bluuebunny/crossref_metadata_2025_split huggingface dataset:
Light deflection angle through velocity profile of galaxies in f(R) model
Authors: Sharma Vipin Kumar , Yadav Bal Krishna , Verma Murli Manohar 
Published: February 2021

AbstractWe explore a new realisation of the galactic scale dynamics via gravitational lensing phenomenon in power-law f(R) gravity theory of the type $$f(R)\propto R^{1+\delta }$$

f

(
R
)

∝

R

1
+
δ

with $$\delta<<1$$

δ
<
<
1

for interpreting the clustered dark matter effects. We utilize the single effective point like potential (Newtonian potential + f(R) background potential) obtained under the weak field limit to study the combined observations of galaxy rotation curve beyond the optical disk size and their lensing profile in f(R) frame work. We calculate the magnitude of light deflection angle with the characteristic length scale (because of Noether symmetry in f(R) theories) appearing in the effective f(R) rotational velocity profile of a typical galaxy with the model parameter $$\delta \approx O(10^{-6})$$

δ
≈
O
(

10

-
6

)

constrained in previous work. For instance, we work with the two nearby controversial galaxies NGC 5533 and NGC 4138 and explore their galactic features by analysing the lensing angle profiles in f(R) background. We also contrast the magnitudes of f(R) lensing angle profiles and the relevant parameters of such galaxies with the generalised pseudo-isothermal galaxy halo model and find consistency.
Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade
Authors: Boshuizen Julia , Pencheva Nora , Krijgsman Oscar , Altimari Daniela D'Empaire , Castro Patricia Garrido , de Bruijn Beaunelle , Ligtenberg Maarten A. , Gresnigt-Van den Heuvel Elke , Vredevoogd David W. , Song Ji-Ying , Visser Nils , Apriamashvili Georgi , Janmaat Maarten L. , Plantinga Theo S. , Franken Patrick , Houtkamp Mischa , Lingnau Andreas , Jure-Kunkel Maria , Peeper Daniel S. 
Published: February 2021

Abstract

Although immune checkpoint blockade (ICB) has shown remarkable clinical benefit in a subset of patients with melanoma and lung cancer, most patients experience no durable benefit. The receptor tyrosine kinase AXL is commonly implicated in therapy resistance and may serve as a marker for therapy-refractory tumors, for example in melanoma, as we previously demonstrated. Here, we show that enapotamab vedotin (EnaV), an antibody–drug conjugate targeting AXL, effectively targets tumors that display insensitivity to immunotherapy or tumor-specific T cells in several melanoma and lung cancer models. In addition to its direct tumor cell killing activity, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells and promoted the induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to either treatment alone in models of melanoma and lung cancer and induced ICB benefit in models otherwise insensitive to anti–PD-1 treatment. Our findings indicate that targeting AXL-expressing, immunotherapy-resistant tumors with EnaV causes an immune-stimulating tumor microenvironment and enhances sensitivity to ICB, warranting further investigation of this treatment combination.

Significance:
These findings show that targeting AXL-positive tumor fractions with an antibody–drug conjugate enhances antitumor immunity in several humanized tumor models of melanoma and lung cancer.
Pan-Cancer Drivers Are Recurrent Transcriptional Regulatory Heterogeneities in Early-Stage Luminal Breast Cancer
Authors: Singh Shambhavi , Sutcliffe Matthew D. , Repich Kathy , Atkins Kristen A. , Harvey Jennifer A. , Janes Kevin A. 
Published: February 2021

Abstract

The heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEG), which were significantly variable in &gt;50% of patients. RHEGs were not strongly confounded by dissociation artifacts, cell-cycle oscillations, or driving mutations for breast cancer. Rather, RHEGs were enriched for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast. These findings indicate that heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to evaluate the effects of potential oncogenes or tumor suppressors on cancer hallmarks.

Significance:
Profiling intratumor heterogeneity of luminal breast carcinoma cells identifies a recurrent set of genes, suggesting sporadic activation of pathways known to drive other types of cancer.
See related articles by Schaff and colleagues, p. 1853 and Sutcliffe and colleagues, p. 1868
RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer
Authors: Arnold Frank , Gout Johann , Wiese Heike , Weissinger Stephanie E. , Roger Elodie , Perkhofer Lukas , Walter Karolin , Scheible Jeanette , Prelli Bozzo Caterina , Lechel André , Ettrich Thomas J. , Azoitei Ninel , Hao Li , Fürstberger Axel , Kaminska Ewa K. , Sparrer Konstantin M.J. , Rasche Volker , Wiese Sebastian , Kestler Hans A. , Möller Peter , Seufferlein Thomas , Frappart Pierre-Olivier , Kleger Alexander 
Published: February 2021

AbstractPancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G2 cell cycle arrest, disruption of Golgi–endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach.Significance:These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.
Preexisting Type 2 Diabetes and Survival among Patients with Colorectal Cancer
Authors: Yuan Chen , Zhang Xuehong , Babic Ana , Morales-Oyarvide Vicente , Zhang Yin , Smith-Warner Stephanie A. , Wu Kana , Wang Molin , Wolpin Brian M. , Meyerhardt Jeffrey A. , Chan Andrew T. , Hu Frank B. , Fuchs Charles S. , Ogino Shuji , Giovannucci Edward L. , Ng Kimmie 
Published: February 2021

Abstract

Background:
Type 2 diabetes increases risk of developing colorectal cancer, but the association of preexisting diabetes with colorectal cancer survival remains unclear.

Methods:
We analyzed survival by diabetes status at cancer diagnosis among 4,038 patients with colorectal cancer from two prospective U.S. cohorts. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CI) for overall and cause-specific mortality, with adjustment for tumor characteristics and lifestyle factors.

Results:
In the first 5 years after colorectal cancer diagnosis, diabetes was associated with a modest increase in overall mortality in women (HR, 1.22; 95% CI, 1.00–1.49), but not in men (HR, 0.83; 95% CI, 0.62–1.12; P heterogeneity by sex = 0.04). Beyond 5 years, diabetes was associated with substantially increased overall mortality with no evidence of sex heterogeneity; in women and men combined, the HRs were 1.45 (95% CI, 1.09–1.93) during &gt;5–10 years and 2.58 (95% CI, 1.91–3.50) during &gt;10 years. Compared with those without diabetes, patients with colorectal cancer and diabetes had increased mortality from other malignancies (HR, 1.78; 95% CI, 1.18–2.67) and cardiovascular disease (HR, 1.93; 95% CI, 1.29–2.91). Only women with diabetes for more than 10 years had increased mortality from colorectal cancer (HR, 1.33; 95% CI, 1.01–1.76).

Conclusions:
Among patients with colorectal cancer, preexisting diabetes was associated with increased risk of long-term mortality, particularly from other malignancies and cardiovascular disease.

Impact:
Our findings highlight the importance of cardioprotection and cancer prevention to colorectal cancer survivors with diabetes.
Sufficient 25-Hydroxyvitamin D Levels 2 Years after Colorectal Cancer Diagnosis are Associated with a Lower Risk of All-cause Mortality
Authors: Wesselink Evertine , Kok Dieuwertje E. , de Wilt Johannes H.W. , Bours Martijn J.L. , van Zutphen Moniek , Keulen Eric T.P. , Kruyt Flip M. , Breukink Stephanie O. , Kouwenhoven Ewout A. , van den Ouweland Jody , Weijenberg Matty P. , Kampman Ellen , van Duijnhoven Fränzel J.B. 
Published: February 2021

Abstract

Background:
Whether changes in 25 hydroxy vitamin D3 (25(OH)D3) levels after colorectal cancer diagnosis influence clinical outcomes is unclear. We investigated the association of trajectories of 25(OH)D3 levels with recurrence and all-cause mortality.

Methods:
In total, 679 patients were included in our data analyses. Trajectories of 25(OH)D3 levels were defined on the basis of vitamin D status at diagnosis, at 6 months, and 2 years after diagnosis. Observed trajectories of 25(OH)D3 levels were consistent deficient levels (20%), consistent sufficient levels (39%), increasing levels (20%), and a temporary drop in levels (13%). Associations of trajectories of 25(OH)D3 with recurrence and all-cause mortality were assessed using multivariable Cox proportional hazards regression models.

Results:
During a follow-up time of 2.2 years for recurrence and 3.5 years for all-cause mortality, 31 and 65 events occurred, respectively. No statistically significant associations were observed for vitamin D trajectories and the risk of recurrence. Patients who were consistently sufficient compared with patients who were consistently deficient had a lower risk of all-cause mortality [HR 0.39; 95% confidence interval (CI), 0.21–0.73]. The risk of all-cause mortality seems lower in patients with increasing levels or a temporary drop in levels (HR 0.54; 95% CI, 0.27–1.10 and HR 0.40 95% CI, 0.17–0.93) relative to patients with consistent deficient levels.

Conclusions:
Patients with colorectal cancer following a trajectory characterized by sufficient levels of 25(OH)D3 2 years after diagnosis all appeared to have a lower risk of all-cause mortality compared with patients having consistent deficient levels.

Impact:
Further studies should investigate how trajectories of 25(OH)D3 levels are associated with colorectal cancer recurrence.
Abstract IA017: Molecular classification and stratification: Diving deeper
Authors: McAlpine Jessica N. 
Published: February 2021

Abstract
As we move forward with integration of molecular classification into clinical care the assessment of additional clinicopathological and molecular features in the context of molecular subtype will enable us to further refine prognosis. In addition, molecular classification can enable stratification of clinical cohorts that have been often thought of as homogeneous but are clearly more diverse than recognized. These last few years have produced an abundance of literature supporting not only the value of consistent categorization and prognostic value but also predictive implications enabling action/change in practice. Molecular classification-driven care in endometrial cancer will reduce variation in practice with improved knowledge translation critical to implementation and uptake.
Citation Format: Jessica N. McAlpine. Molecular classification and stratification: Diving deeper [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA017.
Abstract PO004: Enhancer-promoter chromatin looping is enriched for endometrial cancer GWAS risk variation and reveals biologically relevant candidate susceptibility genes
Authors: Glubb Dylan M. , Pollock Pamela , Spurdle Amanda , O'Mara Tracy A. 
Published: February 2021

Abstract
Large-scale genome-wide association studies (GWAS) conducted by the Endometrial Cancer Association Consortium have identified candidate endometrial cancer risk variants at 16 loci. The vast majority of these candidate endometrial cancer risk variants are located in non-coding genomic regions. Studies of other GWAS have shown enrichment of trait-associated variants in enhancer elements suggesting that they may regulate gene expression through chromatin looping. In the current study, we analysed chromatin looping to identify the genes that may mediate the effects of these variants. We used a modified HiChIP technique to capture chromatin loops associated with H3K27Ac (characteristic of active enhancers and promoters) in a normal immortalized and three tumoral endometrial cell lines. Duplicate HiChIP libraries were analysed using paired-end sequencing and bioinformatic pipelines (HiC-Pro, hichipper and IDR2D) to identify replicating cis chromatin loops. The replicating loops were intersected with gene promoter regions to identify promoter-associated chromatin loops and we found significant enrichment of endometrial cancer risk variation in these loops. We identified 74 candidate target genes at 13 endometrial cancer risk loci by intersecting promoter-associated loops with candidate risk variants and prioritising genes with matching RNA-seq expression. The candidate target genes were more conserved than other genes on average, nearly three times more likely to be differentially regulated in endometrial tumours and their encoded proteins interacted more amongst themselves than would be expected by chance. Moreover, functional prioritisation of the wider protein-protein interaction network revealed a set of interacting proteins that was 9-fold enriched for somatic endometrial cancer drivers. In summary, our findings indicate that endometrial cancer risk variation at least partly mediates its effects through enhancer-promoter chromatin looping and corresponding data reveal a set of biologically relevant candidate target genes.
Citation Format: Dylan M. Glubb, Pamela Pollock, Amanda Spurdle, Tracy A. O'Mara. Enhancer-promoter chromatin looping is enriched for endometrial cancer GWAS risk variation and reveals biologically relevant candidate susceptibility genes [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO004.
Abstract PO012: Characterization of molecular, phenotypic, and drug sensitivity changes due to estrogen receptor alpha mutations in endometrial cancer
Authors: Blanchard Zannel , Vahrenkamp Jeffery M. , Arnesen Spencer , Berrett Kristofer C. , Gertz Jason 
Published: February 2021

Abstract
Estrogen signaling is essential for normal uterine function and has been shown to play critical roles in the development of endometrial cancer. Mutations in the ligand binding domain (LBD) of estrogen receptor alpha (ER) have been identified in primary endometrial cancer and hormone therapy resistant breast cancer. In endometrial cancer, ER mutations are associated with worse outcomes and obesity independent disease. However, additional molecular and phenotypic characterizations of these mutations are needed in the context of endometrial cancer. Utilizing a CRISPR/Cas9 tagging strategy to model the more common Y537S and D538G LBD mutations while epitope tagging ER’s endogenous locus in Ishikawa cells, we studied the regulatory and phenotypic consequences of mutant ER in endometrial cancer and have identified potential targeted therapies for the treatment of this disease. RNA sequencing (RNA-seq) experiments uncovered expression changes caused by ER mutations, including both estradiol-regulated genes and mutation-specific, estradiol-independent genes. We found mutation-specific changes in gene expression were not recapitulated with prolonged estrogen exposure in wildtype cells, suggesting the mutant ER transcriptome is distinct from constitutive ER activity. The unique mutant ER expression program was related to phenotypic changes in ER mutant endometrial cancer cells, including increased proliferation specifically in vivo and increased migration in vitro relative to wildtype cells, consistent with more aggressive endometrial tumors. Based on the transcriptional and phenotypic alterations caused by mutant ER, we explored gene regulation based drugs for the potential treatment of mutant ER endometrial tumors. We found that two small molecules, cyclin dependent kinase 9 (CDK9) inhibitor Alvocidib and steroid receptor coactivator 3 (SRC-3) inhibitor SI-2, decreased mutant ER’s ability to promote proliferation and migration. In conclusion, mutant ER confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells. This activity has led us to identify two drugs that show efficacy in treating mutant ER endometrial cancer cells, however further study is needed to ascertain whether they can be utilized as novel therapeutic targets in this disease.
Citation Format: Zannel Blanchard, Jeffery M. Vahrenkamp, Spencer Arnesen, Kristofer C. Berrett, Jason Gertz. Characterization of molecular, phenotypic, and drug sensitivity changes due to estrogen receptor alpha mutations in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO012.
Abstract PO023: Preliminary data on metformin therapy in DICER1-deleted endometrial cancer
Authors: Wang Xiyin , Emerson Robert , Broaddus Russell , Lydon John , DeMayo Francesco , Hawkins Shannon M. 
Published: February 2021

Abstract
We created and characterized the first genetically engineered mouse model of poorly-differentiated endometrial adenocarcinoma (dcKO, PgrCre; Ptenflox/flox; Dicer1flox/flox). As an additional novel model system, using CRISPR-Cas9, we created and characterized an isogenic cell line with the deletion of DICER1 (DICER1−/− Ishikawa cells). Transcriptomic profiling across mouse and human models revealed activated pathways, including AMP kinase and insulin signaling. Ingenuity Pathway Analysis revealed metformin as a likely therapeutic target. Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer in women. However, recent clinical trials showed combined treatment of metformin with paclitaxel and carboplatin was not significantly associated with increased progression-free survival or overall survival for advanced or recurrent endometrial cancer. To test the effects of metformin in our mouse model, female mice received ad lib water containing metformin (5 mg/mL) or water beginning at weaning. Survival studies showed worse survival for well-differentiated endometrial adenocarcinoma (Pten cKO, PgrCre; Ptenflox/flox; Dicer1+/+) with treatment with metformin (P=0.007), while there was no difference for dcKO mice treated with metformin. Similarly, in vitro studies showed that the treatment of DICER1−/− Ishikawa cells treated with metformin did not affect cellular proliferation. Our in vivo and in vitro model systems represent important tools to study metformin and other therapeutics for rare yet aggressive endometrial cancers.
Citation Format: Xiyin Wang, Robert Emerson, Russell Broaddus, John Lydon, Francesco DeMayo, Shannon M. Hawkins. Preliminary data on metformin therapy in DICER1-deleted endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO023.
Abstract PO048: Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium
Authors: Wilson Mike R. , Reske Jake J. , Chandler Ronald L. 
Published: February 2021

Abstract
Invasion is a hallmark feature of endometrial pathologies, including myometrial invasion of endometrial cancer and invasion of distal sites during endometriosis. Mutations in the chromatin remodeling protein ARID1A have been observed at high rates in endometrial cancer and endometriosis. ARID1A loss, in combination with phosphoinositide 3-kinase (PI3K) pathway activation, has been shown to induce invasion phenotypes in the endometrial epithelium. Using bioinformatic approaches, we identified histone acetyltransferase (HAT) protein P300 as potential co-regulator of ARID1A-deficient gene expression programs. Knockdown of P300 prevented invasive phenotypes in a genetically engineered mouse model and human endometrial epithelial cells through induction of apoptosis, indicating a synthetic-lethal relationship between ARID1A and P300 in the endometrial epithelium. Using the novel HAT inhibitor, A-485, we identified P300 HAT activity as the mechanism by which P300 promotes invasive phenotypes. A-485 treatment rescued invasion in vitro at concentrations which had no effect on cell viability in adherent culture, but induced anoikis in suspension culture. Using an RNA-seq approach, we identified cell adhesion and migration pathways as being regulated by ARID1A knockdown and P300 co-knockdown or A-485 co-treatment. Among genes in these pathways, we identified SERPINE1 as an essential component of P300-dependent invasive processes. SERPINE1 is overexpressed following ARID1A loss in mouse and human models, and SERPINE1 knockdown rescued invasive phenotypes following ARID1A loss. By chromatin immunoprecipitation, we identified a role for P300-dependent acetylation of histone 3 lysine 27 (H3K27ac) at the SERPINE1 super-enhancer. The novel P300 bromodomain inhibitor CCS1477 also rescues invasion and SERPINE1 expression following ARID1A loss, suggesting a role for bromodomain inhibition as a modulator of P300 H3K27ac deposition. These studies suggest the therapeutic utility of P300 inhibition to induce anoikis in mutant endometrium which has detached from the basement membrane, thereby preventing invasion.
Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO048.