bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of Bayesian and frequentist confidence intervals in the presence of a late Universe degeneracy
Authors: Ó. Colgáin Eoin , Pourojaghi Saeed , Sheikh-Jabbari M. M. , Sherwin Darragh
Published: February 2025

Hubble tension is a problem in one-dimensional (1D) posteriors, since local

$$H_0$$

H
0

determinations are only sensitive to a single parameter. Projected 1D posteriors for

$$\Lambda $$

Λ

CDM cosmological parameters become more non-Gaussian with increasing effective redshift when the model is fitted to redshift-binned data in the late Universe. We explain mathematically why this non-Gaussianity arises and show, using observational Hubble data (OHD), that Markov chain Monte Carlo (MCMC) marginalisation leads to 1D posteriors that fail to track the

$$\chi ^2$$

χ
2

minimum at

$$68\%$$

68
%

confidence level in high redshift bins. To gain a second perspective, we resort to profile likelihoods as a complementary technique. Doing so, we observe that

$$z \gtrsim 1$$

z
≳
1

cosmic chronometer (CC) data currently prefer a non-evolving (constant) Hubble parameter over a Planck-

$$\Lambda $$

Λ

CDM cosmology at

$$\sim 2 \sigma $$

∼
2
σ

. Within the Hubble tension debate, it is imperative that subsamples of data sets with differing redshifts yield similar

$$H_0$$

H
0

values. In addition, we confirm that MCMC degeneracies observed in 2D posteriors are not due to curves of constant

$$\chi ^2$$

χ
2

. Finally, on the assumption that the Planck-

$$\Lambda $$

Λ

CDM cosmological model is correct, using profile likelihoods we confirm a

$$>2 \sigma $$

>
2
σ

discrepancy with Planck-

$$\Lambda $$

Λ

CDM in a combination of CC and baryon acoustic oscillations (BAO) data beyond

$$z \sim 1.5$$

z
∼
1.5

. This confirms a discrepancy reported earlier with fresh methodology.
Beyond the inert doublet: imprints of Scotogenic Yukawa interactions at FCC-ee
Authors: Marzo Carlo , Melis Aurora
Published: February 2025

It is tempting to interpret the minuscule scale of neutrino masses as a symptom of its radiative origin. In light of the notable leap in precision expected at the Future Circular Collider, we explore areas of the parameter space that can simultaneously support the detectable Higgs-strahlung signal with parallel ones from forthcoming measurements in low-energy observables. We pinpoint the role that the extra fermions have in shaping a signal distinct from the pure Inert Doublet one. The details of the full one-loop computation and on-shell renormalization are presented. Both normal and inverted hierarchies for the radiatively generated neutrino masses and angles are investigated.
Theoretical study of the open-flavored tetraquark $$T_{c\bar{s}}(2900)$$ in the process $$\Lambda _b\rightarrow K^0D^0\Lambda $$
Authors: Lyu Wen-Tao , Lyu Yun-He , Duan Man-Yu , Wang Guan-Ying , Chen Dian-Yong , Wang En
Published: February 2025

Recently, the LHCb Collaboration has measured the processes

$$B^+\rightarrow D^-D_s^+\pi ^+$$

B
+

→

D
-

D
s
+

π
+

and

$$B^+\rightarrow \bar{D}^0D_s^+\pi ^+$$

B
+

→

D

¯

0

D
s
+

π
+

, where the

$$D_s^+\pi ^-$$

D
s
+

π
-

and

$$D_s^+\pi ^+$$

D
s
+

π
+

invariant mass distributions show the significant signals of two new open-flavored tetraquark states

$$T_{c\bar{s}}(2900)^0$$

T

c

s

¯

(
2900
)

0

and

$$T_{c\bar{s}}(2900)^{++}$$

T

c

s

¯

(
2900
)

+
+

, as the two of the isospin triplet. In this work, we have investigated the process

$$\Lambda _b\rightarrow K^0D^0\Lambda $$

Λ
b

→

K
0

D
0

Λ

by taking into account the tetraquark state

$$T_{c\bar{s}}(2900)^0$$

T

c

s

¯

(
2900
)

0

and the intermediate nucleon resonance

$$N^*(1535)$$

N
∗

(
1535
)

, which could be dynamically generated by the interactions of the

$$D^*K^*/D^*_s\rho $$

D
∗

K
∗

/

D
s
∗

ρ

and the pseudoscalar meson-octet baryon, respectively. Our results show that a clear peak of the open-flavored tetraquark

$$T_{c\bar{s}}(2900)$$

T

c

s

¯

(
2900
)

may appear in the

$$K^0D^0$$

K
0

D
0

invariant mass distribution of the process

$$\Lambda _b\rightarrow K^0D^0\Lambda $$

Λ
b

→

K
0

D
0

Λ

, which could be tested by future experiments.
Exhibiting stable model of dark energy compact star with Tolman-VI solution under complexity free system
Authors: Nazar Hammad , Majeed Abdul , Abbas Ghulam , Ashraf Asifa , Channuie Phongpichit
Published: February 2025

Several recent developments have highlighted the significance of the vanishing complexity factor formalism in understanding the structure and evolution of stellar relativistic compact objects. This formalism, introduced through a novel definition proposed by Herrera (Phys. Rev. D 97:044010, 2018), offers valuable insights into the dynamics of such systems. In this manuscript, we explored a class of realistic solutions to the static and spherically symmetric field equations characterized by two fluid distributions: ordinary stellar matter and dark energy, within the framework of this formalism. Utilizing the well-known Tolman-VI solution as the seed ansatz for the metric coefficient

$$g_{rr},$$

g

rr

,

we employed the complexity-free format to derive an analytic solution for the other metric coefficient,

$$g_{tt}.$$

g

tt

.

Subsequently, we obtained the solutions of gravitational field equations for our proposed spacetime model by incorporating the linear dark energy equation of state. These results were applied to the astrophysical compact star candidate LMC X-4,  with

$$M =1.04 M_\odot $$

M
=
1.04

M
⊙

and

$$R =8.4~\text {km}.$$

R
=
8.4

km
.

The potential viability and credibility of the proposed dark star solutions were thoroughly analyzed by examining key constraints, including the regularity of metric functions, physical adequacy through matter variables, state parameter behavior, energy conditions, stability tests (such as pressure anisotropy and hydrostatic equilibrium), the speed of sound, and the mass–radius relation for this compact star candidate. Notably, the estimated values of the dark energy coupling factor, presented in Table 1, highlight the exotic nature of the fluid distribution and effectively quantify the contribution of dark energy to the structure and evolution of an ultra-relativistic dark compact star. These findings strongly support our model solutions and demonstrate improvements over previously reported results in Rej et al. (Chin J Phys 87:608, 2024).
Physicochemical and Functional Properties and In Vitro Digestibility of Green Banana Flour‐Based Snacks Enriched With Mango and Passion Fruit Pulps by Extrusion Cooking
Authors: Sarmiento-Torres Luisa Fernanda , Murrillo-Franco Sarha Lucia , Galvis-Nieto Juan David , Rodríguez L. Joana , Igual Marta , García-Segovia Purificación , Orrego Carlos E.
Published: February 2025

Surplus banana crops that are not marketable, but still of suitable quality for consumption, are indeed a challenge in terms of underutilization as a post‐harvest by‐product. However, this situation also presents an exciting opportunity: these by‐products can serve as a valuable raw material for the production of extruded snacks. This study examines the impact of incorporating passion fruit and mango pulp (6% w/w) into green banana flour on physicochemical properties, pre‐ and postextrusion cooking, and bioactive compound content, alongside their bioaccessibility during in vitro digestion. Proximate composition analysis revealed that there were no significant changes in lipid and protein content following extrusion. However, there was a notable decrease in fiber due to alterations in starch. Initial values for zinc, sodium, and calcium in banana flour were 0.678 mg/100 g, 9.237 mg/100 g, and 14.214 mg/100 g, respectively. Extrusion resulted in an increase in zinc content (1.032, 0.736, and 0.999 mg/100 g), sodium content (21.904, 17.608, and 18.787 mg/100 g), and calcium content (28.217, 16.884, and 58.207 mg/100 g) in the banana flour extrudates without pulp, with passion fruit pulp, and with mango pulp, respectively. The addition of fruit pulp significantly enhanced the total phenolic compounds and carotenoids, though thermal degradation reduced the compound content postextrusion. Texture analysis demonstrated no significant differences among the samples, which were found to have hardness and crispness values consistent with those reported in the literature, at 20–25 N for hardness and 100–117 for crispness. In vitro digestion demonstrated increased bioaccessibility of total phenolic compounds, flavonoids, and carotenoids in extrudate samples compared to raw mixtures. The enhancements were 41%–72% for total phenolics, 100% for flavonoids, and 22%–78% for carotenoids. The utilization of surplus green banana represents a valuable alternative to produce healthy and functional snacks enriched with fruit pulps.
Supp Figure 9 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 9
Supp Figure 8 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 8
Supp Figure 6 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 6
Supp Figure 5 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 5
Supp Figure 2 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 2
Supp Figure 11 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 11
Figure 4 from Modeling Drug Responses and Evolutionary Dynamics Using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple-Negative Breast Cancer
Authors: Shea Abigail , Eyal-Lubling Yaniv , Guerrero-Romero Daniel , Manzano Garcia Raquel , Greenwood Wendy , O’Reilly Martin , Georgopoulou Dimitra , Callari Maurizio , Lerda Giulia , Wix Sophia , Giovannetti Agnese , Masina Riccardo , Esmaeilishirazifard Elham , Cope Wei , Martin Alistair G. , Nagano Ai , Young Lisa , Kupczak Steven , Cheng Yi , Bardwell Helen , Provenzano Elena , Kane Justine , Lay Jonny , Grybowicz Louise , McAdam Karen , Caldas Carlos , Abraham Jean , Rueda Oscar M. , Bruna Alejandra
Published: February 2025

Short-term olaparib treatment does not cause major genomic changes. A, Growth curves displaying raw data of model 1006 treated with olaparib for 11 weeks (purple) or untreated controls (black). Dotted line indicates end of treatment, after which, tumors were left to progress until size limits. B, Correlation plots comparing mean VAFs of mutations between untreated and treated (left) or untreated and post-treated (right) samples. R value calculated using the Spearman correlation. C, Heatmap displaying VAFs of depleted and emergent mutations in each sample. Columns indicate samples (labeled by mouse number and intratumor region). OC, oncogenic classification as predicted by Cancer Genome Interpreter.
Supp Figure 1 from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Supp Figure 1
Raw PCA Data from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Raw data of the PCA analysis from the Broad Institute Cell Line Encyclopedia
Figure S9 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 9. mtDNA mediates the activation of ICD induced by cEMSY in vivo.
B56-alpha OE Vector Map from Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: February 2025

Vector map for the B56-alpha overexpression (OE) plasmid
Figure S8 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 8. cEMSY activates antiviral immune signaling.
Figure S7 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 7. In vitro-transcribed cEMSY combined with anti-PD-1 promotes antitumor cure.
Figure S2 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 2. Characteristics of cEMSY circRNA and expression profiles in LUAD.
Supplementary Figure 1 from Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type-I IFN Signaling
Authors: Xu Ziyan , Kuhlmann-Hogan Alexandra , Xu Shihao , Tseng Hubert , Chen Dan , Tan Shirong , Sun Ming , Tripple Victoria , Bosenberg Marcus , Miller-Jensen Kathryn , Kaech Susan M.
Published: February 2025

Supplementary Figure 1
Figure S10 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 10. cEMSY modulates immune responses through facilitating the translocation of TDP-43 into mitochondria.
Figure S1 from The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Zhang Yijian , Song Xuming , Feng Yipeng , Qian Yuxian , Chen Bing , Zhang Te , Wang Hui , Chen Yuzhong , Yu Xinnian , Ding Hanlin , Li Rutao , Ge Pengfei , Xu Lin , Dong Gaochao , Jiang Feng
Published: February 2025

Supplementary Fig. 1. Filter ICD related circRNAs.
Fig. S7 from Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR-Mutant Non–Small Cell Lung Cancer
Authors: Wang Simeng , Lai Jia-Cheng , Li Yu , Tang Chengfang , Lu Jiajia , Han Min , Ye Xianjiang , Jia Lina , Cui Wei , Yang Jingyu , Wu Chunfu , Wang Lihui
Published: February 2025

Fig. S7 and its figure legend
Supplementary Figure S7 from PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression
Authors: Zhai Fengxian , Pan Guozheng , Xue Lei , Cheng Can , Wang Jiabei , Liu Yao , Liu Lianxin
Published: February 2025

Supplementary Figure S7
Fig. S5 from Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR-Mutant Non–Small Cell Lung Cancer
Authors: Wang Simeng , Lai Jia-Cheng , Li Yu , Tang Chengfang , Lu Jiajia , Han Min , Ye Xianjiang , Jia Lina , Cui Wei , Yang Jingyu , Wu Chunfu , Wang Lihui
Published: February 2025

Fig. S5 and its figure legend
Supplementary Figure S4 from PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression
Authors: Zhai Fengxian , Pan Guozheng , Xue Lei , Cheng Can , Wang Jiabei , Liu Yao , Liu Lianxin
Published: February 2025

Supplementary Figure S4
Supplementary Figure S2 from PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression
Authors: Zhai Fengxian , Pan Guozheng , Xue Lei , Cheng Can , Wang Jiabei , Liu Yao , Liu Lianxin
Published: February 2025

Supplementary Figure S2
Supplementary Table from Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer
Authors: Zeng Wenfeng , Zhang Ruihua , Huang Penghan , Chen Minxia , Chen Houying , Zeng Xin , Liu Jiang , Zhang Jiahui , Huang Di , Lao Liyan
Published: February 2025

Supplementary Table
Table S3 from Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Authors: Madorsky Rowdo Florencia P. , Martini Rachel , Ackermann Sarah E. , Tang Colin P. , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna E. , Sigouros Michael , Nguyen John , Al Assaad Majd , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Francis S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura
Published: February 2025

List of inhibitors tested in HTDS alone or in combination with gefitinib.
Table S2 from Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Authors: Madorsky Rowdo Florencia P. , Martini Rachel , Ackermann Sarah E. , Tang Colin P. , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna E. , Sigouros Michael , Nguyen John , Al Assaad Majd , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Francis S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura
Published: February 2025

List of primers and vectors used in this study.
Supplementary Figures from Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Authors: Madorsky Rowdo Florencia P. , Martini Rachel , Ackermann Sarah E. , Tang Colin P. , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna E. , Sigouros Michael , Nguyen John , Al Assaad Majd , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Francis S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura
Published: February 2025

Supplementary Figures 1-7
Data from Modeling Drug Responses and Evolutionary Dynamics Using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple-Negative Breast Cancer
Authors: Shea Abigail , Eyal-Lubling Yaniv , Guerrero-Romero Daniel , Manzano Garcia Raquel , Greenwood Wendy , O’Reilly Martin , Georgopoulou Dimitra , Callari Maurizio , Lerda Giulia , Wix Sophia , Giovannetti Agnese , Masina Riccardo , Esmaeilishirazifard Elham , Cope Wei , Martin Alistair G. , Nagano Ai , Young Lisa , Kupczak Steven , Cheng Yi , Bardwell Helen , Provenzano Elena , Kane Justine , Lay Jonny , Grybowicz Louise , McAdam Karen , Caldas Carlos , Abraham Jean , Rueda Oscar M. , Bruna Alejandra
Published: February 2025

Abstract
The intertumor and intratumor heterogeneity of triple-negative breast cancers, which is reflected in diverse drug responses, interplays with tumor evolution. In this study, we developed a preclinical experimental and analytical framework using patient-derived tumor xenografts (PDTX) from patients with treatment-naïve triple-negative breast cancers to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTXs exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of nongenetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes, with functional and therapeutic consequences. High-throughput drug screening methods in ex vivo PDTX cells revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high intermodel variability and permanent nongenomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.

Significance: Patient-derived tumor xenografts from treatment-naïve breast cancer samples can predict patient drug responses and model treatment-induced phenotypic and functional evolution, making them valuable preclinical tools.
Data from PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression
Authors: Zhai Fengxian , Pan Guozheng , Xue Lei , Cheng Can , Wang Jiabei , Liu Yao , Liu Lianxin
Published: February 2025

Abstract
Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in patients with FLT3-ITD+ AML, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacologic suppression of PRDM16 greatly slowed the progression of FLT3-ITD–driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors, and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine-614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacologic suppression of FLT3-ITD methylation in combination with tyrosine kinase inhibitors increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.

Significance: Monomethylation of FLT3-ITD at lysine-614 by PRDM16 induces FLT3 ER localization and enhanced signaling, which can be inhibited by targeting PRDM16 to suppress survival of FLT3-ITD+ AML cells and increase chemosensitivity.
Data from Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Authors: Madorsky Rowdo Florencia P. , Martini Rachel , Ackermann Sarah E. , Tang Colin P. , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna E. , Sigouros Michael , Nguyen John , Al Assaad Majd , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Francis S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura
Published: February 2025

Abstract
Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy.

Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors.

See related commentary by Trembath and Spanheimer, p. 407
Abstract A007: Regulation of DNA methylation and gene expression in T-cell acute lymphoblastic leukemia by IKAROS tumor suppressor
Authors: Ding Yali , He Bing , Bogush Daniel , Schramm Joseph W , Desai Dhimant , Dovat Sinisa
Published: February 2025

The IKZF1 gene encodes IKAROS - a DNA-binding zinc finger protein that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). Deletion of IKZF1 results in the development of high-risk leukemia. The mechanisms through which IKAROS regulates gene expression and cellular proliferation in T-ALL are largely unknown. We studied IKAROS role in regulation of DNA methylation and epigenomic regulation of gene expression in Ikzf1-null mouse T-ALL cells and following Ikzf1 re-introduction into Ikzf1-null mouse T-ALL cells. We used reduced representation bisulfite sequencing (RRBS), with ChIP-seq of IKAROS, histone deacetylase 1 (HDAC1), EZH2, and ATAC-seq along with CUT&Tag of histone modification markers, coupled with RNA-seq to study dynamic effect of IKAROS in IKZF1-null T-ALL and at several time points following Ikzf1 re-introduction. Deletion of Ikzf1 results in severe depletion of facultative heterochromatin, associated with DNA methylation at promoters of several tumor suppressor genes. Re-introduction of Ikzf1 within 24 hours results in global re-distribution of DNA methylation. IKAROS DNA binding was directly associated with de novo DNA methylation at promoters of genes that positively regulate several oncogenic pathways. DNA binding of IKAROS also resulted in the loss of DNA methylation, HDAC1 recruitment to promoters, EZH2 re-distribution, and de novo formation of H3K27me3 facultative heterochromatin. This was associated with cessation of cellular proliferation and induction of T-cell differentiation. Dynamic analysis of DNA methylation for 3 days following Ikzf1 re-introduction, revealed that the large fraction of DNA with altered methylation status due to IKAROS binding, preserved the altered DNA methylation pattern for at least two additional days, despite lack of IKAROS DNA binding in subsequent days following Ikzf1 re-introduction. In conclusion, our results demonstrated that IKAROS’ tumor suppressor function in T-ALL, occurs via regulation of DNA methylation and recruitment of HDAC1 and EZH2 to the promoters of its target genes. Results provide novel insight into the role of DNA methylation in regulation of gene expression in T-ALL with IKZF1-deletion and epigenomic regulation of tumor suppression in T-ALL.

Citation Format: Yali Ding, Bing He, Daniel Bogush, Joseph W Schramm, Dhimant Desai, Sinisa Dovat. Regulation of DNA methylation and gene expression in T-cell acute lymphoblastic leukemia by IKAROS tumor suppressor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A007.
Abstract A010: Dnmt3a2 ensures proper enhancer DNA methylation during embryonic development
Authors: Liu Minmin , Urrutia Guillermo A , Shereda Rachel , Liang Gangning , Jones Peter A
Published: February 2025

Proper enhancer function and switching is essential for the development of vertebrates and is known to be controlled by DNA cytosine methylation. We used isoform-specific knockouts of the two known DNA methyltransferase variants, Dnmt3a1 and Dnmt3a2 to probe their roles in enhancer methylation in embryogenesis and in postnatal development. Mouse embryos lacking Dnmt3a1 showed minimal loss of genomic methylation confirming that this isoform is not required for embryonic development. However, they were smaller than their littermates and died about 4 weeks after birth with considerable demethylation in the brain as has been previously reported. On the other hand, embryos lacking Dnmt3a2 showed widespread genomic hypomethylation which was particularly prevalent in enhancers and imprinted genes. Interestingly these methylation deficits were largely repaired after birth, presumably by the remaining Dnmt3a1 isoform. The mice were viable; however, they showed an increased prevalence of sporadic phenotypes including anophthalmia, hydronephrosis, hydrocephalus and male infertility which have previously been observed in laboratory mice. Hypomethylation of several imprinted genes was also observed in sperm which might potentially explain the infertility phenotype. There is therefore an interplay between the 2 isoforms which is developmentally regulated and a key role for Dnmt3a2 might be the stabilization of enhancer states which lessening the chance of sporadic phenotypes arising after birth.

Citation Format: Minmin Liu, Guillermo A Urrutia, Rachel Shereda, Gangning Liang, Peter A Jones. Dnmt3a2 ensures proper enhancer DNA methylation during embryonic development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A010.
Abstract A016: DNA methylation variability in aging and Clonal Hematopoiesis
Authors: Pompetti Anthony J , Chung Woonbok , Jelinek Jaroslav , Egodage Tanya , Issa Jean-Pierre
Published: February 2025

DNA methylation (DNAm) reflects regions of the genome that are transcriptionally repressed or active depending on the methylation level. Multitudes of DNAm “clocks” have been created to predict biological age and health outcomes. Deviations in biological age from chronological age reflect an alteration in the normal biological aging process. Clonal hematopoiesis of indeterminate potential (CHIP) arises in hematopoietic stem cells that have accumulated somatic mutations in key driver genes which provide a selective advantage for clonal expansion. Subjects with CHIP mutations are more prone to negative clinical outcomes such as coronary heart disease. While DNAm and CHIP have been studied for the past decade, the associations between the two are only now starting to become apparent. In this study we propose an improved measurement of aging based on the Jenson-Shannon distance (JSD) and associate this measurement with CHIP and adverse clinical outcomes. Bisulfite amplicon sequencing of 20 CpG-rich targets that change in methylation with age was performed on an initial cohort of 155 individuals from the National Institute of Neurological Disorders and Stroke (NINDS). JSD was used to construct a DNA methylation chaos clock (DMC) on these targets. DMC provided better predictions of chronological age than DNAm alone (r=0.9; p<0.0001). We validated our findings in 286 individuals from Cooper University Hospital for Management of Trauma where the accuracy of the DMC was confirmed in correlations of predicted vs actual age (r=0.86; p<0.0001). We next examined the association between DMC age acceleration and clinical outcomes. It was found that in individuals over the age of 50, DMC acceleration was associated with smoking and disease incidence (e.g. congestive heart failure and chronic obstructive pulmonary disease) independent of chronological age. The incidence of CHIP mutations in three key driver genes (DNMT3A, TET2, and ASXL1) was assayed in a subset of 345 individuals from both cohorts. Individuals with CHIP mutations in key driver genes had greater deviations in their predicted age than individuals without CHIP mutations (p<0.001). This study demonstrates that the DMC assay is a candidate for improvements in our measurements of biological age and it reflects important changes in an individual’s biological aging process.

Citation Format: Anthony J Pompetti, Woonbok Chung, Jaroslav Jelinek, Tanya Egodage, Jean-Pierre Issa. DNA methylation variability in aging and Clonal Hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A016.
Abstract A020: Clonal hematopoiesis is associated with acute kidney injury in the context of breast, endometrial, and ovarian cancers
Authors: Ruthen Neil , Kim Minsoo , Tan Hui Zhuan , Khandwala Yash , Hakimi A. Ari , Won Alice , Reznik Ed , Jaimes Edgar A
Published: February 2025

Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to a higher risk for acute kidney injury (AKI) (Vlasschaert et al. 2024). The high rate of AKI in the context of cancer is often attributed to the administration of nephrotoxic therapies or comorbidities. However, the effect of the interplay between tumor-associated physiologies, treatment, and CHIP on AKI incidence has yet to be characterized. Here, we model the prognostic value of CHIP in predicting AKI across twenty cancer types. Leveraging a single institutional database, we identified 25,189 patients with longitudinal serum creatinine (sCr) measurements, targeted sequencing of paired tumor and blood samples (MSKCC-IMPACT), and well-documented treatment histories. We called AKI events directly from longitudinal measurements by evaluating increases in sCr compared to the average sCr over the prior 90-day window using diagnostic criteria from the Kidney Disease Improving Global Outcomes (KDIGO) consortium. CHIP mutations were called using a previously reported two-tiered filtering schema (Bolton et al. 2020). In our cohort, we found that 26.5% of patients experienced at least one AKI event and 38.0% of patients presented with at least one CHIP mutation. We then performed competing risks analyses over cox proportional hazards models to test for the association of CHIP and time to AKI from the first creatinine measurement, adjusting for age, gender, histories of diabetes, smoking, and prior receipt of cisplatin. CHIP was significantly associated with decreased time to AKI in the context of breast, endometrial, and ovarian cancers (Benjamini-Hochberg-corrected p < 0.05). Subsequent univariate Kaplan-Meier analyses revealed TP53, PPM1D, SRFS2 mutations were associated with 7.50, 9.05, and 9.73-year decreases in median time to AKI (p < 0.01). Our study reveals specific CHIP mutations as prognostic markers for AKI for patients with breast, endometrial, and ovarian cancers. These findings may guide future clinical decision-making regarding treatment for patients with CHIP mutations.

Citation Format: Neil Ruthen, Minsoo Kim, Hui Zhuan Tan, Yash Khandwala, A. Ari Hakimi, Alice Won, Ed Reznik, Edgar A Jaimes. Clonal hematopoiesis is associated with acute kidney injury in the context of breast, endometrial, and ovarian cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A020.
Abstract B002: DNA methylation protects cancer cells against senescence
Authors: Chen Xiaoying , Yamaguchi Kosuke , Rodgers Brianna , Goehrig Delphine , Vindrieux David , Lahaye Xavier , Nolot Matthieu , Ferry Laure , Martin Nadine , Dubus Pierre , Miura Fumihito , Ito Takashi , Manel Nicolas , Kanemaki Masato , Bernard David , Defossez Pierre-Antoine
Published: February 2025

Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism of action is such that DNA damage inevitably cooccurs with loss of DNA methylation, making it challenging to discern their respective effects. Here we deconvolute the effects of decreased DNA methylation and DNA damage on cancer cells, by using degron alleles of key DNA methylation regulators (DNMT1 and UHRF1). We report that cancer cells with decreased DNA methylation — but no DNA damage— enter cellular senescence, with G1 arrest, senescence-associated secretory phenotype (SASP) expression, and senescence-associated beta-galactosidase (SA-β-gal) positivity. This senescence is independent of p53 and Rb, but involves p21, which is cytoplasmic and inhibits apoptosis. The suppression of cyclic GMP-AMP synthase (cGAS) alleviates SASP response and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Xenograft experiments show that tumor cells can be made senescent in vivo by decreasing DNA methylation. These findings reveal the intrinsic effects of loss of DNA methylation in cancer cells and have practical implications for future therapeutic approaches.

Citation Format: Xiaoying Chen, Kosuke Yamaguchi, Brianna Rodgers, Delphine Goehrig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Nadine Martin, Pierre Dubus, Fumihito Miura, Takashi Ito, Nicolas Manel, Masato Kanemaki, David Bernard, Pierre-Antoine Defossez. DNA methylation protects cancer cells against senescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B002.
Abstract B003: BRAFV600E is essential for maintenance of the CpG island methylator phenotype and DNA methylation of PRC2 target genes in colon cancer
Authors: El Bouazzaoui Layla , Bugter Jeroen M , Küçükköse Emre , Verheem André , Post Jasmin B , Fenderico Nicola , Borel Rinkes Inne H.M , Snippert Hugo J.G , Maurice Madelon M , Kranenburg Onno
Published: February 2025

In colon cancer, the BRAFV600E mutation is strongly associated with the CpG island methylator phenotype (CIMP). Here, we characterized the contribution of BRAFV600E to maintenance of aberrant DNA methylation. A reverse CRISPR gene editing approach was applied to revert the V600E mutation in BRAF back to wildtype (E600V) in organoids derived from a late-stage tumour. DNA methylation analyses identified 5187 differentially methylated CpGs within CpG islands, predominantly hypermethylated (82%) in BRAFV600E organoids, including genes associated with CIMP, as well as Polycomb Repressor Complex 2 (PRC2) target genes. RNA sequencing showed that expression of those genes was concordantly repressed. Furthermore, BRAFV600Einduced high expression of PRC2 core components (EZH2, SUZ12, EED), caused PRC2-induced H3K27 trimethylation in promoter regions, and maintained a PRC2-associated embryonic phenotype. This phenotype was lost following mutation correction or pharmacological inhibition of DNA methylation. These findings show that BRAFV600E maintains aberrant DNA and histone methylation patterns in advanced colon cancer, likely preserving the transformed phenotype by silencing of PRC2 target genes. Epigenetic therapies may have value in the treatment of BRAFV600E-mutant colon cancer.

Citation Format: Layla El Bouazzaoui, Jeroen M Bugter, Emre Küçükköse, André Verheem, Jasmin B Post, Nicola Fenderico, Inne H.M Borel Rinkes, Hugo J.G Snippert, Madelon M Maurice, Onno Kranenburg. BRAFV600E is essential for maintenance of the CpG island methylator phenotype and DNA methylation of PRC2 target genes in colon cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B003.
Abstract B012: The effect of a novel therapy on DNA methylation in Ewing Sarcoma
Authors: Isenhart Emily , Gupta Ajay , Ohm Joyce
Published: February 2025

Ewing sarcoma (EwS) is a rare and aggressive disease affecting the bone and soft tissue of children and young adults. A FET::ETS fusion protein, typically EWSR1-FLI1 is pathognomonic for this disease. EwS is genomically quiet with widespread dysregulation driven by aberrant fusion activity leading to elevated endogenous levels of replication stress and epigenetic drift. While five-year survival rates are moderate for localized primary disease (∼70%), metastasized, relapsed, and refractory disease have much lower rates of survival (15-35%) and are associated with increased epigenetic heterogeneity. Treatment options are currently limited to systemic therapies which have not seen major advancement since the development of interval compression of chemotherapy and often lead to secondary complications for these patients. Our lab has identified a novel combination of replication stress response inhibitors (RSRi), DDK (DDKi) and WEE1 (WEE1i), which sensitize EwS cells to their own elevated levels of replication stress by removing repair strategies and forcing mitotic catastrophe and apoptosis. In one in vivo study, cell line derived xenografts in NSG mice were treated with DDKi (simurosertib) and WEE1i (adavosertib) in the following design: 1) vehicle control (n=5), 2) Irinotecan + Temozolomide (n=9), 3) Irinotecan (full dose) + DDKi + WEE1i (n=7), 4) Irinotecan (half dose) + DDKi + WEE1i (n=9), for a total of 30 samples. We have shown that this RSRi combination is able to effectively limit tumor growth over time even in the context of decreased chemotherapeutic dose. As increased replication stress can cause epigenetic drift, changes in methylation associated with treatment condition were investigated by reduced representation bisulfite sequencing. Differential methylation analysis was performed on individual CpG sites, CpG structures (islands, shores) and transcriptional elements (promoters, enhancers, transcription start sites). In this context, key pathways were found to be differentially methylated between treatment conditions, including those involved in cell signaling, motility, metabolism, and neuronal processes. Overall, this targeted therapy presents a promising therapeutic option for this pediatric patient population.

Citation Format: Emily Isenhart, Ajay Gupta, Joyce Ohm. The effect of a novel therapy on DNA methylation in Ewing Sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B012.