bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance
Authors: Cui Jihong , Christin John R. , Reisz Julie A. , Cendali Francesca Isabelle , Sanawar Rahul , Coutinho De Miranda Marcelo , D’Alessandro Angelo , Guo Wenjun
Published: December 2023

Cancer stem cells (CSCs) drive tumor growth, metastasis, and chemoresistance. While emerging evidence suggests that CSCs have a unique dependency on lipid metabolism, the functions and regulation of distinct lipid species in CSCs remain poorly understood. Here, we developed a stem cell factor SOX9-based reporter for isolating CSCs in primary tumors and metastases of spontaneous mammary tumor models. Transcriptomic analyses uncover that SOX9
high
CSCs up-regulate the ABCA12 lipid transporter. ABCA12 down-regulation impairs cancer stemness and chemoresistance. Lipidomic analyses reveal that ABCA12 maintains cancer stemness and chemoresistance by reducing intracellular ceramide abundance, identifying a CSC-associated function of ABCA subfamily transporter. Ceramide suppresses cancer stemness by inhibiting the YAP-SOX9 signaling pathway in CSCs. Increasing ceramide levels in tumors enhances their sensitivity to chemotherapy and prevents the enrichment of SOX9
high
CSCs. In addition, SOX9
high
and ABCA12
high
cancer cells contribute to chemoresistance in human patient-derived xenografts. These findings identify a CSC-suppressing lipid metabolism pathway that can be exploited to inhibit CSCs and overcome chemoresistance.
Impact of the COVID-19 pandemic on Canadian transplant journeys: a mixed methods study
Authors: Fox Danielle , Hall Marc , Thibodeau Carrie , Coldwell Kristi , Lauder Lydia , Dewell Sarah , Davidson Sandra
Published: December 2023

Background

Navigating the organ donation and transplantation system in Canada can be challenging for individuals on transplant journeys. Although it is likely that the COVID-19 pandemic has further contributed to these challenges, the experiences of individuals during the pandemic in Canada have not been well elicited.

Objective

To illuminate how the COVID-19 pandemic has impacted individuals on transplant journeys in Canada.

Design

Convergent parallel mixed-methods study.

Setting

Canada.

Participants

Adult patients, caregivers, and donors on transplant journeys across Canada.

Data collection

Eight focus groups and an online survey between May and November 2021. Focus group transcripts were analysed using an inductive conventional content analysis approach. Survey data were analysed using descriptive statistics. The study was guided by individuals with lived experience of organ donation and transplantation.

Results

A total of 830 participants completed three COVID-19 related survey questions, with 21 participating in the focus groups.Survey results: over 50% of patients and caregivers reported that the pandemic impacted their access to their healthcare team, their mental health (60% and 65%, respectively) and their comfort going out in public (80% and 75%, respectively). Although many donors reported several factors that impacted their transplant journey, the impact appeared to be greater for patients and caregivers.Qualitative results: three themes emerged from the qualitative data that contextualise participant’s experiences: compounding isolation, disruption amid uncertainty and unforeseen benefits.

Conclusion

The COVID-19 pandemic has exacerbated many of the challenges that individuals on transplant journeys experience. It will be critical for transplant programmes to consider these factors in future care provision.
How do network meta-analyses address intransitivity when assessing certainty of evidence: a systematic survey
Authors: Wang Ying , Xia Ruyu , Pericic Tina Poklepovic , Bekkering Geertruida E , Hou Liangying , Bala Malgorzata M , Gao Ya , Wu Michael , Gloss David , Siemieniuk Reed Alexander , Fei Yutong , Rochwerg Bram , Guyatt Gordon , Brignardello-Petersen Romina
Published: December 2023

Objectives

To describe how systematic reviews with network meta-analyses (NMAs) that used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) NMA approach addressed intransitivity when assessing certainty of evidence.

Design

Systematic survey.

Data sources

Medline, Embase and Cochrane Database of Systematic Reviews from September 2014 to October 2022.

Eligibility criteria

Systematic reviews of randomised controlled trials with aggregate data NMAs that used the GRADE NMA approach for assessing certainty of evidence.

Data extraction and synthesis

We documented how reviewers described methods for addressing intransitivity when assessing certainty of evidence, how often they rated down for intransitivity and their explanations for rating down.

Results

Of the 268 eligible systematic reviews, 44.8% (120/268) mentioned intransitivity when describing methods for assessing the certainty of evidence. Of these, 28.3% (34/120) considered effect modifiers and from this subset, 67.6% (23/34) specified the effect modifiers; however, no systematic review noted how they chose the effect modifiers. 15.0% (18/120) mentioned looking for differences between the direct comparisons that inform the indirect estimate. No review specified a threshold for difference in effect modifiers between the direct comparisons that would lead to rating down for intransitivity. Reviewers noted rating down indirect evidence for intransitivity in 33.1% of systematic reviews, and noted intransitivity for network estimates in 23.0% of reviews. Authors provided an explanation for rating down for intransitivity in 59.6% (31/52) of the cases in which they rated down. Of the 31 in which they provided an explanation, 74.2% (23/31) noted they detected differences in effect modifiers and 67.7% (21/31) specified in what effect modifiers they detected differences.

Conclusions

A third of systematic reviews with NMAs using the GRADE approach rated down for intransitivity. Limitations in reporting of methods to address intransitivity proved considerable. Whether the problem is that reviewers neglected to address rating down for transitivity at all, or whether they did consider but not report, is not clear. At minimum systematic reviews with NMAs need to improve their reporting practices regarding intransitivity; it may well be that they need to improve their practice in transitivity assessment. How to best address intransitivity may remain unclear for many reviewers thus additional GRADE guidance providing practical instructions for addressing intransitivity may be desirable.
Relationship Between Birth Weight and Asthma Diagnosis: A Cross-Sectional Survey Study Based on the National Survey of Children’s Health in the U.S.
Authors: Ni Meng , Li Baihe , Zhang Qianqian , Zhao Jiuru , Li Wei , Qi Sudong , Shen Qianwen , Yao Dongting , Chen Ze , Wang Tao , Ding Xiya , Lin Zhenying , Cheng Chunyu , Liu Zhiwei , Chen Hao
Published: December 2023

Objective

To assess the association between birth weight and childhood asthma risk using data from the 2019–2020 National Survey of Children’s Health database.

Design

Cross-sectional study.

Setting

The USA.

Patients

A representative cohort of American children.

Exposure

The exposure of this study was birth weight regardless of gestational age. Birth weight was divided into three groups: <1500 g, 1500–2500 g and >2500 g.

Main outcome measures

Primary outcomes were parent-reported diagnosis of asthma.

Method

The Rao-Scott χ2test was used to compare the groups. The main analyses examined the association between birth weight and parent-report asthma in children using univariable and multivariable logistic models adjusting for preterm birth, age, sex, race, family poverty, health insurance, smoking, maternal age. Subgroup analysis was performed based on interaction test.

Results

A total of 60 172 children aged 3–17 years were enrolled in this study; of these, 5202 (~8.6%) had asthma. Children with asthma were more likely to be born preterm, with low birth weight (LBW) or very LBW (VLBW). The incidence of asthma was the highest in VLBW children at 20.9% and showed a downward trend with an increase in birth weight class, with rates of 10.7% and 8.1% in the LBW and normal birthweight groups, respectively. Children with VLBW (OR 1.97; 95% CI 1.29 to 3.01) had higher odds of developing asthma in the adjusted analysis model. However, VLBW was only shown to be a risk factor for asthma among Hispanics, black/African-Americans and children between the ages of 6 and 12 years, demonstrating racial and age disparities.

Conclusions

VLBW increases the risk of childhood asthma; however, racial and age disparities are evident.
Preventive strategies for low anterior resection syndrome: a protocol for systematic review and evidence mapping
Authors: Zhang Xin-Yu , Yang Ke-Lu , Li Yang , Li Rui-Shu , Wang Shi-Qi , Liu Xiao-Nan , Wang Quan
Published: December 2023

Introduction

Rectal cancer is one of the top 10 cancers worldwide. Up to 80% of patients with rectal tumours have had sphincter-saving surgery, mainly due to the large expectation of anal preservation. However, patients tend to experience low anterior resection syndrome (LARS) after rectal resection, which is disordered bowel function that includes faecal incontinence, urgency, frequent defecation, constipation and evacuation difficulties. LARS, with an estimated prevalence of 41%, has been reported to substantially decrease the quality of life of patients. However, no comprehensive preventive strategies are currently available for LARS. This systematic review aims to synthesise evidence on the current LARS preventive strategies.

Methods and analysis

This protocol is reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. Literature in PubMed (via Medline), Embase and the Cochrane Library from inception to July 2023 will be searched to identify articles relevant to preventive effectiveness against LARS. The Cochrane Collaboration’s risk of bias tool for randomised controlled trials and the Newcastle-Ottawa Scale for clinical controlled trials, cohort studies and case–control studies will be used to assess the risk of bias. We will group the included studies by the type of LARS prevention strategy and present an overview of the main findings in the form of evidence mapping. A meta-analysis is planned if there is no substantial clinical heterogeneity between the included studies. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) will be used to evaluate the quality of the evidence.

Ethics and dissemination

Ethical approval is not needed for systematic review of published data. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences.

PROSPERO registration number

CRD42023402886.
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia
Authors: Hall Hildegard Nikki , Parry David , Halachev Mihail , Williamson Kathleen A , Donnelly Kevin , Campos Parada Jose , Bhatia Shipra , Joseph Jeffrey , Holden Simon , Prescott Trine E , Bitoun Pierre , Kirk Edwin P , Newbury-Ecob Ruth , Lachlan Katherine , Bernar Juan , van Heyningen Veronica , FitzPatrick David R , Meynert Alison
Published: December 2023

Background

Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the
PAX6
locus.

Methods

Short-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the
PAX6
coding region.

Results

Likely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the
PAX6
locus. Of these 19 families, 1 has a novel heterozygous
PAX6
frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of
PAX6
5′ non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of
PAX6
, 3 have deletions encompassing critical
PAX6 cis
-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the
PAX6
locus and 2 have complex rearrangements disrupting
PAX6
. The remaining 3 of 22 families have deletions encompassing
FOXC1
(a known cause of atypical aniridia). Seven of the causative variants occurred
de novo
and one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in
PAX6 cis
-regulatory elements.

Conclusion

Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.
Anorectal gonorrhoea and chlamydia among transgender women in Brazil: prevalence and assessment of performance and cost of anorectal infection detection and management approaches
Authors: McCartney Daniel Jason , Luppi Carla Gianna , Silva Roberto José Carvalho , de Araújo Sandra , Bassichetto Katia Cristina , Mayaud Philippe , Veras Maria Amélia
Published: December 2023

Objectives

We aimed to determine the prevalence of anorectalNeisseria gonorrhoeae(NG) andChlamydia trachomatis(CT) among transgender women in Brazil, and to assess the performance and costs of various approaches for the diagnosis and management of anorectal NG/CT.

Methods

TransOdara was a multicentric, cross-sectional STI prevalence study among 1317 transgender women conducted in five capital cities representing all Brazilian regions. Participants aged>18 years were recruited using respondent-driven sampling (RDS), completed an interviewer-led questionnaire, offered an optional physical examination and given choice between self-collected or provider-collected samples for NG/CT testing. Performance and cost indicators of predetermined management algorithms based on the WHO recommendations for anorectal symptoms were calculated.

Results

Screening uptake was high (94.3%) and the estimated prevalence of anorectal NG, CT and NG and/or CT was 9.1%, 8.9% and 15.2%, respectively. Most detected anorectal NG/CT infections were asymptomatic (NG: 87.6%, CT: 88.9%), with a limited number of participants reporting any anorectal symptoms (9.1%). Of those who permitted anal examination, few had clinical signs of infection (13.6%). Sensitivity of the tested algorithms ranged from 1.4% to 5.1% (highest for treatment based on the reported anorectal discharge or ulcer and receptive anal intercourse (RAI) in the past 6 months) and specificity from 98.0% to 99.3% (highest for treatment based on the reported anorectal discharge with clinical confirmation or report of RAI). The estimated cost-per-true case of anorectal NG/CT infection treated varied from lowest providing treatment for anorectal discharge syndrome based on the reported RAI ($2.70–4.28), with algorithms including clinical examinations decreasing cost-effectiveness.

Conclusions

High prevalence of mostly asymptomatic anorectal NG and CT was observed among Brazilian transgender women. Multi-site NG/CT screening should be offered to transgender women. Where diagnostic testing capacity is limited, syndromic management for those presenting with anorectal symptoms is recommended.
Frailty and prognosis in lung cancer: systematic review and meta-analysis
Authors: Liu Tianzi , Peng Xintong , Geng Yan , Song Chen , Zhou Ziwen , Huang Yan
Published: December 2023

Lung cancer is one of the most common malignant tumours. Patients are frequently at risk of frailty as lung cancer progresses. The meta-analysis aims to explore the impact of frailty on the long-term prognosis and the incidence of short-term chemotherapy toxicity in patients with lung cancer. This study was designed adhered to the criteria of Cochrane Handbook for Systematic Reviews. Systematic searches were performed on PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies until December 2022. The outcome measures were overall survival, progression-free survival, chemotherapy toxicity and all-cause mortality. We then performed sensitivity analyses, subgroup analyses and evidence quality. This meta-analysis was performed using Review Manager V.5.4 software. Of the included studies, six were retrospective and five were prospective. There was a statistically significant difference between the frail and non-frail groups in overall survival (HR 2.27, 95% CI 1.24 to 4.15, p=0.008), all-cause mortality (HR 1.63, 95% CI 1.00 to 2.65, p=0.05) and chemotherapy toxicity (OR 3.73, 95% CI 1.99 to 7.00, p<0.0001). We conducted a sensitivity analysis, and the result was stable. The study revealed frail group had shorter survival and experienced more severe adverse effects than the non-frail group. Frailty affects the long-term prognosis and the incidence of short-term chemotherapy toxicity of patients with lung cancer. Consequently, medical professionals should focus on frailty screening in patients with lung cancer and implement active intervention measures. PROSPERO registration number is CRD42023398606.
Effects of the illicit market on the price elasticity of cigarette consumption in Brazil
Authors: Divino Jose Angelo , Ehrl Philipp , Candido Osvaldo , Valadao Marcos Aurelio Pereira
Published: December 2023

Background

An important element to consider in tobacco tax policy is the illicit market of cigarette sales. The objective of this paper is to provide estimates of both conditional and unconditional price elasticities of cigarette consumption in the licit and illicit markets in Brazil.

Methodology

Microdata from the National Health Survey in 2013 and 2019 are used to estimate conditional and unconditional price elasticities of cigarette consumption in the licit and illicit cigarette markets by income quartiles and age cohorts. The identification is based on brand information and the official minimum cigarette price defined by the government, as sales below this price are prohibited and illegal.

Findings

The results, robust to potential endogeneity, indicate that there is joint statistical difference in price elasticities across age cohorts and income groups by market type. However, individuals smoking illicit cigarettes, regardless of age cohort and income quartiles, are less sensitive to price changes than those consuming licit brands.

Conclusions

The illicit cigarette market prevents the government from collecting tobacco tax revenues and weakens the social reach of price-oriented antismoking public policies. Fighting the illicit trade should be a major concern of public policies aiming at reducing cigarette consumption.
Dynamic Inverse Analysis of Steel–Concrete Hybrid Wind Turbine Tower
Authors: Li Shou-Zhen , Zhou Xu-Hong , Wang Yu-Hang , Gan Dan , Zhu Rong-Hua
Published: December 2023

The steel–concrete hybrid tower (SCHT) has been popularized as the supporting structure for onshore wind turbines to meet the increasing hub height and rotor diameter. The internal force of the cross-section, which is the prerequisite of the structural design, is based on the load analysis. However, the nonignorable effect of the second-order gravity makes analyzing the external load of the supporting tower a coupled problem, especially for the SCHT, which is higher than a conventional steel tubular tower. Besides, the aerodynamic load of the wind turbine, the main excitation acting on the supporting tower, is usually computed by numerical methods and lack of validation. To optimize the analysis method for the internal force of the SCHT, one feasible approach is evaluating the external excitation directly. Based on the theory of the Kalman filter, this study develops a dynamic inverse method of the SCHT. It aims to estimate the horizontal thrust of the wind turbine and provide an overall evaluation of the dynamic responses of the SCHT by using the measured dynamic responses at the limited point on the SCHT. A rigorous numerical simulation based on ABAQUS is conducted to generate the dynamic responses of the SCHT, which are used to validate the effectiveness of the proposed method. It also investigated the influence of observation type, number of measuring points, and noise level on the estimation accuracy.
Explosion Behaviors of Scaled Shallow-Buried Concrete–Rubber-Laminated Annular Metastructures: Evaluation of Shock Wave Attenuation
Authors: Liu Sanfeng , Wu Jianqin , Yang Yunze , Zhou Yinzhi , Fan Hualin
Published: December 2023

The attenuation of impact inducer vibration is critical to the safety of underground protection structure, equipment and personnel. Metamaterials and metastructures show great potential in terms of sound and impact attenuation. To effectively attenuate ground shock-induced vibration of underground protective structures, scaled shallow-buried annular metastructures with concrete–rubber layered structures were proposed and constructed. Underground explosion experiments were performed to investigate the vibration attenuation effect of annular metastructures with different layered structures. It is clear in this research only annular metastructures with concrete–rubber–concrete structures like annular metastructure model B6 have the most excellent wave attenuation performances, whose rubber layer thickness must be over 6[Formula: see text]mm and hardness is 20[Formula: see text]HA. Other layered structures with rubber layer thickness of 0.3[Formula: see text]cm or with more layers cannot effectively attenuate the shock wave in this research.
Improving Testing of Deep-learning Systems
Authors: Deokuliar Harsh , Sangwan Raghvinder S. , Badr Youakim , Srinivasan Satish M.
Published: December 2023

We used differential testing to generate test data to improve diversity of data points in the test dataset and then used mutation testing to check the quality of the test data in terms of diversity. Combining differential and mutation testing in this fashion improves mutation score, a test data quality metric, indicating overall improvement in testing effectiveness and quality of the test data when testing deep learning systems.
Effects of aerobic exercise on ambulatory blood pressure responses to acute partial sleep deprivation: impact of chronotype and sleep quality
Authors: Bommarito Julian C. , Millar Philip J.
Published: December 2023

We demonstrate that cycling exercise attenuates, but does not fully reverse, the augmented 24-h ambulatory blood pressure (BP) response caused by acute partial sleep deprivation (PSD). This response was primarily observed in late chronotypes. Furthermore, daytime BP after acute PSD is related to habitual sleep quality, with better sleepers being more prone to BP elevations. This suggests that habitual sleeping habits can influence BP responses to acute PSD and their interactions with prior cycling exercise.
Cardiovascular aging: spotlight on mitochondria
Authors: Ali Md Akkas , Gioscia-Ryan Rachel , Yang Dongli , Sutton Nadia R. , Tyrrell Daniel J.
Published: December 2023

Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.
Flexible Lévy-Based Models for Time Series of Count Data with Zero-Inflation, Overdispersion, and Heavy Tails
Authors: Kollie Confort , Ngare Philip , Malenje Bonface
Published: December 2023

The explosion of time series count data with diverse characteristics and features in recent years has led to a proliferation of new analysis models and methods. Significant efforts have been devoted to achieving flexibility capable of handling complex dependence structures, capturing multiple distributional characteristics simultaneously, and addressing nonstationary patterns such as trends, seasonality, or change points. However, it remains a challenge when considering them in the context of long-range dependence. The Lévy-based modeling framework offers a promising tool to meet the requirements of modern data analysis. It enables the modeling of both short-range and long-range serial correlation structures by selecting the kernel set accordingly and accommodates various marginal distributions within the class of infinitely divisible laws. We propose an extension of the basic stationary framework to capture additional marginal properties, such as heavy-tailedness, in both short-term and long-term dependencies, as well as overdispersion and zero inflation in simultaneous modeling. Statistical inference is based on composite pairwise likelihood. The model’s flexibility is illustrated through applications to rainfall data in Guinea from 2008 to 2023, and the number of NSF funding awarded to academic institutions. The proposed model demonstrates remarkable flexibility and versatility, capable of simultaneously capturing overdispersion, zero inflation, and heavy-tailedness in count time series data.
Control of the Cauchy System for an Elliptic Operator: The Controllability Method
Authors: Guel Bylli André B.
Published: December 2023

In this paper, we are dealing with the ill-posed Cauchy problem for an elliptic operator. This is a follow-up to a previous paper on the same subject. Indeed, in an earlier publication, we introduced a regularization method, called the controllability method, which allowed us to propose, on the one hand, a characterization of the existence of a regular solution to the ill-posed Cauchy problem. On the other hand, we have also succeeded in proposing, via a strong singular optimality system, a characterization of the optimal solution to the considered control problem, and this, without resorting to the Slater-type assumption, an assumption to which many analyses had to resort. On occasion, we have dealt with the control problem, with state boundary observation, the problem initially analyzed by J. L. Lions. The proposed point of view, consisting of the interpretation of the Cauchy system as a system of two inverse problems, then called naturally for conjectures in favor of which the present manuscript wants to constitute an argument. Indeed, we conjectured, in view of the first results obtained, that the proposed method could be improved from the point of view of the initial interpretation that we had made of the problem. In this sense, we analyze here two other variants (observation of the flow, then distributed observation) of the problem, the results of which confirm the intuition announced in the previous publication mentioned above. Those results, it seems to us, are of significant relevance in the analysis of the controllability method previously introduced.
Improving Critical Frequency of the Electrothermal V-Shaped Actuator Using the Particle Swarm Optimization Algorithm
Authors: Hong Pham Phuc , Truong Duc Phuc , Trung Hoang Kien , Bui Ngoc-Tam
Published: December 2023

This paper presents a thermal transfer model and optimization of a V-beam dimension to improve the critical frequency fC (i.e., expanding the effective working frequency range) of an electrothermal V-shaped actuator (EVA). The obtained results are based on applying the finite difference model, a method for calculating the critical frequency, as well as conditions to ensure the mechanical stability and thermal safety of EVA. The influence of beam dimensions (i.e., length L, width

w

, and incline angle θ of the beam) on the variation of critical frequency fC is investigated and evaluated. Moreover, the particle swarm optimization (PSO) algorithm is used to figure out the optimal beam dimensions aiming to increase the critical frequency while satisfying conditions such as mechanical stability, thermal safety, and suitable displacement of EVA. With the optimal dimensions of V-beam (L = 679 µm,

w

 = 4 µm, and θ = 1.8°), the critical frequency of the V-shaped actuator can be achieved up to 136.22 Hz at a voltage of 32 V (average increment of fC is 33.1% with the driving voltage changing from 16 V to 32 V) in comparison with the nonoptimal structure (fC is only 102.34 Hz at 32 V).
Side Null Analysis of the Main-Auxiliary Antenna Array for Noncooperative Interference Cancellation
Authors: Li ZheYu , Zhang JiaHao , Li YaXing , He FangMin , Gao HongZhang , Meng Jin
Published: December 2023

In interference cancellation, the null at the angle of arrival (AoA) of interference can suppress interference. However, due to the large spacing between array elements and the periodicity of the array, some small nulls at the angles of noninterference are formed inevitably. When the AoA of the desired signal is in these small nulls, they impair the effectiveness of interference cancellation by attenuating the desired signal. This paper proposes the concept of a side null to represent these nulls in the noninterference direction. And the cancellation ratio of the desired signal (SCR) is deduced to quantitatively characterize the side null. The spatial noncooperative interference cancellation model based on the main-auxiliary antenna array is established. Based on this, the SCR is derived to evaluate the amount of desired signal attenuation. Then the simulation, respectively, in two-dimensional plane and three-dimensional space, describes the side null visually. Moreover, the method of side null reduction is discussed by modulation of the array. Finally, the existence of side null and its influence on interference cancellation are verified through the experiments. The results of the simulation and experiment are in good agreement, and both support the theoretical analysis.
Figure 4 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S.
Published: December 2023

Camizestrant has superior in vivo activity to fulvestrant in ESR1wt and ESR1m PDX models (2). A, Characteristics of ER+ breast cancer models used. B, Change in ER pathway gene activation after treatment, expressed as change in ER pathway gene score and in cell-cycle G1–S checkpoint genes. See Supplementary Methods for details. Statistical analysis comparing fulvestrant and camizestrant was done using one-way analysis of covariance (n ≥ 4 animals per group). Models shown in bold (x-axis) are fulvestrant sensitive; those in regular type are fulvestrant resistant. ***, P < 0.001; ****, P < 0.0001. Amp, amplification; CCND1, cyclin D1; Del, deletion; MET, metastasis; Mut, mutation; PIK3CA, phosphatidylinositol 3-kinase subunit α; PR, progesterone receptor; PRIM, primary; RESIST, resistant; RB1, retinoblastoma gene; SENS, sensitive. Patient treatment reported: Be, bevacizumab; Ch, chemotherapy; E, exemestane; Ev, everolimus; F, fulvestrant; I, investigational; L, letrozole, T, tamoxifen; X, radiotherapy.
Figure 4 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , S Carnevalli Larissa
Published: December 2023

Camizestrant has superior in vivo activity to fulvestrant in ESR1wt and ESR1m PDX models (2). A, Characteristics of ER+ breast cancer models used. B, Change in ER pathway gene activation after treatment, expressed as change in ER pathway gene score and in cell-cycle G1–S checkpoint genes. See Supplementary Methods for details. Statistical analysis comparing fulvestrant and camizestrant was done using one-way analysis of covariance (n ≥ 4 animals per group). Models shown in bold (x-axis) are fulvestrant sensitive; those in regular type are fulvestrant resistant. ***, P < 0.001; ****, P < 0.0001. Amp, amplification; CCND1, cyclin D1; Del, deletion; MET, metastasis; Mut, mutation; PIK3CA, phosphatidylinositol 3-kinase subunit α; PR, progesterone receptor; PRIM, primary; RESIST, resistant; RB1, retinoblastoma gene; SENS, sensitive. Patient treatment reported: Be, bevacizumab; Ch, chemotherapy; E, exemestane; Ev, everolimus; F, fulvestrant; I, investigational; L, letrozole, T, tamoxifen; X, radiotherapy.
Data from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , S Carnevalli Larissa
Published: December 2023

Abstract
Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor–positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER–co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.
Significance:
Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Abstract A008: An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors
Authors: Wang Stephanie
Published: December 2023

Tongtong Liu, Feng He, Xuyang Duan, Shuliang Li, Chang Liu, Jingying Ning, Feng Hao* KYinno Biotechnology (Beijing) Co., Ltd. No.3 Building, Yizhuang Biomedical Park, Beijing, China.  Correspondence: Feng.hao@kyinno.com  Protein kinases have become very popular targets in the treatment of cancer and other diseases, and since 2001, the FDA has approved more than 70 kinase inhibitor drugs. However, due to innate or acquired resistance in tumors, most of these small molecule inhibitors only delay tumor progression. The development of next-generation kinase inhibitors with better specificity and lower resistance is still ongoing. Ba/F3 is a mouse pro-B cell line whose survival and proliferation depend on IL-3. After transduction with driver genes such as kinase genes or their mutants, Ba/F3 cells switch from IL-3 dependence to driver gene dependence, making Ba/F3 cells a powerful tool for discovering new kinase inhibitors.   Our group has constructed over 700 Ba/F3 engineered cell lines stably transfected with kinase gene mutants. These Ba/F3 kinase cell lines have been fully validated by sequencing, western blotting, and inhibitor testing, covering many popular kinases including EGFR (>150 cell lines), RAS (80 cell lines), FGFR (55 cell lines), ERBB2 (49 cell lines), MET (41 cell lines), RET (39 cell lines), BCR-ABL (37 cell lines), EML4-ALK (33 cell lines), and FLT3 (26 cell lines), etc. Most of these transformed Ba/F3 cell lines can be used for xenograft models in immunodeficient mice. Based on these Ba/F3 kinase cell line-derived xenograft models, we have established an in vivo screening platform to evaluate the efficacy and toxicity of candidate drugs against specific kinase mutation types, as well as their comparison with previous generation drugs. Overall, our data suggest that xenograft models derived from Ba/F3 kinase cell lines are powerful models for discovering next-generation kinase inhibitors.

Citation Format: Stephanie Wang. An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A008.
Abstract A024: Preclinical profile of novel and potent small molecule inhibitors of KIF18A inhibitors in chromosomally unstable solid tumor lines
Authors: Patra Sukanya , Pothuganti Manoj , Karche Navnath , Gudade Ganesh , Sankeshi Venu , Kummari Githavani , Vishwanadha Srikant
Published: December 2023

Accurate alignment of chromosomes at the equator region and equal chromosome separation during cell division is essential for maintenance of genome integrity. KIF18A belongs to kinesin superfamily of microtubule associated motor proteins and is responsible for maintenance of bipolar spindle fiber integrity during mitotic phase. Cancer cells with chromosomally unstable (CIN+) DNA show synthetic lethal phenotype with genetic ablation of KIF18A. Thus, pharmacological inhibition of KIF18A represents a potential strategy aimed at attenuating growth of CIN +ve tumors. A microtubule dependent ADP Glo kinase assay was used to identify potent KIF18A inhibitors. Mitotic arrest, manifested by an increase in phosphoH3, was determined in cells using fluorescent microscopy. Anti-proliferative activity was confirmed in CIN+ve solid tumor cells with significant selectivity over CIN-ve cancer cells. Compounds inhibited KIF18A at with potencies ranging from 50-80 nM.  A dose dependent increase in mitotic index in CIN+ve OVCAR-3 cells (via fluorescence microscopy) was observed in contrast to CIN-ve HCT-116 cells (10-100X selectivity). Translation was evident in an antiproliferation assay using CIN-ve cancer cells with IC50 <10 nM. Selected KIF18A inhibitors demonstrated favorable physicochemical, ADME and PK properties. In Vivo efficacy studies are planned.

Citation Format: Sukanya Patra, Manoj Pothuganti, Navnath Karche, Ganesh Gudade, Venu Sankeshi, Githavani Kummari, Srikant Vishwanadha. Preclinical profile of novel and potent small molecule inhibitors of KIF18A inhibitors in chromosomally unstable solid tumor lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A024.
Abstract A033: Anti-proliferative effects of lentinan, a beta-glucan from shiitake mushroom (lentinula edodes)
Authors: Sombuor Titus , Broughton Kenneth Shane , Bergel Michael
Published: December 2023

Cancer is one of the most significant health challenges worldwide. Lentinan, a β-glucan from shiitake mushroom, Lentinula edodes, has been demonstrated to have an inhibitory effect on selected cancer cells, but results are inconclusive. The aim of the present study was to investigate the anti-proliferative effect of lentinan on breast adenocarcinoma cells (MCF-7), prostate carcinoma (DU-145), and ovarian carcinoma (SKOV3) using MTS (3-(4,5-dimethylthiazol-2-yl)-5—(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and explore possible mechanisms of action of this compound. In the MCF-7 cells that were used as a positive control, lentinan without phenol red resulted in a significant inhibition of cell viability by 96% while in the presence of phenol red, the weak estrogen effect attributable to phenol red eliminated the significant inhibitory effect of lentinan. Treatment of DU-145 cells with different doses of lentinan resulted in up to a 42% inhibition in cell growth. In SKOV3 cells, lentinan induced a biphasic response where doses of 800 µg/ml or less increased cell viability by 76% – 148%; however, a dose of 1.6 mg/ml inhibited cell proliferation significantly by 87%. When SKOV3 cells were co-treated with lentinan (800 µg/ml or less) and laminarin (a Dectin-1 receptor antagonist), the proliferation-promoting effect of lentinan was dominant over the proliferation-inhibiting effect of laminarin. However, when lentinan was presented at significant higher levels (1600 µg/ml), the inhibitory effect of the two agents became additive in suppressing SKOV3 cell proliferation. Lentinan induced a biphasic response in human ovarian surface epithelial cells (HOSEpC) similar to SKOV3 cells, where the highest dose (1600 µg/ml) resulted in the inhibition of cell growth by 53%. Western blots after treatment of SKOV3 cells with 1600 µg/ml of lentinan demonstrated caspase-3 activation and a decreased anti-apoptotic protein Bcl-2 levels. Our findings reveal that lentinan can be considered as a potential anti-cancer drug for effective treatment of breast and prostate cancer.

Citation Format: Titus Sombuor, Kenneth Shane Broughton, Michael Bergel. Anti-proliferative effects of lentinan, a beta-glucan from shiitake mushroom (lentinula edodes) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A033.
Abstract A064: Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC)
Authors: Wilson Molly M. , Adam Ammar , Amaral Victoria , Mikse Oliver , Elliott GiNell , Lahr David L. , Gartin Ashley K. , Wan Jessica , Johannessen Liv , Ichikawa Kana , Feldman Katharine , Piel Jessica , Sandoval Gabriel J. , Centore Richard C. , Bellon Steven F. , Hentemann Martin
Published: December 2023

The BRG/BRM-associated factor (BAF) complex plays critical roles in chromatin regulation. Within this complex, the two mutually exclusive ATPases BRM and BRG1 (SMARCA2 and SMARCA4, respectively) drive chromatin remodeling activity. Genetic alterations in the SMARCA4 gene, encoding BRG1, are found in approximately 10% of non-small cell lung cancer (NSCLC) patients, leaving this subset of BRG1-deficient tumors highly susceptible to BRM inhibition. In addition, BRG1 has oncogenic activity in NSCLC, rationalizing the use of a dual BRM/BRG1 ATPase inhibitor, such as the highly potent clinical stage compound FHD-286, in NSCLC patients, regardless of SMARCA4 status. Here, we demonstrate that a panel of NSCLC cell lines respond to dual BAF ATPase inhibition in both in vitro and in vivo settings, regardless of SMARCA4 mutation status. Interestingly, dual BRM/BRG1 inhibition in cell lines reduces chromatin accessibility at motifs normally bound by AP-1 transcription factors, which play tumorigenic roles in NSCLC.  We also find that expression of the stemness-associated glycoprotein CD44 is decreased by FHD-286, suggesting that dual BRM/BRG1 inhibition impacts the differentiation state of NSCLC. Moreover, transcriptional analyses of NSCLC xenograft models reveal that a basal cell gene expression signature, which is associated with a less differentiated cell state, is downregulated by FHD-286 treatment.  Finally, genome-wide CRISPR knockout screening with FHD-286 in 2 NSCLC lines further elucidates mechanisms of action and molecular vulnerabilities induced by dual BAF ATPase inhibition. Collectively, these results indicate a path forward for the development of FHD-286 for the treatment of NSCLC patients.

Citation Format: Molly M. Wilson, Ammar Adam, Victoria Amaral, Oliver Mikse, GiNell Elliott, David L. Lahr, Ashley K. Gartin, Jessica Wan, Liv Johannessen, Kana Ichikawa, Katharine Feldman, Jessica Piel, Gabriel J. Sandoval, Richard C. Centore, Steven F. Bellon, Martin Hentemann. Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A064.