 months) dual antiplatelet therapy (DAPT) and DAPT de-escalation become attractive for patients with acute coronary syndrome.

METHODS:

A systemic search identified randomized controlled trials that included patients with acute coronary syndrome treated using (1) standard DAPT (12 months) with clopidogrel, prasugrel (standard/low dose), or ticagrelor; (2) extended DAPT (≥18 months); (3) short-term DAPT (≤6 months) followed by P2Y
12
inhibitor or aspirin; (4) 12-month DAPT with unguided de-escalation from potent P2Y
12
inhibitors to low-dose potent P2Y
12
inhibitor or clopidogrel at 1 month; and (5) guided selection DAPT with genotype or platelet function tests. The primary efficacy outcome (major adverse cardiovascular events) was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding.

RESULTS:

This meta-analysis included 32 randomized controlled trials with 103 497 patients. While there were no differences in efficacy between short, unguided de-escalation and guided selection strategies, unguided de-escalation was associated with reduced risk of major adverse cardiovascular events compared with standard DAPT with clopidogrel or ticagrelor (hazard ratio [95% CI], 0.67 [0.49–0.93] and 0.68 [0.50–0.93]). Both short DAPT followed by P2Y
12
inhibitor and unguided de-escalation were associated with reduced risks in safety compared with other strategies, including guided selection (hazard ratio [95% CI], 0.66 [0.47–0.93] and 0.48 [0.33–0.71]). Short DAPT followed by a P2Y
12
inhibitor was associated with reduced risk of major bleeding and all-cause death compared with standard, extended DAPT (eg, versus DAPT with clopidogrel; hazard ratio [95% CI], 0.64 [0.42–0.97] and 0.60 [0.44–0.82]). By rankogram, unguided de-escalation strategy was the safest and most effective strategy in reducing major adverse cardiovascular events and major or minor bleeding while short DAPT followed by P2Y
12
inhibitor was ranked the best for major bleeding and all-cause death.

CONCLUSIONS:

In patients with acute coronary syndrome, unguided de-escalation was associated with the lowest risk of major adverse cardiovascular events and major or minor bleeding outcomes, while short DAPT followed by P2Y
12
inhibitor was associated with the lowest risk of major bleeding and all-cause death.
Elevated Plasma Levels of Ketone Bodies Are Associated With All‐Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS
Authors: Niezen Sebastian , Connelly Margery A. , Hirsch Calvin , Kizer Jorge R. , Benitez Maria E. , Minchenberg Scott , Perez‐Matos Maria Camila , Jiang Zhenghui Gordon , Mukamal Kenneth J.
Published: August 2023

Background

Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all‐cause mortality and incident heart failure.

Methods and Results

We analyzed the association between plasma metabolite levels with all‐cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all‐cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose‐response relationship of 50% increase in all‐cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0–1.9];
P
=0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0–1.3];
P
=0.02). Using K‐means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin‐6, and B‐type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all‐cause mortality (HR, 1.7 [95% CI, 1.1–2.7];
P
=0.01).

Conclusions

Higher concentrations of ketone bodies predict incident heart failure and all‐cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization
Authors: Reddy Rohin K. , Ardissino Maddalena , Ng Fu Siong
Published: August 2023

Background

Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors.

Methods and Results

Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome‐wide significance (
P
<5×10
−8
). Genetic association estimates for cardiometabolic exposures were obtained from genome‐wide association studies including 188 577 individuals for low‐density lipoprotein‐C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two‐sample, inverse‐variance weighted MR formed the primary analyses. The MR‐TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02–1.13],
P
=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR‐base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier‐adjusted effect estimate remained consistent with the original inverse‐variance weighted estimate (OR, 1.07 [95% CI, 1.02–1.12],
P
=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low‐density lipoprotein‐C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95–1.13],
P
=0.40).

Conclusions

These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D.