bluuebunny/crossref_metadata_2025 huggingface dataset:
Skill Decay of a Standing Handcuffing Technique on Brazilian Police Officers
Authors: Ziel-Beltrão Renan , Eleutério-da-Rocha José , Freire Flávio Dalossa
Published: January 2025

This study investigated skill decay among Brazilian police officers in handcuffing techniques. The aim was to assess whether officers maintained their performance approximately 1 month after retraining and if there were differences between officers on bureaucratic versus regular duties. Twenty-one officers were distributed into two groups (bureaucratic and regular groups) and a retraining session on a standardized handcuffing technique. Participants practiced until achieving a performance threshold, measured by the number of correct steps. The experimenters also registered handcuffing execution times. Results from the retest 4 weeks later showed a decline in correct steps below the threshold for both groups, indicating skill decay. However, between-group differences were not significant, and there was no statistically significant impact on execution times. These findings suggest a failure to retain skills, with similar decay observed among bureaucratic and patrol officers. Possible explanations and implications of these results were discussed.
Inequalities in Survival of US Olympians
Authors: Ukolova Elizabeta , Kahoun Lukáš
Published: January 2025

Objective: To determine the disparities in length of live and age-specific probabilities of death of US Olympians by sex, performance level, and age at debut at the Olympics. Methods: We apply parametric models of mortality to estimate probabilities of death by age. The best performing model (Gompertz model) is then used to calculate life tables for subpopulations of Olympians. The life table functions are then used to decompose the differences in life expectancies by age. Results: Olympians live longer than the general population but are a diverse population in terms of survival. Gender gap in survival is substantially smaller in Olympians than in general population. Medalists have a shorter lifespan than nonmedalists. Olympians debuting at extremely young ages (<22) have a survival disadvantage compared with Olympians debuting at older ages. The differences between general population and Olympians are widening in younger cohorts. Conclusion: US Olympians outlive the general population, but they constitute diverse group in terms of survival by sex, age at debut, and performance level. Studying and monitoring health disparities within the Olympic population is crucial for informing policies and regulations in sports organizations.
Empagliflozin in patients with autosomal dominant polycystic kidney disease (EMPA-PKD): study protocol for a randomised controlled trial
Authors: Bahlmann-Kroll Elisabeth , Häckl Sebastian , Kramer Stefanie , Wulfmeyer Vera Christine , Glandorf Julian , Kaufeld Jessica , Koch Armin , Hartung Dagmar , Schmidt Bernhard M W , Schmidt-Ott Kai , Schmitt Roland
Published: January 2025

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that causes the formation of cysts primarily in the kidneys. The continuous growth of multiple cysts leads to the destruction of functional parenchyma, which may progress to end-stage kidney disease. Tolvaptan is the only drug specifically approved for slowing down the progression of ADPKD. Sodium-glucose transporter 2 inhibitors might provide additional benefits but there is currently no information on safety and outcome effects of SGLT2i in patients with ADPKD, as these patients were excluded in SGLT2i trials. In particular, there has been speculation that SGLT2i might increase cyst growth and accelerate the loss of kidney function in ADPKD. The EMPA-PKD trial is assessing the safety of empagliflozin in patients with rapid progressive ADPKD with and without concomitant tolvaptan use by monitoring the total kidney volume and the loss of kidney function.

Methods and analysis

This is an investigator-initiated, double-blind, single-centre, placebo-controlled, randomised clinical trial including patients with rapidly progressive ADPKD (n=44). Participants will be randomly allocated (1:1) to receive a daily dose of either empagliflozin (10 mg/day) or placebo for 18 months. Patients will be stratified according to concomitant tolvaptan use. The primary endpoint is the progression of cystic kidney growth by monitoring MRI-based changes in total kidney volume and the secondary endpoint is the change in glomerular filtration rate. Additional endpoints include changes in copeptin levels, albuminuria and blood pressure.

Ethics and dissemination

The protocol has been approved by the German Federal Institute for Drugs and Medical Devices (BfArM) after review by the independent ethics committee Landesarztekammer Rheinland-Pfalz. Participation in this study will be voluntary and informed consent will be obtained. Regardless of the outcome, the results will be disseminated through a peer-reviewed international medical journal.

Trial registration numbers

EU-CT number 2023-505890-34-00,NCT06391450.
Applying the health capability profile: an analytical study of leading causes of death in the USA and of pressing public health issues
Authors: Coste Marion , Prah Jennifer J.
Published: January 2025

Public health problems are complex; investigating them requires a framework that both accounts for multiple interactions among individuals and their intermediate and broader environment and also integrates equity concerns. Incorporating internal and external influences at the individual level, the health capability profile (HCP)’s 15 different health capabilities address this need.

Using a systematic three-step deductive content analysis process, we examine hypothetical case studies representing leading causes of death in the USA (eg, heart disease, cancer and diabetes) as well as pressing public health issues such as COVID-19, alcohol use disorder, stigma and discrimination, intimate partner violence and firearm violence. After reviewing the profile (1), each case study is analysed through the framework of the HCP and developed into a flow diagram, through which we identify shortfalls between the observed and optimal levels of each health capability, as well as detrimental or enabling interactions among capabilities (2). We then determine factors and interventions that could help improve overall health capability (3).

The HCP harnesses the multitude of unique individual profiles, and through aggregation and analysis, reveals common vulnerabilities (eg, discriminatory social norms and non-evidence-based information), and strengths. It recommends cross-cutting structural policy and programme reforms for institutions, schools, community resources and for individuals to develop a positive set of norms, knowledge, goals, attitudes and habits to chart the path towards health and well-being for all.
A unique, far-travelled graptolite-bearing erratic pebble from the Lowestoft Till (Quaternary: Anglian Stage) of North Lopham, Norfolk
Authors: Yonan Yasmin , Zalasiewicz Jan , Holt-Wilson Tim , Harvey Thomas H. P. , Kozłowska Anna , Porębska Elżbieta , Danelian Taniel , Molyneux Stewart , Williams Mark , Hoare Peter G. , Wong Hearing Thomas W. , Rose James
Published: January 2025

An erratic chert pebble discovered on an exposure of the Lowestoft Till (Anglian Stage, Pleistocene) of North Lopham, Norfolk, UK, contains graptolites preserved three-dimensionally in silica in a mode not known in the UK. The graptolites are
Monograptus parapriodon
,
Monograptus priodon
,
Monoclimacis linnarssoni
and an undetermined retiolitid that indicate an
Oktavites spiralis
Biozone (mid-late Telychian, Late Llandovery, Silurian) age. The graptolites are associated with organic-walled microfossils, some containing internal bodies. The combination of lithology, preservation and low thermal maturity seem to exclude a British origin. The closest comparison is with Silurian chert pebbles in Miocene and Pleistocene gravels in central Germany, thought to be derived from bedrock in the Frankenwald region of Thuringia. A conjectured natural transport vector for this pebble involves drainage along the proto-Rhine system flowing into early/mid Pleistocene North Sea deltaic/marine deposits, with subsequent glacial transport to Norfolk. The possibility of an anthropogenic vector is also considered, but dismissed.
Control Engineer Roles in the Next Power Market Transition
Authors: Ballouz Hala , Mathias Joel , Meyn Sean , Moye Robert , Warrington Joseph
Published: January 2025

This survey of power operations and power markets is a collaboration between members of academia and industry. It describes the thinking behind rules in organized electricity markets, which are rooted in the theory of efficient markets, and why this theory is ill suited to address the range of challenges in real-world power systems operations. The mismatch between market theory and reality includes a lack of consideration of fixed costs and a lack of understanding of value to the consumers. Moreover, the efficient equilibrium is the solution to a risk-neutral, single-objective optimal control problem. Every control engineer knows that such solutions are rarely the final answer to a practical control problem. It is hoped that this work will inspire the control community to collaborate with industry in the design of the next generation of power markets.
Beyond Aromas: Exploring the Development and Potential Applications of Electroencephalography in Olfactory Research—From General Scents to Food Flavor Science Frontiers
Authors: Wang Zhen , Chang Xiaoyue , Zhang Chongyu , Lan Haihui , Huang Mingquan , Zhou Bin , Sun Baoguo
Published: January 2025

Olfaction is crucial to our dietary choices and significantly influences our emotional and cognitive landscapes. Understanding the underlying neural mechanisms is pivotal, especially through the use of electroencephalography (EEG). This technology has strong temporal resolution, allowing it to capture the dynamics of neural responses to odors, bypassing the need for subjective interpretations. The application of EEG in food flavor research is still relatively new, but it has great potential. This review begins with an examination of general scent stimulation, charts the advances in using EEG to understand odor perception, and explores its future in food flavor science. By analyzing EEG's ability to detect distinct patterns and strengths in brain activity, we can elucidate the perceptual, affective, and cognitive frameworks associated with food odors. Event-related potentials and oscillatory activities, markers of central olfactory processing, provide insights into the neural architecture of olfaction. These markers are instrumental in assessing the influence of food odors on health, emotions, and decision-making processes. We argue that EEG's application in olfaction research holds considerable promise for the food industry to innovate products that are not only healthier but also more appealing, thereby promoting human well-being.
Chemical and Microbiological Hazards Arising from New Plant-Based Foods, Including Precision Fermentation–Produced Food Ingredients
Authors: Jin Jing , den Besten Heidy M.W. , Rietjens Ivonne M.C.M. , Widjaja Frances
Published: January 2025

The growing human population, climate change, and environmental pollution pose urgent threats to global food security. New plant-based foods and precision fermentation that enable the production of new food ingredients can contribute to a revolutionary change in the food industry and can contribute to food security, yet they do not come without hazards. In this review, we describe the hazards of new plant-based foods, including precision fermentation–produced food ingredients. For these foods derived from plant-based raw materials, chemical and microbiological hazards are presented, including natural hazards, environmental hazards, and hazards derived from (inadequate) food processing. In addition, prospects for safety improvement of new plant-based foods and precision fermentation–produced food ingredients are also discussed. Chemical and microbiological hazards of new plant-based foods and precision fermentation–produced food ingredients are to be included in the hazard analysis and critical control point plans. New plant-based foods present hazards carried over from the plant-based raw materials and new hazards from the production process and storage, whereas the risks appear lower for precision fermentation–produced food ingredients than for regular fermented foods because of the use of a more controlled environment and purification of the targeted ingredients.
Next Steps in Efforts to Address the Obesity Epidemic
Authors: Chang Chusan Yuilyn A. , Eneli Ihuoma , Hennessy Erin , Pronk Nicolaas P. , Economos Christina D.
Published: January 2025

Obesity prevalence continues to rise globally at alarming rates, with adverse health and economic implications. In this state-of-the-art review, we provide an analysis of selected evidence about the current knowledge in the obesity literature, including a synthesis of current challenges in obesity and its determinants. In addition, we review past and current efforts to combat the obesity epidemic, highlighting both successful efforts and areas for further development. Last, we offer insights into the next steps to address the obesity epidemic and advance the field of obesity through both research and practice by (a) adopting a systems perspective, (b) fostering cross-sector and community collaborations, (c) advancing health equity, (d) narrowing the research-to-practice and research-to-policy gaps with multidisciplinary approaches, and (e) embracing complementary approaches for concurrent obesity prevention and treatment.
The Microstructure and Electrochemical Properties of Tm2O3-Doped CaZrO3
Authors: Lei Chonggui , Ruan Fei , Wu Xi , Bao Jinxiao , Zhang Yonghe , Ma Yuwei , Yang Junting , Liu Guoqi
Published: January 2025

To understand the microstructure and electrochemical performance of Tm-doped CaZrO3-based proton conductor in more detail, CaZr1−x
Tm
x
O3−δ
(x = 0, 0.025, 0.05, 0.075 and 0.1) proton-conducting electrolyte samples were prepared by solid state reaction method at 1523 and 1873 K for 8 h. The crystal structure of the proton-conducting solid electrolyte was characterized by X-ray diffraction, scanning electron microscopy, energy-dispersive spectroscopy. An electrochemical workstation was used to measure the electrical conductivity, the H/D isotope effect, and the chemical diffusion coefficient of hydrogen for the CaZr1−x
Tm
x
O3−δ
electrolyte. According to the results, the total conductivity of electrolyte CaZr1−x
Tm
x
O3−δ
falls in 4.83 × 10–6 ∼ 7.22 × 10–4 S cm−1 and the conductivity activation energy is 0.78 to 1.37 eV in oxygen and hydrogen atmosphere at 973 to 1173 °C. The chemical diffusion coefficient of proton in CaZr1−x
Tm
x
O3−δ
proton conductor is between 5.9 × 10–7 and 4.5 × 10–6 cm2 s−1 in the temperature range of 973 to 1373 K and the diffusion activation energy is 55486 kJ mol−1. The interstitial proton concentration falls in 7.97 × 10–4 ∼ 1.21 × 10–3 at 973 to 1073 K under hydrogen rich atmosphere. When the doping concentration (mol/mol) of Tm is 0.05, the electrolyte specimen has excellent electrochemical performance, the concentration of non-associated state Tm is approximately 2% of the total doping amount.
Preparation and Study of Coprecipitated Indium and Dysprosium Hydroxides by Thermal and X-ray Diffraction Analyses
Authors: Malinovskaya Tatiana , Ghyngazov Sergei , Maksimova Nadezhda , Zhek Valentina , Korusenko Petr
Published: January 2025

X-ray diffraction and thermal analyses, electron microscopy, Brunnauer-Emmett-Teller method, and infrared spectroscopy were used to study the products of coprecipitated indium and dysprosium hydroxides obtained under different conditions of aging in the mother liquor. The paper analyzed the effect of aging conditions on the phase composition, degree of crystallinity, and dispersion of the resulting powders. Samples with a molar ratio of In(III):Dy(III) = 1:1 were studied after aging in the mother liquor under stirring for 10 min, 3 d, and 7 d without heating, and for 7 d at 70 °C. No correlation was found between the aging time of the precipitates and the crystallite size. It was shown that the specific surface and the degree of crystallinity of the precipitates increased significantly at increased aging time. Two mechanisms of precipitate aging were verified: ordering of the structure of hydroxides with the transition from the X-ray amorphous state to the crystalline state and dehydration of metal hydroxides. The study evidenced significant absorption of carbon dioxide by hydroxides during precipitate aging with the formation of carbonates, which result in the release of carbon dioxide during thermal decomposition.
Effect of different intensity aerobic exercise on remodeling immune microenvironment of adipose tissue in obesity mouse
Authors: Lu Zhimin , Meng Chang , Yang JinRu , Wang Xuecong , Li Xueying , Zhang Jie , Tian Xuewen , Wang Qinglu
Published: January 2025

The present study has revealed that obesity is capable of altering the immune microenvironment within adipose tissue, thereby giving rise to inflammation. It has been demonstrated that exercise holds the potential to reverse the onset of inflammatory responses, with high-intensity intermittent aerobic exercise emerging as the most efficacious approach.
Table S3 from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Indexed primers for CUT&Tag library preparation
Table S1 from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Primers for qPCR
Figure S8 from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Supplementary figure 8
Figure 6 from Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR–ABL–Positive Leukemia
Authors: Luo Ziwei , Lin Chencen , Yu Chuwei , Yuan Changxian , Wu Wenyong , Xu Xiaowei , Sun Renhong , Jia Yan , Wang Yafang , Shen Jie , Wang Dingyan , Wang Sinan , Jiang Hualiang , Jiang Biao , Yang Xiaobao , Xie Chengying
Published: January 2025

SIAIS562055 sensitizes CML cell lines to TKIs in vitro. A, SIAIS562055 and TKIs had synergistic effects on the proliferation of K562 and KU812 cells after treatment of 72 hours. Histogram shows the CI values. B, Cell apoptosis (Annexin V+) of the K562 and KU812 cells treated with SIAIS562055, TKIs such as imatinib, nilotinib, or olverembatinib (olvere), alone or in combination, for 48 hours. C, Western blot analysis of P-BCR–ABL, pSTAT5, SOS1, pERK, and cleaved caspase-3 in K562 and KU812 cells treated with SIAIS562055 or TKIs, alone or in combination. D, Western blot analysis of SLC22A4 in K562 and KU812 cells treated with SIAIS562055 (62.5 and 50 nmol/L, respectively) for 24 hours. E, High-performance liquid chromatography analysis examined the relative intracellular concentrations of imatinib (10 μmol/L in the media) in K562 and KU812 cells after being treated with SIAIS562055 (1,000 nmol/L, 24 hours) or SOS1 siRNAs (50 nmol/L, 48 hours). F, Cell viability of K562 treated with SLC22A4 siRNAs (25 nmol/L), SIAIS562055 (125 nmol/L), or imatinib (25 nmol/L), alone or in combination, for 72 hours was assessed by MTT assay. Data are presented as mean ± SD, n = 3. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
Figure S5 from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Supplementary figure 5
Figure S3 from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Supplementary figure 3
Figure 2 from Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR–ABL–Positive Leukemia
Authors: Luo Ziwei , Lin Chencen , Yu Chuwei , Yuan Changxian , Wu Wenyong , Xu Xiaowei , Sun Renhong , Jia Yan , Wang Yafang , Shen Jie , Wang Dingyan , Wang Sinan , Jiang Hualiang , Jiang Biao , Yang Xiaobao , Xie Chengying
Published: January 2025

SIAIS562055 sensitizes KRAS-mutant cancer cells to KRAS inhibition in vitro. A, Western blot analysis of SOS1 in NCI-H358 (G12C), GP2d (G12D), and SW620 (G12V) cells treated with a concentration gradient of SIAIS562055 for 24 hours. B, Western blot analysis of SOS1 and pERK in NCI-H358 cells after the treatment of SIAIS562055 (1,000 nmol/L), SIAIS562092 (1,000 nmol/L), and BI-3406 (1,000 nmol/L) at different time points. C, Western blot analysis of SOS1 in MIA PaCa-2 (G12C), HPAF-II (G12D), and SW620 (G12V) cells after treatment with SIAIS562055 (1,000 nmol/L) for 12 hours, followed by wash-out and incubation with fresh media for another 0, 24, 48, 72, and 96 hours. D, Antiproliferative effects of SIAIS562055 and BI-3406 for 120 hours on KRAS-WT (293T, BxPC-3) and KRAS-mutant (NCI-H358, GP2d, HPAF-II, and SW620) cells. Histogram showed the IC50 values of compounds assessed in three-dimensional (3D) cultured cells. Data are shown as mean ± SD, n = 3. E, Inhibition rates of cell proliferation in NCI-H358 and GP2d cells treated with SIAIS562055 and KRAS inhibitors, alone or in combination, at different concentrations for 72 hours. CI values were calculated based on the data in red oval frames. F, Colony formation of NCI-H358 cells after treatment with SIAIS562055 (800 nmol/L), KRASG12C inhibitors (AMG510 or MRTX849, 5 nmol/L), or their combination for 7 days. G, Western blot analysis of SOS1 and pERK in NCI-H358 and GP2d cells after treatment with SIAIS562055 (1,000 nmol/L) combined with AMG510 (5 nmol/L), MRTX849 (5 nmol/L), or MRTX1133 (0.8 nmol/L) for 24 hours. Data are shown representatively from three independent repetitions.
Table S5 from TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis
Authors: Li Yinlam , Ming Ren , Zhang Tianyi , Gao Zixu , Wang Lu , Yang Yang , Shen Kangjie , Wei Chenlu , Zhu Yu , Li Jianrui , Zheng Shaoluan , Luo Zucheng , Ding Yiteng , Xuan Jiangying , Hu Qianrong , Yang Yanwen , Gu Jianying , Wei Chuanyuan
Published: January 2025

Table S5
Table S2 from TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis
Authors: Li Yinlam , Ming Ren , Zhang Tianyi , Gao Zixu , Wang Lu , Yang Yang , Shen Kangjie , Wei Chenlu , Zhu Yu , Li Jianrui , Zheng Shaoluan , Luo Zucheng , Ding Yiteng , Xuan Jiangying , Hu Qianrong , Yang Yanwen , Gu Jianying , Wei Chuanyuan
Published: January 2025

Table S2
Table S1 from TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis
Authors: Li Yinlam , Ming Ren , Zhang Tianyi , Gao Zixu , Wang Lu , Yang Yang , Shen Kangjie , Wei Chenlu , Zhu Yu , Li Jianrui , Zheng Shaoluan , Luo Zucheng , Ding Yiteng , Xuan Jiangying , Hu Qianrong , Yang Yanwen , Gu Jianying , Wei Chuanyuan
Published: January 2025

Table S1
Figure S4 from TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis
Authors: Li Yinlam , Ming Ren , Zhang Tianyi , Gao Zixu , Wang Lu , Yang Yang , Shen Kangjie , Wei Chenlu , Zhu Yu , Li Jianrui , Zheng Shaoluan , Luo Zucheng , Ding Yiteng , Xuan Jiangying , Hu Qianrong , Yang Yanwen , Gu Jianying , Wei Chuanyuan
Published: January 2025

Figure S4
Supplementary Figure S5 from SpatialDeX Is a Reference-Free Method for Cell-Type Deconvolution of Spatial Transcriptomics Data in Solid Tumors
Authors: Liu Xinyi , Tang Gongyu , Chen Yuhao , Li Yuanxiang , Li Hua , Wang Xiaowei
Published: January 2025

Supplementary Figure S5
Supplementary Tables S1-S4 from Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
Authors: Kawai-Kawachi Asuka , Lenormand Madison M. , Astier Clémence , Herbel Noé , Cutrona Meritxell B. , Ngo Carine , Garrido Marlène , Eychenne Thomas , Dorvault Nicolas , Bordelet Laetitia , Song Feifei , Bouyakoub Ryme , Loktev Anastasia , Romo-Morales Antonio , Henon Clémence , Colmet-Daage Léo , Vibert Julien , Drac Marjorie , Brough Rachel , Schwob Etienne , Martella Oliviano , Pinna Guillaume , Shipley Janet M. , Mittnacht Sibylle , Zimmermann Astrid , Gulati Aditi , Mir Olivier , Le Cesne Axel , Faron Matthieu , Honoré Charles , Lord Christopher J. , Chabanon Roman M. , Postel-Vinay Sophie
Published: January 2025

Supplementary Tables S1-S4
Supplementary Figure S1 from SpatialDeX Is a Reference-Free Method for Cell-Type Deconvolution of Spatial Transcriptomics Data in Solid Tumors
Authors: Liu Xinyi , Tang Gongyu , Chen Yuhao , Li Yuanxiang , Li Hua , Wang Xiaowei
Published: January 2025

Supplementary Figures S1
Figure 4 from Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
Authors: Kawai-Kawachi Asuka , Lenormand Madison M. , Astier Clémence , Herbel Noé , Cutrona Meritxell B. , Ngo Carine , Garrido Marlène , Eychenne Thomas , Dorvault Nicolas , Bordelet Laetitia , Song Feifei , Bouyakoub Ryme , Loktev Anastasia , Romo-Morales Antonio , Henon Clémence , Colmet-Daage Léo , Vibert Julien , Drac Marjorie , Brough Rachel , Schwob Etienne , Martella Oliviano , Pinna Guillaume , Shipley Janet M. , Mittnacht Sibylle , Zimmermann Astrid , Gulati Aditi , Mir Olivier , Le Cesne Axel , Faron Matthieu , Honoré Charles , Lord Christopher J. , Chabanon Roman M. , Postel-Vinay Sophie
Published: January 2025

EWS–WT1 is a determinant of DSRCT cells’ sensitivity to PARPi and ATRi. A, Western blot of EWS–WT1 in JN1 and R cells transfected with either siCNTRL or siEWS–WT1. Whole-cell lysates were generated 48 hours after transfection. B–E, Dose–response survival curves of JN1 or R cells exposed to PARPi talazoparib (B and C) or ATRi M4344 (D and E) for 7 days in the presence or absence of siRNA-mediated silencing of EWS–WT1. Mean ± SD; n = 3. F and G, Quantification of γH2AX in JN1 cells exposed to DMSO control, PARPi talazoparib, ATRi M4344, or a combination of both for 72 hours, in the presence or absence of siRNA-mediated silencing of EWS–WT1. Cisplatin was used as the positive control. A minimum of 500 nuclei was analyzed per condition. Violin plots show the absolute number of foci per nucleus. Thick line, median; thin lines, bottom and top quartiles; two-way ANOVA and post hoc Dunn test. H and I, Western blots of pCHK1, CHK1, pRPA2, RPA2, γH2AX, H2AX, and EWS–WT1 in JN1 (H) or R (I) cells exposed to DMSO control, PARPi talazoparib (Tala), ATRi M4344, or a combination of both for 48 hours, in the presence or absence of siRNA-mediated silencing of EWS–WT1. ****, P < 0.0001; ns, not significant.
Figure 1 from Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
Authors: Kawai-Kawachi Asuka , Lenormand Madison M. , Astier Clémence , Herbel Noé , Cutrona Meritxell B. , Ngo Carine , Garrido Marlène , Eychenne Thomas , Dorvault Nicolas , Bordelet Laetitia , Song Feifei , Bouyakoub Ryme , Loktev Anastasia , Romo-Morales Antonio , Henon Clémence , Colmet-Daage Léo , Vibert Julien , Drac Marjorie , Brough Rachel , Schwob Etienne , Martella Oliviano , Pinna Guillaume , Shipley Janet M. , Mittnacht Sibylle , Zimmermann Astrid , Gulati Aditi , Mir Olivier , Le Cesne Axel , Faron Matthieu , Honoré Charles , Lord Christopher J. , Chabanon Roman M. , Postel-Vinay Sophie
Published: January 2025

A small-molecule inhibitor and drug screen identifies PARPi and ATRi as candidate therapies for DSRCT. A, Schematic illustration of the workflow of small-molecule inhibitor and drug screen performed on the JN1 cell line. B, Waterfall plot displaying the difference in AUC between the JN1 cell line (AUCJN1) and the panel of 92 cell lines used for comparison (AUCmedian) for the 79 evaluated small-molecule inhibitors or drugs. Red, PARPi; blue, ATRi; green, conventional cytotoxic. C–F, Dose–response survival curves of the DSRCT cell lines JN1 and R, and the A673 (Ewing sarcoma) and SaOS-2 (osteosarcoma) cell lines exposed to talazoparib (C), olaparib (D), M4344 (E), or AZD6738 (F) for 7 days. Mean ± SD; n = 3. G and H, Violin plots showing the relative sensitivity (log2-fold change of cell viability) of cell lines exposed to the PARPi talazoparib (G) or olaparib (H) after a single-dose exposure at 2.5 μmol/L for 5 days in the DepMap database (PRISM Repurposing 23Q2), in comparison with that of the JN1 and R cell lines. JN1 and R cell line sensitivities were extrapolated from the survival assays presented in C and E; SFs were calculated at 2.5 μmol/L and log2 transformed. Ewing sarcoma cell lines (n = 16): RDES, A673, SKES1, CADOES1, EWS502, MHHES1, EW8, A673STAG2KO16, A673STAG2KO45, A673STAG2NT14, A673STAG2NT23, CBAGPN, CHLA10, SKNEP1, SKPNDW, and TC32; osteosarcoma cell lines (n = 5): G292CLONEA141B1, MG63, U2OS, HOS, and SJSA1; soft-tissue sarcoma cell lines (n = 7): S117, TE617T, HT1080, HS729, RD, RKN, and RH30, including rhabdomyosarcoma (n = 4), leiomyosarcoma (n = 1), fibrosarcoma (n = 1), and NOS sarcoma cell lines (n = 1), respectively. The BRCA1/2-mutant IGROV1 ovarian cancer cell line and BRCA1-mutant MDA-MB-436 breast cancer cell line were used as positive controls for sensitivity to PARPi. **, P < 0.01; ****, P < 0.0001; ns, not significant.
Supplementary Figure S5 from LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer
Authors: Ladaika Christopher A. , Ghobashi Ahmed H. , Boulton William C. , Miller Samuel A. , O’Hagan Heather M.
Published: January 2025

Knocking down NEUROG3 decreases cell viability.
Supplementary Figure S3 from LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer
Authors: Ladaika Christopher A. , Ghobashi Ahmed H. , Boulton William C. , Miller Samuel A. , O’Hagan Heather M.
Published: January 2025

LSD1 interacts with STAT3 and CoREST2 and STAT3 interacts with CoREST2 in additional mCRC cell lines and colon cancer organoids.
Figure S9 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SOS2 expression determines the extent of G12Ci:SOS1i synergy.
Figure S8 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SOS2 expression determines the extent of G12Ci:SOS1i synergy.
Figure S3 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SOS1i synergizes with G12Ci to limit MAPK pathway signaling under 2D and 3D conditions.
Figure S21 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

KEAP1 and STK11 co-mutations alter basal ERK and AKT phosphorylation.
Figure S20 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SOS1 inhibition limits the development of acquired G12Ci resistance.
Figure S2 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SOS1i synergizes with G12Ci to drive transcriptional changes regulating MAPK signaling.
Figure S18 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

G12Ci DTPs show increased CD133+ / ALDHhigh cells.
Figure S16 from SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma
Authors: Daley Brianna R. , Sealover Nancy E. , Finniff Bridget A. , Hughes Jacob M. , Sheffels Erin , Gerlach Daniel , Hofmann Marco H. , Kostyrko Kaja , LaMorte Joseph P. , Linke Amanda J. , Beckley Zaria , Frank Andrew M. , Lewis Robert E. , Wilkerson Matthew D. , Dalgard Clifton L. , Kortum Robert L.
Published: January 2025

SHP2i prevents G12Ci-induced TIC outgrowth.
Supplementary Tables from Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Authors: Kuett Laura , Bollhagen Alina , Tietscher Sandra , Sobottka Bettina , Eling Nils , Varga Zsuzsanna , Moch Holger , de Souza Natalie , Bodenmiller Bernd
Published: January 2025

Supplementary Tables 1-9
Figure 6 from Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Authors: Kuett Laura , Bollhagen Alina , Tietscher Sandra , Sobottka Bettina , Eling Nils , Varga Zsuzsanna , Moch Holger , de Souza Natalie , Bodenmiller Bernd
Published: January 2025

Immune environment in different metastatic sites and the effect of the PT on the immune cell composition. A and B, T-cell (A) and myeloid cell (B) subtype enrichment in PT or metastasis determined via differential abundance testing using paired design and grouped by the site of metastasis. Bar plot shows the log2-fold abundance changes (n = 76 patients). C, Boxplot of compositional similarity between each individual patient-matched PT and metastatic sample based on the proportional abundance of cell types grouped by the site of metastasis for general immune cell types (top), T-cell subtype proportions (middle), or myeloid cluster proportions (bottom). Plotted is the Aitchison distance as a measure of compositional dissimilarity. D and E, Compositional similarity of metastatic samples displayed using PCA on the per-patient immune cell type abundances (n = 76 patients; after applying the centered log ratio transformation) and corresponding variable factor map [right; only factors with a combined absolute contribution (to PC1 + PC2) >4 are displayed]. T-cell subtypes (D) and myeloid cell subtypes (E) are visually represented using arrow colors corresponding to the cell types listed in A and B, respectively. Each point represents a single patient sample. Colored squares indicate group centroids. Results of the PERMANOVA test for centroid difference are given (top). Patients with multiple metastatic sites were excluded to ensure the independence of individual samples. F and G, Immune cell phenotypic cluster enrichment in each clinical breast cancer subtype (F) or metastasis-defined patient group (G) at metastatic sites compared with average metastasis composition by differential abundance testing. Circles display significantly enriched (red) or decreased (blue; FDR < 0.05; multiple testing correction with the Benjamin–Hochberg method) results, with size indicating the log-transformed fold change.  moDC, monocyte-derived DCs; pDC, plasmacytoid dendritic cells.
Figure 2 from Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Authors: Kuett Laura , Bollhagen Alina , Tietscher Sandra , Sobottka Bettina , Eling Nils , Varga Zsuzsanna , Moch Holger , de Souza Natalie , Bodenmiller Bernd
Published: January 2025

Phenotypic composition of tumor cells from PT and distant metastasis. A, Left, heatmap showing the median expression level for each tumor cell cluster after flowSOM clustering. Markers used for clustering are on the x-axis, and flowSOM clusters are on the y-axis. For clustering, all cells were pooled across samples (n = 87 patients, 559,953 cells), and the cell counts in each cluster are shown (bar plot, gray). Euclidean distance with Ward-D2 linkage was used for the hierarchical clustering of rows. Right, box plot shows the per patient proportion of tumor cell phenotypic clusters out of all tumor cells for PT (left) and metastatic (right) samples (n = 76 patients with paired samples). B, Stacked bar plot of all tumor cell phenotypic clusters as a proportion of all tumor cells in PT and metastatic samples for paired patient samples. Rows were hierarchically clustered into 14 patient groups using Euclidean distance of tumor phenotype composition in metastases with Ward-D2 linkage. C, Tumor cell phenotypic cluster enrichment in PT or metastasis determined with differential abundance testing using paired design. The bar plot shows the log2-fold abundance changes (n = 76 patients). D, Tumor cell phenotypic cluster enrichment in each metastatic patient group compared with average metastasis composition by differential abundance testing. Circles display significantly enriched (red) or decreased (blue; FDR < 0.05; multiple testing correction with the Benjamin–Hochberg method) results, with size indicating the log-transformed fold change.
Figure 1 from Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Authors: Kuett Laura , Bollhagen Alina , Tietscher Sandra , Sobottka Bettina , Eling Nils , Varga Zsuzsanna , Moch Holger , de Souza Natalie , Bodenmiller Bernd
Published: January 2025

Overview of the clinical cohort and the project workflow. A, Overview of the clinical cohort and experimental workflow. The study includes primary breast cancer tissue samples with metastases to four different sites (bone, brain, liver, and soft tissue). Three antibody panels were used for IMC on consecutive slides, targeting tumor and immune phenotypes. B, Targets of the three antibody panels with their associated function. C, Proportion of the indicated cell types per patient in different tumor sites after the first graph-based clustering step of all cells from the tumor panel. Only images from intratumoral regions were used. Each dot represents a single patient [n = 528,518 cells, 464 images; n of patients = 87 (PT), 26 (bone), 24 (brain), 10 (liver), and 28 (soft tissue)]. D, Representative image of a region of interest from a PT showing expression of the indicated markers. (A, Created with BioRender.com.)
Supplementary Data from HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment
Authors: Luo Yu-Wei , Fang Yang , Zeng Hui-Xian , Ji Yu-Chen , Wu Meng-Zhi , Li Hui , Chen Jie-Ying , Zheng Li-Min , Fang Jian-Hong , Zhuang Shi-Mei
Published: January 2025

Supplementary Data (clean)
Data from H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells
Authors: Ramponi Valentina , Richart Laia , Kovatcheva Marta , Stephan-Otto Attolini Camille , Capellades Jordi , Lord Alice E. , Yanes Oscar , Ficz Gabriella , Serrano Manuel
Published: January 2025

Abstract
Anticancer therapies can induce cellular senescence or drug-tolerant persistence, two types of proliferative arrest that differ in their stability. While senescence is highly stable, persister cells efficiently resume proliferation upon therapy termination, resulting in tumor relapse. Here, we used an ATP-competitive mTOR inhibitor to induce and characterize persistence in human cancer cells of various origins. Using this model and previously described models of senescence, we compared the same cancer cell lines under the two types of proliferative arrest. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (senescence-associated secretory phenotype or SASP). A genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacologic inhibition of serine hydroxymethyltransferase, a key enzyme that feeds methyl groups from serine into 1C metabolism. Investigation into the relationship between 1C metabolism and the epigenetic regulation of transcription uncovered the presence of the repressive heterochromatic mark H4K20me3 at the promoters of SASP and IFN response genes in persister cells, whereas it was absent in senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study identifies distinctive features and actionable vulnerabilities of persister cancer cells and provides mechanistic insight into their low inflammatory activity.

Significance: Cell persistence and senescence are distinct states of proliferative arrest induced by cancer therapy, with persister cells being characterized by the silencing of inflammatory genes through the heterochromatic mark H4K20me3.

See related commentary by Schmitt, p. 7
Data from Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR–ABL–Positive Leukemia
Authors: Luo Ziwei , Lin Chencen , Yu Chuwei , Yuan Changxian , Wu Wenyong , Xu Xiaowei , Sun Renhong , Jia Yan , Wang Yafang , Shen Jie , Wang Dingyan , Wang Sinan , Jiang Hualiang , Jiang Biao , Yang Xiaobao , Xie Chengying
Published: January 2025

Abstract
Son of sevenless homolog 1 (SOS1) is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR–ABL in leukemogenesis. Despite this, small-molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS-mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 proteolysis targeting chimera (PROTAC) SIAIS562055, which was designed by connecting a CRBN ligand to an analog of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior antiproliferative activity compared with small-molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR–ABL–positive CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR–ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR–ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary samples from patients with CML. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR–ABL–harboring leukemia.

Significance: The PROTAC SIAIS562055 sustainably degrades SOS1 and inhibits downstream ERK signaling, showing strong antiproliferative activity and synergistic effects with KRAS inhibitors in KRAS-mutant cancers and BCR–ABL inhibitors in chronic myeloid leukemia.