bluuebunny/crossref_metadata_2025 huggingface dataset:
The formulation and in vitro evaluation of WS Biotin, a novel encapsulated form of D‐Biotin with improved water solubility for hair and skin treatment applications
Authors: Duchi Shaher , Rebollo Torregrosa Paloma , Hajuj Akram , Molho Danit , Shkoor Rawya , Saada Nadeen Abo , Fernández David González , Goldstein Danny , Pérez‐Fernández Alejandro
Published: October 2023

Objective

To develop and evaluate the efficacy of WS Biotin, a novel water‐soluble form of D‐Biotin, for cosmetic use.

Methods

A new encapsulated form of D‐Biotin was developed with the purpose of improving the water solubility of biotin. This novel form of encapsulated biotin was characterized by its physicochemical properties: particle size, D‐Biotin content and solubility in water. Also, proliferation and gene expression in vitro tests in cell culture were performed to evaluate its effectiveness in promoting hair growth, an ELISA test was conducted for hair keratinization and skin lightening property was tested by analysing the intracellular melanin content.

Results

The developed WS Biotin microcapsules exhibit a particle size range of 2–30 μm with D‐Biotin content of ~50% (w/w). The water solubility of WS Biotin was found to be 20‐fold greater than free biotin. The obtained in vitro results indicated that WS Biotin enhances the expression of hair‐related keratins in hair follicle keratinocytes, as well as the expression of hair growth‐promoting genes in dermal papilla cells. Moreover, the melanin content in UVA‐exposed epidermal melanocytes was reduced upon exposure to WS Biotin.

Conclusion

In this work, a novel form of encapsulated biotin, WS Biotin, was developed in order to improve the water solubility of free biotin and was found to be effective for cosmetic use in both hair and skin applications.
The interplay of app characteristics and smartphone addiction in mobile shopping behaviour
Authors: Prodanova Jana , Chopdar Prasanta Kr.
Published: October 2023

In recent years, we have witnessed accelerated digital interactions among new technology users as a means of communication, leading to addictive behaviours owing to the overuse of smartphones and other new technological interfaces that have reshaped our daily routines. Thus, we adopted the social cognitive theory and the attachment theory to explore and understand the users' app adaptations and how mobile app characteristics, through their influence on smartphone addiction, impact mobile shopping behaviour. We designed an online survey to gather responses from 302 mobile app shoppers in India. We analysed the data using the partial least squares structural equation modelling technique. The results indicate that perceived privacy and security, personalization, contextual offers, and retailers' reputations trigger smartphone addiction. Moreover, the interaction between smartphone addiction and app incentives encourages mobile shopping intentions and frequent purchases. These findings would presumably enhance mobile app characteristics as the stimulus of a closer relationship between consumers and retailers. We present valuable avenues for practitioners to strategically manage their businesses' mobile app environment.
A Spoonful of Sugar: Deference at the Court of Justice
Authors: López Zurita Lucía , Brekke Stein Arne
Published: October 2023

This article analyses the European Court of Justice's strategic use of deference as a resilience technique in the preliminary reference procedure. It focuses on the strategic potential of using deference in two scenarios: first, when the Court uses teleological interpretation or expands the scope of the EU legal order and, second, when it declares national measures incompatible with EU law. The findings indicate that the Court is more likely to use deference when expanding EU law and less likely to defer when it declares national measures incompatible with EU law. The article challenges commonly held assumptions regarding the use of deference. First, the findings substantially qualify accounts linking the increase of deference to the maturity of the EU legal order and a certain halt of judicial activism. Deference allows the Court to explore new frontiers of EU law, suggesting that although the legal order might have matured, the Court does not perceive the project of legal integration as completed. Second, the article defies claims that deference is used by the Court as a ‘weapon of restraint’.
The effect of embryo selection using time‐lapse monitoring on IVF/ICSI outcomes: A systematic review and meta‐analysis
Authors: Jiang Yanbiao , Wang Liyan , Wang Sha , Shen Haofei , Wang Bin , Zheng Jianxiu , Yang Jinwei , Ma Bin , Zhang Xuehong
Published: October 2023

Aim

To explore the effect of embryo selection using the time‐lapse monitoring (TLM) system compared with conventional morphological selection (CMS) on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes.

Methods

We searched PubMed, Ovid‐Embase, and The Cochrane Library for the following studies: At Comparison 1, embryo selection using TLM images in a TLM incubator based on morphology versus embryo selection using CMS in a conventional incubator based on morphology; at Comparison 2, embryo selection using TLM based on morphokinetics versus embryo selection using CMS based on morphology. The primary outcomes were the live birth rate (LBR), ongoing pregnancy rate (OPR), clinical pregnancy rate (CPR), and implantation rate (IR), and the secondary outcome was the miscarriage rate (MR).

Results

A total of 14 randomized control trials (RCTs) were included. Both based on morphology, TLM incubators increased the IR (risk ratio [RR]: 1.10; 95% confidence interval [CI]: 1.01, 1.18; I2 = 0%, moderate‐quality evidence) compared to conventional incubators. Low‐ to moderate‐quality evidence suggests that TLM incubators did not improve LBR, OPR, CPR, and MR compared to conventional incubators. In addition, low‐ to moderate‐quality evidence indicates that embryo selection using TLM based on morphokinetics did not improve LBR, OPR, CPR, IR, or MR compared to CMS based on morphology.

Conclusions

Low‐ to moderate‐quality evidence suggests that neither TLM incubators nor embryo selection using TLM based on morphokinetics improved clinical outcomes (LBR, OPR, CPR, and MR) compared with CMS based on morphology. TLM is still an investigational procedure for IVF/ICSI practice.
Zombies and India: The neoMONSTERS Epidemiology
Authors: Khan Sami Ahmad
Published: October 2023

This paper hunts for zombies – both “real” and “unreal”– in contemporary Indian Science Fiction. It investigates how India's undead appropriate semantic markers of the global zombie industry via metaphors of monstrosity and how they simultaneously propagate a monstrosity of metaphors that disrupts social cohesion and communal harmony. Adopting the filters of genre, form, monster, and location, it advances a neoMONSTERS (Mutating/Mutagenic Ontological Narratives in Space‐Time Echoing Realistic Situations) epidemiology that identifies: (a) etiology (birth/cause) of the zombie, (b) transmission of the infection, (c) treatment/cure of the infected, and (d) teratology, epicentre and ideology of the outbreak.
The role of microboards in enhancing quality of life for children with intellectual disability and their families
Authors: Taylor Susan , David Jennifer , Dew Angela , Watson Joanne
Published: October 2023

Disability support systems have not consistently used family‐centered practices when supporting families of children with disability. Families have experienced structural and interpersonal barriers that have negatively impacted not only their child's quality of life, but also family quality of life (FQOL). The eight domains of QOL as defined by the International Association for the Scientific Study of Intellectual Disabilities [IASSID] are reflected in a family‐centered model of support developed for children and young people by Microboards Australia. The Microboards for Children [MB4C] model reflects best family centered practice based on principles that integrate well with recognised FQOL domains such as family relationships, support from other people and from disability‐related services, and leisure and enjoyment of life. The MB4C model aims to enhance families’ knowledge, skills, confidence, and sense of wellbeing to support them develop a vision for an active, socially connected, and happy future with their child. The model consists of a structured network of formal and informal support to enhance not only their child or young person's personal relationships, social networks, and community inclusion but also to enable parents and siblings to access education, employment and to enjoy life in their community – all indicators of FQOL. In this paper we explore how these features of MB4C policies and practice align with family‐centered practice principles and with FQOL domains. We argue that the MB4C model provides an example of how FQOL may be enhanced by a holistic family‐centered disability service system that works in partnership with families with disability.
Risk Budgeting portfolios: Existence and computation
Authors: Cetingoz Adil Rengim , Fermanian Jean‐David , Guéant Olivier
Published: October 2023

Modern portfolio theory has provided for decades the main framework for optimizing portfolios. Because of its sensitivity to small changes in input parameters, especially expected returns, the mean–variance framework proposed by Markowitz in 1952 has, however, been challenged by new construction methods that are purely based on risk. Among risk‐based methods, the most popular ones are Minimum Variance, Maximum Diversification, and Risk Budgeting (especially Equal Risk Contribution) portfolios. Despite some drawbacks, Risk Budgeting is particularly attracting because of its versatility: based on Euler's homogeneous function theorem, it can indeed be used with a wide range of risk measures. This paper presents mathematical results regarding the existence and the uniqueness of Risk Budgeting portfolios for a very wide spectrum of risk measures and shows that, for many of them, computing the weights of Risk Budgeting portfolios only requires a standard stochastic algorithm.
Prevalence of sarcopenia and its association with diet and physical activity in older adults with type 2 diabetes: A cross‐sectional study
Authors: Yen Hsin‐Yen , Lee Shu‐Chun , Lin Chiou‐Fen , Lai Hsiang‐Ru , Yamaguchi Yuko , Lee Pi‐Hsia
Published: October 2023

This cross‐sectional study explored the prevalence of sarcopenia in older adults with type 2 diabetes and investigated the effects of diet and physical activity on sarcopenia. In total, 577 older adults with diabetes were recruited from a teaching hospital in Taiwan. Diet and physical activity were assessed using self‐rated questionnaires, including the Healthy Diet Inventory, the Mini Nutritional Assessment‐Short Form, and the International Physical Activity Questionnaire‐Short Form. Sarcopenia was defined in accordance with the Asian Working Group for Sarcopenia 2019 guidelines. In total, 51.12% of participants had either possible sarcopenia, sarcopenia, or severe sarcopenia. Participants who were female, old age, prolonged sedentary times, poor nutritional status, and lower level of moderate‐to‐vigorous physical activity were identified as risk factors for possible to severe sarcopenia. Older adults with diabetes and possible to severe sarcopenia had poor nutrition status and engaged in inadequate physical activity. The findings indicate that sarcopenia may be related to nutrition status and physical activity, especially in older adults with diabetes.
The short‐term effect of hemodialysis on the level of high‐sensitive cardiac troponin T — A systematic review
Authors: Hunderup Michael Mejer , Kampmann Jan Dominik , Kristensen Frans Brandt , Hafsund Marius
Published: October 2023

Introduction

Patients with end‐stage renal disease (ESRD) have an increased risk of cardiovascular disease, but interpreting cardiac troponin is difficult in this population. The effect of renal replacement therapy (RRT) is important to consider when interpreting serial cardiac troponin T (cTnT) results for patients with ESRD suspected of acute coronary syndrome (ACS). The aim of this systematic review is to answer how low‐flux hemodialysis (LF‐HD), high‐flux hemodialysis (HF‐HD), and hemodiafiltration (HDF) affect the blood concentration of high‐sensitive cardiac troponin T (hs‐cTnT).

Method

Several databases were searched and identified records were evaluated independently by two of the authors. Pre‐ and postdialysis hs‐cTnT concentrations together with other relevant data were extracted from the included studies. The quality (potential bias and applicability issues) were assessed for each of the included studies.

Results

The literature search identified 2,540 records and 15 studies were included. The relative pre‐ to postdialysis change of hs‐cTnT varied from −41 to 29%. LF‐HD increased the hs‐cTnT concentration with relative changes between 2 and 17%. HDF decreased the concentration with relative changes from −41% to −9%. Both increases and decreases were seen for HF‐HD (−16% to 12%).

Discussion/Conclusion

In this systematic review, we found LF‐HD to increase the hs‐cTnT concentration and HDF to decrease the concentration. Results for HF‐HD and unspecified HD are more heterogeneous. Because of the differences between the included studies, a meta‐analysis was not meaningful. This systematic review can help with the assessment of patients with ESRD suspected of ACS in relation to hemodialysis/HDF treatment.
REVIEWS OF ACOUSTICAL PATENTS
Authors: Fulop Sean A.
Published: October 2023

The purpose of these acoustical patent reviews is to provide enough information for a Journal reader to decide whether to seek more information from the patent itself. Any opinions expressed here are those of the reviewers as individuals and are not legal opinions. Patents are available via the internet at the USPTO website.
Implications of porpoise echolocation and dive behaviour on passive acoustic monitoring
Authors: Macaulay Jamie Donald John , Rojano-Doñate Laia , Ladegaard Michael , Tougaard Jakob , Teilmann Jonas , Marques Tiago A. , Siebert Ursula , Madsen Peter Teglberg
Published: October 2023

Harbour porpoises are visually inconspicuous but highly soniferous echolocating marine predators that are regularly studied using passive acoustic monitoring (PAM). PAM can provide quality data on animal abundance, human impact, habitat use, and behaviour. The probability of detecting porpoise clicks within a given area (P̂) is a key metric when interpreting PAM data. Estimates of P̂ can be used to determine the number of clicks per porpoise encounter that may have been missed on a PAM device, which, in turn, allows for the calculation of abundance and ideally non-biased comparison of acoustic data between habitats and time periods. However, P̂ is influenced by several factors, including the behaviour of the vocalising animal. Here, the common implicit assumption that changes in animal behaviour have a negligible effect on P̂ between different monitoring stations or across time is tested. Using a simulation-based approach informed by acoustic biologging data from 22 tagged harbour porpoises, it is demonstrated that porpoise behavioural states can have significant (up to 3× difference) effects on P̂. Consequently, the behavioural state of the animals must be considered in analysis of animal abundance to avoid substantial over- or underestimation of the true abundance, habitat use, or effects of human disturbance.
Blowing the whistle on mixed gender hospital rooms in Australia and New Zealand: a human rights issue
Authors: Towns Cindy , Ballantyne Angela
Published: October 2023

The practice of placing men and women in the same hospital room (mixed gender rooms) has been prohibited in the UK National Health Service for over a decade. However, recent research demonstrates that the practice is common and increasing in a major New Zealand public hospital. Reports and complaints show that the practice also occurs in Australia. We argue that mixed gender rooms violate the fundamental human rights of personal security and dignity. The high rates of cognitive impairment, sensory impairment and frailty in hospital wards exacerbates the risk for these violations and subsequent harm. We argue for the adoption of specific national policies prohibiting mixed gender rooms and public reporting of breaches. Importantly, these guidelines can be adopted without compromising the rights of gender minorities. In the long term, hospitals should be built with single occupancy rooms.
A machine learning-based assessments of customer satisfaction levels in Indian Postal Services (ML-ACSLIPS) for selected Tamilnadu districts from social media content
Authors: Sangeetha T. , Subatra B.
Published: October 2023

The Indian Postal Services (IPSs) have above 155,333 post offices distributed globally. They are one of the most known and established government-owned institutions with sizable customer bases. They provide accessible and affordable services in India thanks to the unrivalled postal systems with various new services added in the last decades which include money transfers, distribution of mutual funds, and mail/parcel deliveries. IPSs have positioned themselves as dependable agencies for the Government of India. It has a competitive advantage of geographical accessibility. The system has also established centralized core banking solutions with alternative delivery channels enabling everywhere, anytime banking settings in India. Since the current marketplaces focus on clientele; businesses need to regard them as profit-making entities creating needs for high-quality services and management essential for customer satisfaction and retention. Globalization has added to acute competition to IPSs making it imperative to improve the overall quality of their services. This study’s goal is to identify the primary drivers of consumer happiness with IPSs. Since social media is the most widely used for views, references, and product information, this study effort suggests a system based on social media data called Machine learning-based Assessments of Customer Satisfaction Levels in Indian Postal Services (ML-ACSLIPS). Regression analysis and machine learning techniques (MLTs) were used in this study to examine Indian customer satisfaction levels in IPSs.
Task Recommendation via Heterogeneous Multi-modal Features and Decision Fusion in Mobile Crowdsensing
Authors: Wang Jian , Wang Xiao , Zhao Guosheng
Published: October 2023

In the decision-making process of the behavior of mobile crowdsensing, using a single view to learn a user's preference will lead to a mismatch between the user's wishes and the final task recommendation list, resulting in the low efficiency of the model recommendation. Aiming at the lack of perceptual representation and cognitive fusion of multimodal coupled information, a task recommendation method based on heterogeneous multimodal features and decision fusion is proposed. According to the content characteristics of multi-source data in the user's historical task set, several task-task similarity matrices are constructed to align feature dimensions and feature semantics. Using the improved similarity network fusion algorithm, networks composed of multiple content similarity matrices are effectively fused into a similarity network. Considering the influence of the time factor, the tasks that have had interest drift are filtered out from the set of tasks that the user has participated in. Finally, the updated similarity network is clustered to predict the current preference of the user for new tasks. Experimental results based on simulation and real datasets show that the proposed method can effectively improve the accuracy and efficiency of task assignments while improving user satisfaction.
Fitting with matrix exponential mixtures generated by discrete probabilistic scaling
Authors: Bor Julianna , Casale Giuliano , Knottenbelt William , Smirni Evgenia , Stathopoulos Andreas
Published: October 2023

Matrix exponential (ME) distributions generalize phase-type distributions; however, their use in queueing theory is hampered by the difficulty of checking their feasibility. We propose a novel ME fitting algorithm that produces a valid distribution by construction. The ME distribution used during the fitting is a product of independent random variables that are easy to control in isolation. Consequently, the calculation of the CDF and the Mellin transform factorizes, making it possible to use these measures for the fitting without significant restriction on the distribution order. Trace-driven queueing simulations indicate that the resulting distributions yield highly accurate results.
Exponential Tail Bounds on Queues
Authors: Jhunjhunwala Prakirt , Hurtado-Lange Daniela , Theja Maguluri Siva
Published: October 2023

A popular approach to computing performance measures of queueing systems (such as delay and queue length) is studying the system in an asymptotic regime. However, these results are only valid in the limit and often provide bounds for the pre-limit systems that are not optimized and, hence, give loose bounds for the tail probabilities. In this paper, we provide optimized bounds for the tail probabilities of the scaled total queue length in a load-balancing system under Join the Shortest Queue (JSQ). Our bounds characterize the rate of convergence of the tail probabilities to the corresponding heavy traffic values. For the tail probability of the JSQ system, our bounds yield a multiplicative error that arises from three factors: pre-limit tail, pre-exponent error, and State-Space Collapse (SSC). As an immediate corollary of our main theorem, we provide a bound to the tail probabilities of a single-server queue. In this case, the multiplicative error only consists of pre-limit tail and pre-exponent error, since there is no state-space collapse.
Reducing Heavy-Traffic Response Time with Asymmetric Dispatching
Authors: Xie Runhan , Scully Ziv
Published: October 2023

Reducing mean response time has always been a desirable goal in queueing systems. If job sizes (a.k.a. service times) are known to the scheduler, the policy that minimizes mean response time of a single-server queue is SRPT (Shortest Remaining Processing Time). This is true even for queues that are part of a larger system, such as immediate-dispatch systems where jobs are sent to one of multiple single-server queues upon arrival.
Quantum Switch Scheduling for Information Qubits
Authors: Promponas Panagiotis , Valls V´ctor , Tassiulas Leandros
Published: October 2023

This paper studies the problem of designing a scheduling policy for a quantum switch that teleports information qubits. The problem is analogous to scheduling photons in highspeed optical switches, with the difference that an optical switch is modeled as a bipartite graph instead of a complete graph. The paper's contributions are to model the problem of designing a scheduling policy as decomposing a symmetric doubly stochastic matrix, and to show that we can use Birkhoff's algorithm to obtain such a decomposition.
Towards Future-Based Explanations for Deep RL Network Controllers
Authors: Patel Sagar , Abdu Jyothi Sangeetha , Narodytska Nina
Published: October 2023

Lack of explainability is hindering the practical adoption of high-performance Deep Reinforcement Learning (DRL) controllers. Prior work focused on explaining the controller by identifying salient features of the controller's input. However, these feature-based methods focus solely on inputs and do not fully explain the controller's policy. In this paper, we put forward future-based explainers as an essential tool for providing insights into the controller's decision-making process and, thereby, facilitating the practical deployment of DRL controllers. We highlight two applications of futurebased explainers in the networking domain: online safety assurance and guided controller design. Finally, we provide a roadmap for the practical development and deployment of future-based explainers for DRL network controllers.
Electro-Oxidative Dehydrogenation of Ethane to Ethylene Using Lanthanum-Strontium-Iron Oxide Perovskite Electrocatalysts
Authors: Kasick Andrew , Hajer Ahmad Abu , Wolfe Kody D. , Velraj Samgopiraj , Daramola Damilola A. , Trembly Jason P.
Published: October 2023

Developing alternative, industrially viable ethylene production routes has received important research attention. One chemical pathway of interest is the oxidative dehydrogenation (ODH) of ethane, although issues such as product selectivity, combustion hazards, and oxidizer supply have hindered the practical scale-up of this technology. The presented work describes the use of a solid oxide fuel cell (SOFC) platform employing lanthanum-strontium-iron oxide perovskite (La1-xSrxFeO3-δ
, or LSFx) electrocatalysts to perform electrochemical-ODH (e-ODH), a process design that has the potential to address the challenges of ODH implementation. The effects of La and Sr stoichiometry, operating temperature, and current density are reported. The highest performance was observed using a La:Sr ratio of 0.50 (LSF0.50) at 750 °C and a current density of 0.50 A·cm−2, achieving an ethane conversion of 18.7 ± 0.3%, ethylene selectivity of 91.4 ± 1.9%, and ethylene yield of 17.1 ± 0.1%. These results demonstrate several potential advantages for utilizing a SOFC platform to perform e-ODH of ethane to ethylene.
Ultrasensitive Catechol Detection via Core-Shell Nanofibers: Effect of Type of Conducting Polymer and MWCNT Reinforcement
Authors: Çetin Merih Zeynep , Apetrei Roxana-Mihaela , Guven Nese , Camurlu Pinar
Published: October 2023

The detection of phenols is one of the main research directions due to impact of phenols on human life. Herein, novel biosensing matrices based on pristine and composite (including MWCNTs) electrospun nanofibers coated with conducting polymers (poly(3,4-ethylenedioxythiphene (PEDOT) or polypyrrole (PPy)) were employed for immobilization of Tyrosinase enzyme and further evaluated for phenol detection. The current study is meant to provide a comparison between the two conducting polymers in terms of electron transfer and biocompatibility with the chosen enzyme, as resulted from analytical characterization of the biosensor and analysis of Michaelis-Menten behaviour. The developed biosensors (Pt/PAN(-MWCNTs)/PEDOT NFs/PPO and Pt/PAN(-MWCNTs)/PPy NFs/PPO) displayed high sensitivity values of 6846.83 and 10364 μA mM−1.cm−2 within linear ranges of 5.0 − 1.0 × 10−5 and 5.0 − 1.0 × 10−7 M, with limit of detection values in the nanomolar range (1.14 and 4.04 × 10−7 M) depending on the polymer employed (PEDOT and PPy, respectively). Given the nanostructured conducting matrix based on the synergistic effect between MWCNTs and CPs and the principle of detection employed, the analytical parameters of the current study are competent in catechol detection. In addition, the platform screened possible interferences allowing accurate detection of trace amounts of phenolics in spiked water samples.
The role of fibrosis in the pathophysiology of muscular dystrophy
Authors: Mogharehabed Farnaz , Czubryt Michael P.
Published: October 2023

Muscular dystrophy exerts significant and dramatic impacts on affected patients, including progressive muscle wasting leading to lung and heart failure, and results in severely curtailed lifespan. Although the focus for many years has been on the dysfunction induced by the loss of function of dystrophin or related components of the striated muscle costamere, recent studies have demonstrated that accompanying pathologies, particularly muscle fibrosis, also contribute adversely to patient outcomes. A significant body of research has now shown that therapeutically targeting these accompanying pathologies via their underlying molecular mechanisms may provide novel approaches to patient management that can complement the current standard of care. In this review, we discuss the interplay between muscle fibrosis and muscular dystrophy pathology. A better understanding of these processes will contribute to improved patient care options, restoration of muscle function, and reduced patient morbidity and mortality.
Data from Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer
Authors: Gou Xuxu , Kim Beom-Jun , Anurag Meenakshi , Lei Jonathan T. , Young Meggie N. , Holt Matthew V. , Fandino Diana , Vollert Craig T. , Singh Purba , Alzubi Mohammad A. , Malovannaya Anna , Dobrolecki Lacey E. , Lewis Michael T. , Li Shunqiang , Foulds Charles E. , Ellis Matthew J.
Published: October 2023

Abstract
Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen–binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)–based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET–resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF–driven ET-resistant breast cancer.
Significance:
Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target.

See related commentary by Wu and Subbiah, p. 3159
Data from Allosteric regulation of switch-II domain controls KRAS oncogenicity
Authors: Yang Moon Hee , Tran Timothy H. , Hunt Bethany , Agnor Rebecca , Johnson Christian W. , Shui Bing , Waybright Timothy J. , Nowak Jonathan A. , Stephen Andrew G. , Simanshu Dhirendra K. , Haigis Kevin M.
Published: October 2023

Abstract
RAS proteins are GTPases that regulate a wide range of cellular processes. RAS activity is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). KRAS can be acetylated at lysine 104 (K104), and an acetylation-mimetic mutation of K104 to glutamine (K104Q) attenuates the in vitro transforming capacity of oncogenic KRAS by interrupting GEF induced nucleotide exchange. To assess the effect of this mutation in vivo, we used CRISPR-Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional KrasLSL-G12D alleles. Homozygous animals for K104Q were viable, fertile, and arose at the expected Mendelian frequency, indicating that K104Q is not a complete loss of function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of KRASG12D was significantly attenuated by mutation at K104. Biochemical and structural analysis indicated that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic KRAS. Furthermore, K104 functioned in an allosteric network with M72, R73 and G75 on the α2 helix of the switch-II region. Intriguingly, point mutation of glutamine 75 to alanine (G75A) showed a strong negative regulatory effect on KRASG12D. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant KRAS and suggest that modulating the sites in its allosteric network may provide a unique therapeutic approach in cancers expressing mutant KRAS.
RETooling the RET Inhibitor Pralsetinib for ESR1 Fusion–Positive Breast Cancer and Beyond
Authors: Wu Jie , Subbiah Vivek
Published: October 2023

Transcriptionally active fusions of ESR1 (ESR1-TAF) and somatic mutations in the estrogen receptor alpha (ERα) ligand-binding domain (LBD) cause endocrine therapy resistance in breast cancer. In searching for therapeutic target kinase(s) in these breast cancers, Gou and colleagues identified FLT4, RET, JAK1, and IGF1R as the top upregulated kinases induced by ESR1-TAFs and ERα LBD mutants in breast cancer cells. Among them, inhibition of RET by pralsetinib suppressed ESR1-TAF–driven and ERα LBD mutant–driven cell proliferation and patient-derived xenograft growth. Pralsetinib is an inhibitor of the RET protein tyrosine kinase that is approved for treating oncogenic RET mutation–positive and RET fusion–positive thyroid cancers and non–small cell lung cancer. The work by Gou and colleagues reinforces the knowledge of RET as an ESR1 target gene and highlights that RET interacts with ERα to promote breast cancer tumorigenesis and antiestrogen resistance. It also raises the prospect of repositioning pralsetinib to target wildtype RET in ER-positive breast cancer.

See related article by Gou et al., p. 3237
Distinct Mechanisms of Resistance to CDK4/6 Inhibitors Require Specific Subsequent Treatment Strategies: One Size Does Not Fit All
Authors: Wingate Hannah F. , Keyomarsi Khandan
Published: October 2023

Cyclin-dependent kinase (CDK) 4/6 inhibitors have transformed the treatment landscape of patients with hormone receptor–positive breast cancers. However, despite improvements in clinical outcomes, the approximately 70% of patients with tumors that are not intrinsically resistant to a CDK4/6 inhibitor still ultimately acquire resistance, which leads to a dilemma for clinicians when deciding which treatment to offer patients when they demonstrate disease progression on a CDK4/6 inhibitor. As such, many groups have sought to understand the mechanisms of resistance to CDK4/6 inhibitors, mostly focusing on genetic alterations associated with resistance. Though several recurrent mutations have been described, they are not consistent enough to guide clinical practice or generate novel rational treatment options. Two recent publications have used transcriptomic analysis to unravel distinct mechanisms driving resistance to individual CDK4/6 inhibitors and in doing so have identified biomarkers that could potentially help identify the next course of treatment for patients following disease progression.
A Landmark Paper That Introduced Proteasome Inhibition in Myeloma
Authors: Devasia Anup Joseph , Lancman Guido , Stewart A. Keith
Published: October 2023

The ongoing therapeutic revolution in multiple myeloma care can be traced to the turn of the millennium with the unanticipated discovery in 1999 that the cereblon binding small molecule thalidomide had profound clinical effectiveness and, simultaneously, the emergence of a new class of targeted therapies inhibiting the proteasome, both of which ultimately target ubiquitinated protein degradation. These contemporaneous discoveries forever changed the landscape of multiple myeloma care, substantially extending survival. Foreshadowing this seismic change, Nobel Prize winning work on the proteasome ubiquitin pathway had stimulated the development of highly specific proteasome inhibitor small molecules, particularly PS-341 (later named bortezomib). An abundance of the proteasome in hematologic malignancies had been recognized and thus PS-341 was logically being explored in relevant preclinical models. Concurrent with phase I trials, which were soon to prove the significant clinical relevance of preclinical models, the laboratory of Dr. Kenneth Anderson and colleagues at Dana-Farber, in partnership with Dr. Julian Adams and scientists at ProScript (later Millennium Pharmaceuticals) first demonstrated that the proteasome inhibitor PS-341 inhibited growth, induced apoptosis, and overcame drug resistance in human multiple myeloma cells. This landmark paper in Cancer Research set the stage for a paradigm shift in how multiple myeloma was managed across all stages of the disease, which changed the lives of patients worldwide.

See related article by Hideshima and colleagues, Cancer Res 2001;61:3071–6
Data from Uncoupling CD4+ TIL-Mediated Tumor Killing from JAK-Signaling in Melanoma
Authors: Draghi Arianna , Presti Mario , Jensen Agnete W.P. , Chamberlain Christopher A. , Albieri Benedetta , Rasmussen Anne-Christine K. , Andersen Mads H. , Crowther Michael D. , Svane Inge Marie , Donia Marco
Published: October 2023

AbstractPurpose:
Impaired MHCI-presentation and insensitivity to immune effector molecules are common features of immune checkpoint blockade (ICB)-resistant tumors and can be, respectively, associated with loss of β2 microglobulin (B2M) or impaired IFNγ signaling. Patients with ICB-resistant tumors can respond to alternative immunotherapies, such as infusion of autologous tumor-infiltrating lymphocytes (TIL). CD4+ T cells can exert cytotoxic functions against tumor cells; however, it is unclear whether CD4+ T-cell responses can be exploited to improve the clinical outcomes of patients affected by ICB-resistant tumors.
Experimental Design:
Here, we exploited CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing to reproduce immune-resistant tumor phenotypes via gene knockout (KO). To determine the role of cytotoxic CD4+ TILs in ICB-resistant tumors, we investigated CD4+ TIL-mediated cytotoxicity in matched pairs of TILs and autologous melanoma cell lines, used as a model of patient-specific immune-tumor interaction. Around 40% of melanomas constitutively express MHC Class II molecules; hence, melanomas with or without natural constitutive MHC Class II expression (MHCIIconst+ or MHCIIconst−) were used.
Results:
CD4+ TIL-mediated cytotoxicity was not affected by B2M loss but was dependent on the expression of CIITA. MHCIIconst+ melanomas were killed by tumor-specific CD4+ TILs even in the absence of IFNγ-mediated MHCII upregulation, whereas IFNγ was necessary for CD4+ TIL-mediated cytotoxicity against MHCIIconst- melanomas. Notably, although tumor-specific CD4+ TILs did not kill JAK1KO MHCIIconst- melanomas even after IFNγ stimulation, sensitivity to CD4+ TIL-mediated cytotoxicity was maintained by JAK1KO MHCIIconst+ melanomas.
Conclusions:
In conclusion, our data indicate that exploiting tumor-specific cytotoxic CD4+ TILs could help overcome resistance to ICB mediated by IFNγ-signaling loss in MHCIIconst+ melanomas.

See related commentary by Betof Warner and Luke, p. 3829
Data from Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Adjuvant Therapy Era
Authors: Dermawan Josephine K. , Kelly Ciara , Gao Zhidong , Smith Shaleigh , Jadeja Bhumika , Singer Samuel , Tap William D. , Chi Ping , Antonescu Cristina R.
Published: October 2023

AbstractPurpose:
Traditional risk stratification schemes in gastrointestinal stromal tumors (GIST) were defined in the pre-imatinib era and rely solely on clinicopathologic metrics. We hypothesize that genomic-based risk stratification is prognostically relevant in the current era of tyrosine kinase inhibitor (TKI) therapeutics.
Experimental Design:
Comprehensive mutational and copy-number profiling using MSK-IMPACT was performed. We integrated clinicopathologic and genomic parameters and utilized an elastic-net penalized Cox proportional hazards machine learning model for outcome risk stratification.
Results:
A 3-tier genomic risk stratification model for recurrence-free survival (RFS) in 152 primary localized gastric and 80 small bowel GISTs was proposed. Gastric GISTs were classified as high risk if chr1p deletion or SDHB loss was present, and intermediate risk if chr14q deletion was present or KIT exon 11 mutation was absent. Small bowel GISTs were classified as high risk if MAX/MGA/MYC, CDKN2A, or RB1 alterations were present, and intermediate risk if chr1p deletion or chr5q amplification was present. Compared with conventional risk stratification, genomic risk stratification both upgrades and downgrades, suggesting that conventional risk stratification may underestimate or overtreat some high-risk and low-risk patients, respectively. Longitudinal sequencing detected most KIT-independent genomic alterations at baseline. Subanalysis in 26 SDH-deficient GISTs revealed that presence of TP53 mutations or chr1q amplifications portends worse RFS and disease-free survival.
Conclusions:
We developed a novel, next-generation genomic risk stratification model for primary gastric and small bowel GISTs, complementing traditional clinicopathologic models. Future independent validation of our model in external cohorts is essential.
Can We De-escalate Therapy for HER2-Positive Metastatic Breast Cancer?
Authors: Huppert Laura A. , Rugo Hope S.
Published: October 2023

A recent phase Ib/II trial evaluated the combination of tucatinib, letrozole, and palbociclib in patients with HR+/HER2+ metastatic breast cancer, demonstrating a manageable safety profile and encouraging efficacy data. An all-oral, chemotherapy-free regimen is an appealing strategy, and could be a possible maintenance or primary therapy option in select patients.

See related article by Shagisultanova et al., p. 5021
Data from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: October 2023

Abstract
Interleukin (IL)-15 is a potent inducer of differentiation and proliferation of CD8+ T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL-15 suggests needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anti-cancer treatment that elicits massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL-15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL-15 was more effective than intraperitoneal IL-15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL-15-secreting MC38 (hIL-15-MC38) and parental MC38 tumors, the hIL-15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. Additionally, the hIL-15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8+ T, NK, and natural killer T cells compared to the treated parental line. Furthermore, intratumoral IL-15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL-15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL-15 administration synergistically improves the efficacy of cancer cell-targeted NIR-PIT probably by inducing stronger anti-cancer immunity, indicating its potential as an anti-cancer treatment strategy.
Data from MTX-13, a Novel PTK7-Directed Antibody–Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: October 2023

Abstract
Protein tyrosine kinase 7 (PTK7) is a Wnt signaling pathway protein implicated in cancer development and metastasis. When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody–drug conjugate (ADC), h6M24-vc0101 (PF-06647020/cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial. To improve patient response and to expand responding tumor types, we designed MTX-13, a PTK7-targeting ADC consisting of a novel antibody (Ab13) conjugated to eight molecules of topoisomerase I inhibitor exatecan through T1000, a novel self-immolative moiety. MTX-13 exhibited PTK7-specific cell binding, efficient internalization, and exatecan release to cause cytotoxic activity through DNA damage and apoptosis induction, and a strong bystander killing. MTX-13 displayed potent antitumor activities on cell line–derived xenograft and patient-derived xenograft models from a wide range of solid tumors, significantly outperforming h6M24-vc0101. PTK7 was shown to be an actionable target in small cell lung cancer for which MTX-13 showed complete and durable responses. With a consistent overexpression of PTK7 in squamous cell carcinomas derived from diverse anatomic sites, strong potency of MTX-13 in this group of heterogenous tumors suggested a common treatment strategy. Finally, MTX-13 inhibited tumor growth and metastasis in an orthotopic colon cancer xenograft model. MTX-13 displayed a favorable pharmacokinetic and safety profile in monkeys with the highest non-severely toxic dose (HNSTD) of ≥30 mg/kg, significantly higher than 3–5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with the potential to expand the responding patient population beyond that of current PTK7-targeting ADCs.
Data from Mitochondrial Uncoupling Inhibits Reductive Carboxylation in Cancer Cells
Authors: Jiang Haowen , He Clifford Jiajun , Li Albert M. , He Bo , Li Yang , Zhou Meng-Ning , Ye Jiangbin
Published: October 2023

Abstract
When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U–13C-glutamine and 1–13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative tricarboxylic acid (TCA) cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor–deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth.
Implications:
Mitochondrial uncoupling is a novel strategy to target RC in cancer.
Data from LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation
Authors: Zhang Shenghua , Zhang Zheng , Liu Xiaolong , Deng Yibin , Zheng Jian , Deng Jieqiong , Wang Yirong , Guo Binbin , Li Fanrong , Chen Xiaoyue , Pan Yacheng , Wang Jieyu , Lu Jiachun , Wu Siqi , Guo Qiang , Zhou Yifeng
Published: October 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC.
Implications:
This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.