bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and outcome of biliary atresia in Shanghai, China from 2015 to 2016: a cohort study
Authors: Yang Yifan , Dong Rui , Chen Gong , Zheng Shan , Yan Weili , Shen Zhen
Published: September 2024

Demographic characteristics and clinical data of all newly diagnosed biliary atresia patients in Shanghai were collected from 1 January 2015 to 31 October 2016. The total number of live births was 377 420 during the study period, and the incidence of biliary atresia in Shanghai was 10.86 per 100 000 (95% CI 7.8 to 17.74), with 62.9% and 45.7% cases retaining native liver survival at 2 and 5 years after Kasai procedure, respectively. Implementation of systematic screening measures for biliary atresia in China is needed.
Pretransplant cardiac stress testing and transplant wait time in kidney transplantation candidates
Authors: Lee Ming-Sum , Batiste Columbus , Onwuzurike James , Elkoustaf Rachid , Wu Yi-Lin , Chen Wansu , Kahwaji Joseph , Sahota Amandeep , Lee Roland L
Published: September 2024

Objective

Routine screening for cardiovascular disease before kidney transplantation remains controversial. This study aims to compare cardiac testing rates in patients with end-stage renal disease, referred and not referred for transplantation, and assess the impact of testing on transplant wait times.

Methods

This is a retrospective cohort study of 22 687 end-stage renal disease patients from 2011 to 2022, within an integrated health system. Cardiac testing patterns, and the association between cardiac testing and transplant wait times and post-transplant mortality were evaluated.

Results

Of 22 687 patients (median age 66 years, 41.1% female), 6.9% received kidney transplants, and 21.0% underwent evaluation. Compared with dialysis patients, transplant patients had a 5.6 times higher rate of stress nuclear myocardial perfusion imaging with single-photon emission (rate ratio (RR) 5.64, 95% CI 5.37 to 5.92), a 6.5 times higher rate of stress echocardiogram (RR 6.51, 95% CI 5.65 to 7.51) and 16% higher cardiac catheterisation (RR 1.16, 95% CI 1.06 to 1.27). In contrast, revascularisation rates were significantly lower in transplant patients (RR 0.46, 95% CI 0.36 to 0.58). Transplant wait times were longer for patients who underwent stress testing (median 474 days with no testing vs 1053 days with testing) and revascularisation (1796 days for percutaneous intervention and 2164 days for coronary artery bypass surgery). No significant association was observed with 1-year post-transplant mortality (adjusted OR 1.99, 95% CI 0.46 to 8.56).

Conclusions

This study found a higher rate of cardiac testing in dialysis patients evaluated for kidney transplants. Cardiac testing was associated with longer transplant wait time, but no association was observed between testing and post-transplant mortality.
Pregnancy complications and long-term risk of cardiovascular events in women with structural heart disease
Authors: Cederlöf Elin Täufer , Lindhagen Lars , Lundgren Maria , Lindahl Bertil , Christersson Christina
Published: September 2024

Background

To determine the frequency of pregnancy complications and their association with the risk of cardiovascular outcomes in women with structural heart disease (SHD).

Methods

This nationwide registry-based cohort study included women in Sweden with SHD (pulmonary arterial hypertension, congenital heart disease or acquired valvular heart disease) with singleton births registered in the national Medical Birth Register (MBR) between 1973 and 2014. Exposures were pregnancy complications; pre-eclampsia/gestational hypertension (PE/gHT), preterm birth and small for gestational age (SGA) collected from MBR. The outcomes were cardiovascular mortality and hospitalisations defined from the Cause of Death Register and the National Patient Register. Cox regression models were performed with time-dependent covariates, to determine the possible association of pregnancy complications for cardiovascular outcomes.

Results

Among the total of 2 134 239 women included in the MBR, 2554 women with 5568 singleton births were affected by SHD. Women without SHD (N=2 131 685) were used as a reference group. PE/gHT affected 5.8% of pregnancies, preterm birth 9.7% and SGA 2.8%. Preterm birth (adjusted HR, aHR 1.91 (95% CI 1.38 to 2.64)) was associated with an increased risk of maternal all-cause mortality. PE/gHT (aHR 1.64 (95% CI 1.18 to 2.29)) and preterm birth (aHR 1.56 (95% CI 1.19 to 2.04)) were associated with an increased risk of hospitalisations for atherosclerotic CVD.

Conclusions

Pregnancy complications were frequent in women with SHD. With a median follow-up time of 22 years, preterm birth was associated with a higher risk of cardiovascular mortality, and PE/gHT and preterm birth were associated with cardiovascular morbidity. In women with SHD, pregnancy complications may provide additional information for the risk assessment of future cardiovascular outcomes.
Optimal duration of dual antiplatelet therapy for minor stroke within 72 hours of symptom onset: a prospective cohort study
Authors: Liu Tingting , Wang Yongle , Zhang Kaili , Fan Haimei , Li Yanan , Ren Jing , Li Juan , Li Yali , Li Xinyi , Xuemei Wu , Wang Junhui , Xue Lixi , Gao Xiaolei , Yan Yuping , Li Gaimei , Liu Qingping , Niu Wenhua , Du Wenxian , Liu Yuting , Niu Xiaoyuan
Published: September 2024

Objectives

Despite the potential spillover effect, the optimal duration of dual antiplatelet therapy for minor stroke within 72 hours of symptom onset is still uncertain.

Methods

Safety and Efficacy of Aspirin-Clopidogrel in Acute Noncardiogenic Minor Ischemic Stroke (National Institutes of Health Stroke Scale (NIHSS) score≤5) is a prospective cohort study involving patients with minor ischaemic stroke within 72 hours of symptom onset. The DAPT group was further categorised into three subgroups: shorter duration (<10 days), short duration (10–21 days) and long duration (>21 days). The primary efficacy and safety outcomes were composite vascular event and severe bleeding during 90 days.

Results

Among 3061 eligible patients (age was 61.7±12.0 years, 73.3% were men, median (IQR) NIHSS score, 2 (1–3)), 2977 (97.4%) completed the follow-up. Dual antiplatelet therapy (DAPT) and single antiplatelet therapy (SAPT) were administered in 61.0% and 39.0% of patients. Among them, 305 patients (16.8%) received a shorter duration of DAPT, 937 patients (51.7%) received a short duration and 572 patients (31.5%) received a long duration. In the propensity-weighted Cox proportional hazards regression analysis, the use of DAPT in the short-duration group was associated with a lower risk of the primary vascular event outcome (HR (HR)=0.66, 95% CI 0.46 to 0.94, p=0.02) compared with SAPT group. The incidence of severe bleeding events at 90 days was similar. Similar findings were obtained from the propensity score-matching analysis.

Conclusion

Short duration of DAPT (10–21 days) is superior to SAPT in minor stroke within 72 hours, reducing 90-day composite vascular events without increasing bleeding risk.
Effects of cow feed efficiency, longevity, heterosis, and lifetime productivity on profitability of heifer selection and cow–calf operations
Authors: Khakbazan Mohammad , Olson Cameron A. , Block Hushton C. , Li Changxi , Basarab John A.
Published: September 2024

This study investigated factors influencing heifer replacement and cow–calf profitability using 361 cows (born 2011–2018) at the Lacombe Research and Development Centre, Alberta, Canada. Profitability was measured by marginal returns (MR) incorporating feed costs, heifer opportunity cost, calf and cull revenues, and a premium for cows retained in the herd. The study evaluated the linear effects of lifetime productivity, feed efficiency (residual feed intake adjusted for off-test backfat thickness; RFIfat), and genomic retained heterozygosity, an indicator of heterosis, on MR, feed costs, total costs, and net revenue (NR). Lifetime productivity, defined by the cumulative weight of calves weaned, was positively associated with MR and NR ( P < 0.01). RFIfat influenced total cost, MR, and NR ( P < 0.05), with MR improved by $168.50 cow−1 year−1 for each unit decrease in RFIfat, although regression and group mean comparisons were not fully consistent. Genomic retained heterozygosity positively impacted MR and NR, with a 10% increase enhanced MR and NR by $21.80 and $20.50 cow−1 year−1, respectively. Cow breed type did not affect longevity, MR, or NR. In conclusion, RFIfat and genomic diversity were important factors to consider in heifer replacement decisions when lifetime DMI was estimated as described in the present study.
The nuclear many-body problem
Authors: Blaschke David , Horiuchi Hisashi , Ring Peter , Röpke Gerd
Published: September 2024

This Topical Collection of the European Physics Journal A is devoted to recent progress in the nuclear many-body problem. In particular, it aims at a comprehensive compilation of developments related to the work of a pioneer in that field, Peter Schuck, who passed away in 2022. Together with Peter Ring, he co-authored the book on “The Nuclear Many-Body Problem”. Different concepts presented in this seminal book have been elaborated further within a broad international collaboration. For instance, the quasi-particle approaches in connection with nuclear superfluidity and cluster formation in nuclear systems, in particular alpha-particle condensation and quartetting at subsaturation densities, have been put forward inspired by Peter Schuck. These advances obtained in the nuclear many-body problem can also be applied to other systems, for instance solid state physics. This Topical Collection is considered as addendum and continuation of the textbook of P. Ring and P. Schuck.
Thermodynamics of a rotating hadron resonance gas with van der Waals interaction
Authors: Pradhan Kshitish Kumar , Sahoo Bhagyarathi , Sahu Dushmanta , Sahoo Raghunath
Published: September 2024

Studying the thermodynamics of the systems produced in ultra-relativistic heavy-ion collisions is crucial in understanding the QCD phase diagram. Recently, a new avenue has opened regarding the implications of large initial angular momentum and subsequent vorticity in the medium evolution in high-energy collisions. This adds a new type of chemical potential into the partonic and hadronic systems, called the rotational chemical potential. We study the thermodynamics of an interacting hadronic matter under rotation, formed in an ultra-relativistic collision. We introduce attractive and repulsive interactions through the van der Waals equation of state. Thermodynamic properties like the pressure (P), energy density ($$\varepsilon $$
ε
), entropy density (s), trace anomaly ($$(\varepsilon - 3P)/T^{4}$$

(
ε
-
3
P
)

/

T
4

), specific heat ($$c_\textrm{v}$$

c
v

) and squared speed of sound ($$c_\textrm{s}^{2}$$

c
s
2

) are studied as functions of temperature (T) for zero and finite rotation chemical potential. The conserved charge fluctuations, which can be quantified by their respective susceptibilities, are also studied. The rotational (spin) density corresponding to the rotational chemical potential is explored. In addition, we explore the possible liquid–gas phase transition in the hadron gas with van der Waals interaction in the T – $$\omega $$
ω
phase space.
On the optical soliton solutions of the perturbed Fokas–Lenells equation having parabolic law of self-phase modulation in the presence of spatio-temporal dispersion
Authors: Onder Ismail , Ozisik Muslum , Secer Aydin , Bayram Mustafa
Published: September 2024

In this study, we aimed to obtain optical soliton solutions of the perturbed Fokas–Lenells equation having the parabolic law of self-phase modulation in the presence of spatio-temporal dispersion. The Fokas–Lenells equation is significant in nonlinear optics, particularly for modeling femto-second pulse propagation. By implementing the enhanced Kudryashov method, we derive dark, bright, and kink optical solitons for the investigated model. Visualizing the obtained results supported by 3D and 2D simulations and examining the effects of the parameters within the model on the soliton behavior constitute the other branches of the study. Considering that the interaction of various self-phase modulation forms with the chromatic dispersion term is different and its effects on soliton behavior are different, the parabolic law nonlinearity form is examined in the study and the results obtained are aimed at contributing to studies on both the model and nonlinear optics.
Towards a New Typology of Digitalized Co-production: Implementing Local Emergency Response Initiatives Nationwide
Authors: Pilemalm Sofie , Alkusaibati Wael
Published: September 2024

In Sweden, a decade ago, digitalized co-production emergency response initiatives of a hybrid bottom-up type emerged. They targeted local efforts to recruit groups of citizens to provide first responses for other citizens in accidents. Benefits in terms of shorter response times, saved lives, reduced human suffering, and material damage have been demonstrated. Recently, national authorities recognized the need to support the initiatives to expand to all rescue services, and the potential to scale up the use of citizen first responders, also in large-scale crisis management and as part of civil preparedness. Previous research has studied the initiatives and developed three models aimed at supporting the implementation of digitalized co-production. In this study, we report from the initial phase of the nationwide effort, carry out an initial evaluation, and present revised models. The models are adapted to rural versus urban settings and complemented with a model providing national support. Information and communication technology plays a crucial role in all of them. We define the hybrid type as interdependent digitalized co-production where government citizen sourcing is not direct but includes the intermediate level of the rescue services. Implications are discussed, e.g., on how to achieve a balance between centralization and decentralization.
FedNIDS: A Federated Learning Framework for Packet-Based Network Intrusion Detection System
Authors: Nguyen Quoc H. , Hore Soumyadeep , Shah Ankit , Le Trung , Bastian Nathaniel D.
Published: September 2024

Network intrusion detection systems (NIDS) play a critical role in discerning between benign and malicious network traffic. Deep neural networks (DNNs), anchored on large and diverse datasets, exhibit promise in enhancing the detection accuracy of NIDS by capturing intricate network traffic patterns. However, safeguarding distributed computer networks against emerging cyber threats is increasingly challenging. Despite the abundance of diverse network data, decentralization persists due to data privacy and security concerns. This confers an asymmetric advantage to adversaries, as distributed networks face the formidable task of securely and efficiently sharing non-independently and identically distributed data to counter cyber-attacks. To address this, we propose the federated NIDS (
FedNIDS
), a novel two-stage framework that combines the power of federated learning and DNNs. It aims to enhance the detection accuracy of known attacks, robustness and resilience to novel attack patterns, and privacy preservation, using packet-level granular data. In the first stage, a global DNN model is collaboratively trained on distributed data, and the second stage adapts it to novel attack patterns. Our experiments on real-world intrusion datasets demonstrate the effectiveness of
FedNIDS
by achieving an average F1 score of 0.97 across distributed networks and quickly disseminating novel attack information within four rounds of communication.
Deformation Monitoring Model of Buried Pipeline Mechanical Parts Based on the Distributed Optical Fiber Monitoring System
Authors: Shen Bihua , Wang Xiangchao , Sun Mengya , Qian Wei
Published: September 2024

Oil pipeline projects in China are mostly long‐distance, linear projects, making pipelines vulnerable to safety problems. Consequently, pipeline monitoring is crucial for their effective maintenance. In this study, a recently developed optical fiber sensing technology was employed to monitor pipeline crossing projects and conduct tests to study the coordination deformation of buried‐pipeline‐soil systems using a comprehensive deformation monitoring system model based on optical fiber sensing technology developed for the test. The test realized three‐dimensional monitoring of the pipeline and soil deformation when lateral displacement occurred in the soil. In addition, the feasibility of monitoring the deformation of different encapsulation types of optical fiber gratings and different sheath types of distributed optical fibers was demonstrated using this test model. The test results showed that both distributed optical fibers and fiber Bragg gratings (FBGs) could effectively reflect the strain distribution status of a pipeline during deformation monitoring. However, distributed optical fibers could detect data between two points, making them more suitable for pipeline monitoring. The FBG displacement and soil‐pressure gauges could effectively monitor pipeline displacement and soil‐pressure changes, thereby providing a basis for predicting the direction of slider movement during pipeline deflection and landslide monitoring. This test realized the multiparameter monitoring of pipeline deformation, pipeline displacement, and soil pressure along the pipeline, thereby providing a theoretical basis for developing prediction and warning systems for buried pipelines.
HWOA‐TTA: A New Hybrid Metaheuristic Algorithm for Global Optimization and Engineering Design Applications
Authors: Najm Huda Y. , Khaleel Elaf Sulaiman , Hamed Eman T. , Ahmed Huda I.
Published: September 2024

Hybrid metaheuristics is one of the most exciting improvements in optimization and metaheuristic algorithms. A current research topic combines two algorithms to provide a more advanced solution to optimization problems. The present study applies a new approach called HWOA‐TTA which means a hybrid of the whale optimizer algorithm (WOA) and tiki‐taka algorithm (TTA). The hybrid WOA‐TTA combines the exploitation phase of WOA with the exploration phase of TTA. Two stages in the hybridized model are suggested. First, the WOA exploitation phase incorporates the TTA mechanism. Second, a new approach is included in the research phase to enhance the result with each iteration to a set of unconstrained benchmark test functions and engineering design applications. To verify the performance of the improved algorithm, thirteen benchmark functions have been used to compare HWOA‐TTA with the classical intelligent population algorithms (PSO, TTA, and WOA). The hybrid algorithm is applied to two well‐known engineering mathematical models. The experiments show that the HWOA‐TTA outperforms other algorithms.
Supplementary Table S1-19 from Germline cancer gene expression quantitative trait loci are associated with local and global tumor mutations
Authors: Liu Yuxi , Gusev Alexander , Kraft Peter
Published: September 2024

Supplementary Table S1-19
Table S2 from Single-cell discovery and multi-omic characterization of therapeutic targets in multiple myeloma
Authors: Yao Lijun , Wang Julia T. , Jayasinghe Reyka G. , O'Neal Julie , Tsai Chia-Feng , Rettig Michael P. , Song Yizhe , Liu Ruiyang , Zhao Yanyan , Ibrahim Omar M. , Fiala Mark A. , Fortier Julie M. , Chen Siqi , Gehrs Leah , Martins Rodrigues Fernanda , Wendl Michael C. , Kohnen Danny , Shinkle Andrew , Cao Song , Foltz Steven M. , Zhou Daniel Cui , Storrs Erik , Wyczalkowski Matthew A. , Mani Smrithi , Goldsmith Scott R. , Zhu Ying , Hamilton Mark , Liu Tao , Chen Feng , Vij Ravi , Ding Li , DiPersio John F.
Published: September 2024

Novelty description of candidate tumor markers. Each gene is ranked according to existing literature and/or clinical trials investigating its role in multiple myeloma. Representative studies are listed.
Supplementary Video from Short-wave infrared imaging enables high-contrast fluorescence-guided surgery in neuroblastoma
Authors: Privitera Laura , Waterhouse Dale J. , Preziosi Alessandra , Paraboschi Irene , Ogunlade Olumide , Da Pieve Chiara , Barisa Marta , Ogunbiyi Olumide , Weitsman Gregory , Hutchinson J. Ciaran , Cross Kate , Biassoni Lorenzo , Stoyanov Danail , Sebire Neil , Beard Paul , De Coppi Paolo , Kramer-Marek Gabriela , Anderson John , Giuliani Stefano
Published: September 2024

Supplementary video showing fluorescence-guided resection of a subcutaneous model of Neuroblastoma injected with anti-GD2 fluorescence probes
Supplementary Tables from Large B-cell lymphomas of immune privileged sites relapse via parallel clonal evolution from a common progenitor B-cell
Authors: Los-de Vries G. Tjitske , Stathi Phylicia , Rutkens Ryanne , Hijmering Nathalie J. , Luijks Jeroen A.C.W. , Groenen Patricia J.T.A. , de Jong Daphne , Ylstra Bauke , Roemer Margaretha G.M.
Published: September 2024

Supplementary Tables
Supplementary Data from A self-propagating c-Met-SOX2 axis drives cancer-derived IgG signaling that promotes lung cancer cell stemness
Authors: Huang Xinmei , Zhang Shenghua , Tang Jingshu , Tian Tian , Pan Yilin , Wu Lina , Zhang Jingxuan , Liu Yang , Huang Jing , Dai Hui , Xu Weiyan , Zhang Youhui , Chen Jinfeng , Cao Mengshu , Zhang Liang , Qiu Xiaoyan
Published: September 2024

Supplementary figures and tables.
Supplementary Data from Metabolic reprogramming driven by IGF2BP3 promotes acquired resistance to EGFR inhibitors in non-small cell lung cancer
Authors: Lin Ziyou , Li Jingwei , Zhang Jian , Feng Weineng , Lu Jiaye , Ma Xiaofan , Ding Wen , Ouyang Shumin , Lu Jin-Jian , Yue Peibin , Wan Guohui , Liu Peiqing , Zhang Xiaolei
Published: September 2024

Supplementary Data
Table S2 from Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation of Transposable Element Loci
Authors: Kanholm Tomas , Rentia Uzma , Hadley Melissa , Karlow Jennifer A. , Cox Olivia L. , Diab Noor , Bendall Matthew L. , Dawson Tyson , McDonald James I. , Xie Wenbing , Crandall Keith A. , Burns Kathleen H. , Baylin Stephen B. , Easwaran Hariharan , Chiappinelli Katherine B.
Published: September 2024

Table S2
Figure S4 from Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation of Transposable Element Loci
Authors: Kanholm Tomas , Rentia Uzma , Hadley Melissa , Karlow Jennifer A. , Cox Olivia L. , Diab Noor , Bendall Matthew L. , Dawson Tyson , McDonald James I. , Xie Wenbing , Crandall Keith A. , Burns Kathleen H. , Baylin Stephen B. , Easwaran Hariharan , Chiappinelli Katherine B.
Published: September 2024

Supplemental Figure 4
Supplementary Data from A genetic locus within the FMN1/GREM1 gene region interacts with body mass index in colorectal cancer risk
Authors: Aglago Elom K. , Kim Andre E. , Lin Yi , Qu Conghui , Evangelou Marina , Ren Yu , Morrison John , Albanes Demetrius , Arndt Volker , Barry Elizabeth L. , Baurley James W. , Berndt Sonja I. , Bien Stephanie A. , Bishop D. Timothy. , Bouras Emmanouil , Brenner Hermann , Buchanan Daniel D. , Budiarto Arif , Carreras-Torres Robert , Casey Graham , Cenggoro Tjeng Wawan , Chan Andrew T. , Chang-Claude Jenny , Chen Xuechen , Conti David V. , Devall Matthew , Díez-Obrero Virginia , Dimou Niki , Drew David , Figueiredo Jane C. , Gallinger Steven , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Gunter Marc J. , Hampel Heather , Harlid Sophia , Hidaka Akihisa , Harrison Tabitha A. , Hoffmeister Michael , Huyghe Jeroen R. , Jenkins Mark A. , Jordahl Kristina , Joshi Amit D. , Kawaguchi Eric S. , Keku Temitope O. , Kundaje Anshul , Larsson Susanna C. , Le Marchand Loic , Lewinger Juan Pablo , Li Li , Lynch Brigid M. , Mahesworo Bharuno , Mandic Marko , Obón-Santacana Mireia , Moreno Victor , Murphy Neil , Nan Hongmei , Nassir Rami , Newcomb Polly A. , Ogino Shuji , Ose Jennifer , Pai Rish K. , Palmer Julie R. , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Platz Elizabeth A. , Potter John D. , Prentice Ross L. , Rennert Gad , Ruiz-Narvaez Edward , Sakoda Lori C. , Scacheri Peter C. , Schmit Stephanie L. , Schoen Robert E. , Shcherbina Anna , Slattery Martha L. , Stern Mariana C. , Su Yu-Ru , Tangen Catherine M. , Thibodeau Stephen N. , Thomas Duncan C. , Tian Yu , Ulrich Cornelia M. , van Duijnhoven Fränzel J.B. , Van Guelpen Bethany , Visvanathan Kala , Vodicka Pavel , Wang Jun , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Zemlianskaia Natalia , Hsu Li , Gauderman W. James. , Peters Ulrike , Tsilidis Konstantinos K. , Campbell Peter T.
Published: September 2024

supplementary materials
Table S2 from Breast cancer mutations HER2 V777L and PIK3CA H1047R activate the p21-CDK4/6 –Cyclin D1 axis driving tumorigenesis and drug resistance.
Authors: Cheng Xiaoqing , Sun Yirui , Highkin Maureen , Vemalapally Nagalaxmi , Jin Xiaohua , Zhou Brandon , Prior Julie L. , Tipton Ashley R. , Li Shunqiang , Iliuk Anton , Achilefu Samuel , Hagemann Ian S. , Edwards John R. , Bose Ron
Published: September 2024

Phosphopeptides
Table S5 from Characterizing evolutionary dynamics reveals strategies to exhaust the spectrum of subclonal resistance in EGFR-mutant lung cancer
Authors: Müller Nina , Lorenz Carina , Ostendorp Jenny , Heisel Felix S. , Friese Ulrich P. , Cartolano Maria , Plenker Dennis , Tumbrink Hannah L. , Heimsoeth Alena , Baedeker Philipp , Ortiz-Cuaran Sandra , Weiss Jonathan , Büttner Reinhard , Peifer Martin , Thomas Roman K. , Sos Martin L. , Berg Johannes , Brägelmann Johannes
Published: September 2024

Table S5 mutations from Whole exome sequencing
Supplementary Data 2. from The genomic and epigenomic landscape of double-negative metastatic prostate cancer
Authors: Lundberg Arian , Zhang Meng , Aggarwal Rahul , Li Haolong , Zhang Li , Foye Adam , Sjöström Martin , Chou Jonathan , Chang Kevin , Moreno-Rodriguez Thaidy , Shrestha Raunak , Baskin Avi , Zhu Xiaolin , Weinstein Alana S. , Younger Noah , Alumkal Joshi J. , Beer Tomasz M. , Chi Kim N. , Evans Christopher P. , Gleave Martin , Lara Primo N. , Reiter Rob E. , Rettig Matthew B. , Witte Owen N. , Wyatt Alexander W. , Feng Felix Y. , Small Eric J. , Quigley David A.
Published: September 2024

List of enriched motifs identified in the hyper- and hypo-methylated regions of mCRPC subtypes
Data from Fructose metabolism in tumor endothelial cells promotes angiogenesis by activating AMPK signaling and mitochondrial respiration
Authors: Fang Jian-Hong , Chen Jie-Ying , Zheng Jia-Lin , Zeng Hui-Xian , Chen Jun-Guang , Wu Chen-Hui , Cai Jia-Li , Wang Zhi-Yong , Zhuang Shi-Mei
Published: September 2024

Abstract
Angiogenesis is vital for tumor growth and metastasis. Emerging evidence suggests that metabolic reprogramming in endothelial cells (ECs) may affect angiogenesis. Here, we showed that multiple regulators in the fructose metabolism pathway, especially fructose transporter SLC2A5 and fructose-metabolizing enzyme ketohexokinase (KHK), were upregulated in tumor endothelial cells from hepatocellular carcinoma (HCC). In mouse models with hepatoma xenografts or with Myc/sgp53-induced liver cancer, dietary fructose enhanced tumor angiogenesis, tumor growth, and metastasis, which could be attenuated by treatment with an inhibitor of SLC2A5. Furthermore, vessel growth was substantially increased in fructose-containing matrigel compared to PBS-matrigel. Inhibiting fructose metabolism in EC cells in vivo using EC-targeted nanoparticles loaded with siRNA against KHK significantly abolished fructose-induced tumor angiogenesis. Fructose treatment promoted the proliferation, migration and tube formation of ECs and stimulated mitochondrial respiration and ATP production. Elevated fructose metabolism activated AMPK to fuel mitochondrial respiration, resulting in enhanced EC migration. Fructose metabolism was increased under hypoxic conditions as a result of HIF1α-mediated upregulation of multiple genes in the fructose metabolism pathway. These findings highlight the significance of fructose metabolism in ECs for promoting tumor angiogenesis. Restricting fructose intake or targeting fructose metabolism is a potential strategy to reduce angiogenesis and suppress tumor growth.
Data from Bayesian machine learning enables identification of transcriptional network disruptions associated with drug-resistant prostate cancer
Authors: Blatti Charles , de la Fuente Jesús , Gao Huanyao , Marín-Goñi Irene , Chen Zikun , Zhao Sihai D. , Tan Winston , Weinshilboum Richard , Kalari Krishna R. , Wang Liewei , Hernaez Mikel
Published: September 2024

Abstract
Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to overcome resistance. Given the complexity of the transcriptional dynamics in cells, differential gene expression analysis of bulk transcriptomics data cannot provide sufficient detailed insights into resistance mechanisms. Incorporating network structures could overcome this limitation to provide a global and functional perspective of Abi-resistance in mCRPC. Here, we developed TraRe, a computational method using sparse Bayesian models to examine phenotypically-driven transcriptional mechanistic differences at three distinct levels: transcriptional networks, specific regulons, and individual transcription factors. TraRe was applied to transcriptomic data from 46 mCRPC patients with Abi-response clinical data and uncovered abrogated immune response transcriptional modules that showed strong differential regulation in Abi-responsive compared to Abi-resistant patients. These modules were replicated in an independent mCRPC study. Further, key rewiring predictions and their associated transcription factors were experimentally validated in two prostate cancer cell lines with different Abi resistance features. Among them, ELK3, MXD1, and MYB played a differential role in cell survival in Abi-sensitive and Abi-resistant cells. Moreover, ELK3 regulated cell migration capacity, which could have a direct impact on mCRPC. Collectively, these findings shed light on the underlying transcriptional mechanisms driving abiraterone response, demonstrating that TraRe is a promising tool for generating novel hypotheses based on identified transcriptional network disruptions.
Data from G-quadruplex structures are key modulators of somatic structural variants in cancers
Authors: Zhang Rongxin , Shu Huiling , Wang Yuqi , Tao Tiantong , Tu Jing , Wang Cheng , Mergny Jean-Louis , Sun Xiao
Published: September 2024

Abstract
G-quadruplexes (G4s) are non-canonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SVs) in cancers could provide a better understanding of the role of G4 formation in cancer development and progression. In this study, we combined bioinformatic approaches and multi-omics data to investigate the connection between G4s and the somatic SVs. Somatic SV breakpoints were significantly enriched in G4 regions, regardless of SV subtypes. This enrichment was only observed in regions demonstrated to form G4s in cells (“active quadruplexes”), rather than in regions with a sequence compatible with G4 formation but without confirmed G4 formation (“potential quadruplexes”). Several genomic features impacted the connection between G4s and SVs, with the enrichment being notably strengthened at the boundary of topologically associated domains. Somatic breakpoints were also preferentially associated with G4 regions with earlier replication timing and open chromatin status. In cancer patients with homologous recombination repair defects, G4s and somatic breakpoints were substantially more strongly associated. Machine learning models were constructed that showed that G4 propensity is a potent feature for predicting the density of SV breakpoints. Altogether, these findings suggest that the G4 structures play a critical role in modulating the production of somatic SVs in cancers.
Data from RBM10 loss promotes EGFR-driven lung cancer and confers sensitivity to spliceosome inhibition
Authors: Bao Yufang , Zhang Sirui , Zhang Xiaoyu , Pan Yunjian , Yan Yueren , Wang Ning , Ren Yunpeng , Zuo Ji , Zong Wei-Xing , Wang Zefeng , Wang Yongbo
Published: September 2024

Abstract
In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD datasets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. RBM10 loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, RBM10 deficiency conferred high sensitivity to spliceosome inhibition in EGFR-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD.
Data from ANO1 reprograms cholesterol metabolism and the tumor microenvironment to promote cancer metastasis
Authors: Deng Chun-Miao , Zhang Guo-Geng , Liu Qin-Wen , Xu Jiao-Jiao , Liu Zhi-Chao , Yang Jing , Xu Tao-Yang , Li Zhi-Gang , Zhang Fan , Li Bin
Published: September 2024

Abstract
Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues. High expression of ANO1 was associated with poor patient survival, and ANO1 overexpression promoted cancer invasion and metastasis. Mechanistically, ANO1 inactivated the LXR pathway and increased intracellular cholesterol accumulation by interacting with JUN to repress the transcription of cholesterol hydroxylase, CYP27A1. In a paracrine manner, interleukin 1β (IL-1β) secreted from ANO1-expressing ESCC cancer cells activated NFκB signaling in fibroblasts to stimulate production of the chemokine CCL1, which in turn enhanced invasion of ESCC cancer cells. Furthermore, molecular docking and in silico screening of 1,500,000 small molecules identified K786-4469 as a lead compound that targeted ANO1 and suppressed cancer metastasis in vitro and in vivo. Overall, these findings uncover a non-canonical function of ANO1 in regulating cholesterol metabolism and fibroblast function, revealing ANO1 as a potential prognostic biomarker and therapeutic target for metastatic ESCC.
Data from Large B-cell Lymphomas of Immune-Privileged Sites Relapse via Parallel Clonal Evolution from a Common Progenitor B Cell
Authors: Los-de Vries G. Tjitske , Stathi Phylicia , Rutkens Ryanne , Hijmering Nathalie J. , Luijks Jeroen A.C.W. , Groenen Patricia J.T.A. , de Jong Daphne , Ylstra Bauke , Roemer Margaretha G.M.
Published: September 2024

Abstract
Large B-cell lymphoma of immune-privileged sites (LBCL-IP) arise in immune sanctuaries including the testis and central nervous system (CNS). After initially reaching complete response, relapses occur in almost 50% of patients, typically at other immune-privileged sites. Resolution of the clonal relationships and evolutionary patterns of LBCL-IP is required to understand the unique clinical behavior. We collected a unique set of 33 primary–relapse LBCL-IP sample pairs and performed next-generation sequencing for copy number, mutation, translocation, and immunoglobulin clonality analysis. All LBCL-IP sample pairs were clonally related, and both tumors developed from a common progenitor cell (CPC) with MYD88 and TBL1XR1 mutations and/or BCL6 translocations in 30/33 cases, indicating that these are early genetic events. This was succeeded by intermediate genetic events including shared, as well as unique alterations in targets of aberrant somatic hypermutation (aSHM), CD79B mutations, and 9p21.3/CDKN2A loss. Genetic alterations in genes involved in immune escape (HLA, CD274/PDCD1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center reentry, aSHM and immune escape.
Significance:
Genomic analyses reveal that primary and relapse LBCL-IP originate from a common progenitor cell with a small set of genetic alterations, followed by extensive parallel diversification, elucidating the clonal evolution of LBCL-IP.
Data from Extrachromosomal Amplification of Human Papillomavirus Episomes is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Alvirez Freites Enrique , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: September 2024

Abstract
HPV16 is the most oncogenic type of human papillomavirus (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. Large tandem arrays of full-length and unique truncated viral genomes integrated into multiple chromosomes were identified in two HPV16+ cell lines. The dispersion of characteristic viral variants to multiple integrations sites indicated that viral deletions formed as extrachromosomal DNA (a phenomenon we termed HPV superspreading). In addition, an HPV16+ cell line was identified with unintegrated (episomal) DNA that had tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). Cytogenetic analysis of this cell line showed intense extrachromosomal HPV staining, including structures resembling double-minute chromosomes. Whole genome sequencing of HPV16+ cervical tumor samples from Latin America revealed that 11/20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining nine EP tumors had multimer and rearranged HPV genomes. The majority (80%) of HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations displayed HPV multimers and concatemers of human and viral sequences. This data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication to form rearranged, mutated, and multimer episomes.
Data from Syk inhibition reprograms tumor-associated macrophages and overcomes gemcitabine-induced immunosuppression in pancreatic ductal adenocarcinoma
Authors: Rohila Deepak , Park In Hwan , Pham Timothy V. , Weitz Jonathan , Hurtado de Mendoza Tatiana , Madheswaran Suresh , Ishfaq Mehreen , Beaman Cooper , Tapia Elisabette , Sun Siming , Patel Jay , Tamayo Pablo , Lowy Andrew M. , Joshi Shweta
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low five-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAMs) that promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting pro-tumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, “re-educated” pro-tumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the anti-tumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.
Data from Temozolomide sensitizes ARID1A-mutated cancers to PARP inhibitors
Authors: Yu Zheng-Cheng , Li Tianhe , Tully Ellen , Huang Peng , Chen Chih-Ning , Oberdoerffer Philipp , Gaillard Stephanie , Shih Ie-Ming , Wang Tian-Li
Published: September 2024

Abstract
ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation.
Data from A non-conserved histidine residue on KRAS drives paralog selectivity of the KRASG12D inhibitor MRTX1133
Authors: Keats Miles , Han John J.W. , Lee Yeon-Hwa , Lee Chih-Shia , Luo Ji
Published: September 2024

Abstract
MRTX1133 is the first non-covalent inhibitor against the KRASG12D mutant that demonstrated specificity and potency in pre-clinical tumor models. Here, we used isogenic cell lines expressing a single Ras allele to evaluate the selectivity of this compound. In addition to KRASG12D, MRTX1133 showed significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibited no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to H95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three Ras paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, H95 is an essential selectivity handle for MRTX1133 towards KRAS. Amino acid diversity at residue 95 could facilitate the discovery of pan‐KRAS inhibitors as well as HRAS and NRAS paralog‐selective inhibitors.
Data from Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear-cell renal cell carcinoma
Authors: Davidson Guillaume , Helleux Alexandra , Vano Yann A. , Lindner Véronique , Fattori Antonin , Cerciat Marie , Elaidi Reza Thierry. , Verkarre Virginie , Sun Cheng-Ming , Chevreau Christine , Bennamoun Mostefa , Lang Hervé , Tricard Thibault , Fridman Wolf Herman. , Sautes-Fridman Catherine , Su Xiaoping , Plassard Damien , Keime Celine , Thibault-Carpentier Christelle , Barthélémy Philippe , Oudard Stéphane Marie. , Davidson Irwin , Malouf Gabriel G.
Published: September 2024

Abstract
Immune checkpoint inhibitors (ICI) represent the cornerstone for treatment of patients with metastatic clear-cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease highlighting the need to precisely understand plasticity of cancer cells and their crosstalk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial to mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public datasets and in data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAFs), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. This data highlights the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance.
Data from CD36 drives metastasis and relapse in acute myeloid leukemia
Authors: Farge Thomas , Nakhle Jean , Lagarde Damien , Cognet Guillaume , Polley Nathaniel , Castellano Remy , Nicolau Marie-Laure , Bosc Claudie , Sabatier Marie , Sahal Ambrine , Saland Estelle , Jeanson Yannick , Guiraud Nathan , Boet Emeline , Bergoglio Camille , Gotanègre Mathilde , Mouchel Pierre-Luc , Stuani Lucille , Larrue Clement , Sallese Marie , De Mas Véronique , Moro Cédric , Dray Cedric , Collette Yves , Raymond-Letron Isabelle , Ader Isabelle , Recher Christian , Sarry Jean-Emmanuel , Cabon Florence , Vergez Francois , Carriere Audrey
Published: September 2024

Abstract
Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematological malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.