bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimal chimera states in phase-lag coupled mechanical oscillators
Authors: Ebrahimzadeh P. , Schiek M. , Jaros P. , Kapitaniak T. , van Waasen S. , Maistrenko Y. 
Published: October 2020

AbstractWe obtain experimental chimera states in the minimal network of three identical mechanical oscillators (metronomes), by introducing phase-lagged all-to-all coupling. For this, we have developed a real-time model-in-the-loop coupling mechanism that allows for flexible and online change of coupling topology, strength and phase-lag. The chimera states manifest themselves as a mismatch of average frequency between two synchronous and one desynchronized oscillator. We find this kind of striking “chimeric” behavior is robust in a wide parameter region. At other parameters, however, chimera state can lose stability and the system behavior manifests itself as a heteroclinic switching between three saddle-type chimeras. Our experimental observations are in a qualitative agreement with the model simulation.
Differential Galois cohomology and parameterized Picard–Vessiot extensions
Authors: Sánchez Omar León , Pillay Anand 
Published: October 2020

Assuming that the differential field [Formula: see text] is differentially large, in the sense of [León Sánchez and Tressl, Differentially large fields, preprint (2020); arXiv:2005.00888], and “bounded” as a field, we prove that for any linear differential algebraic group [Formula: see text] over [Formula: see text], the differential Galois (or constrained) cohomology set [Formula: see text] is finite. This applies, among other things, to closed ordered differential fields in the sense of [Singer, The model theory of ordered differential fields, J. Symb. Logic 43(1) (1978) 82–91], and to closed[Formula: see text]-adic differential fields in the sense of [Tressl, The uniform companion for large differential fields of characteristic [Formula: see text], Trans. Amer. Math. Soc. 357(10) (2005) 3933–3951]. As an application, we prove a general existence result for parameterized Picard–Vessiot (PPV) extensions within certain families of fields; if [Formula: see text] is a field with two commuting derivations, and [Formula: see text] is a parameterized linear differential equation over [Formula: see text], and [Formula: see text] is “differentially large” and [Formula: see text] is bounded, and [Formula: see text] is existentially closed in [Formula: see text], then there is a PPV extension [Formula: see text] of [Formula: see text] for the equation such that [Formula: see text] is existentially closed in [Formula: see text]. For instance, it follows that if the [Formula: see text]-constants of a formally real differential field [Formula: see text] is a closed ordered[Formula: see text]-field, then for any homogeneous linear [Formula: see text]-equation over [Formula: see text] there exists a PPV extension that is formally real. Similar observations apply to [Formula: see text]-adic fields.
Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma
Authors: Turner Joel G. , Cui Yan , Bauer Alexis A. , Dawson Jana L. , Gomez Juan A. , Kim Jongphil , Cubitt Christopher L. , Nishihori Taiga , Dalton William S. , Sullivan Daniel M. 
Published: October 2020

Abstract

High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609).

Significance:
Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.
Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial
Authors: Wong Connie C. , Baum Jason , Silvestro Angela , Beste Michael T. , Bharani-Dharan Bharani , Xu Siyan , Wang Ying A. , Wang Xiaoshan , Prescott Margaret F. , Krajkovich Lynne , Dugan Margaret , Ridker Paul M. , Martin Anne-Marie , Svensson Eric C. 
Published: October 2020

Abstract

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer.

Significance:
These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.
A Global and Integrated Analysis of CINSARC-Associated Genetic Defects
Authors: Lesluyes Tom , Chibon Frédéric 
Published: October 2020

Abstract

The Complexity Index in Sarcomas (CINSARC) signature is a transcriptomic marker that identifies high-risk soft-tissue sarcomas and is associated with high metastatic potential. During the last decade, CINSARC has been successfully developed and validated and is currently being assessed in two prospective phase III clinical trials for stratification of therapy. Although the link between CINSARC expression and tumor aggressiveness is well established, questions remain about how CINSARC genes are regulated. In this study, we leveraged a The Cancer Genome Atlas multiomics study on sarcomas with complex genetics to appraise the association between CINSARC profile, genomic features, and two potential regulation mechanisms, DNA methylation and miRNA expression. CINSARC expression was associated with an increase of ploidy, intratumor heterogeneity, copy-number alteration, altered expression of 37 miRNAs, and a decrease of DNA methylation. These genetic changes are not independent, but rather act together to promote or repress CINSARC expression. These findings depict new insights into CINSARC regulation.

Significance:
These findings demonstrate that CINSARC is associated with a variety of genomic aberrations that contribute to higher risk for metastasis and may serve as a prognostic factor in sarcomas and beyond.
Field Carcinogenesis in Cancer Evolution: What the Cell Is Going On?
Authors: Sinjab Ansam , Han Guangchun , Wang Linghua , Kadara Humam 
Published: October 2020

Abstract
Field carcinogenesis describes the prevalence of tumor-related alterations in normal appearing tissues. Here, we summarize recent efforts in profiling molecular field dynamics for resolving early events in cancer evolution. We also highlight gaps in our knowledge of the molecular and cellular heterogeneity of field carcinogenesis and propose directions to tackle these voids using single-cell–based approaches and unique tissue sampling models. By interrogating both the mutagenized epithelium and its microenvironment, we surmise that single-cell–guided studies will help chart the spatiotemporal molecular and cellular “atlas” of field carcinogenesis, will further delineate preneoplastic initiation and progression, and will help identify cancer prevention and early intervention targets.
Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity
Authors: Shani Ophir , Vorobyov Tatiana , Monteran Lea , Lavie Dor , Cohen Noam , Raz Yael , Tsarfaty Galia , Avivi Camila , Barshack Iris , Erez Neta 
Published: October 2020

AbstractLungs are one of the main sites of breast cancer metastasis. The metastatic microenvironment is essential to facilitate growth of disseminated tumor cells. Cancer-associated fibroblasts (CAF) are prominent players in the microenvironment of breast cancer. However, their role in the formation of a permissive metastatic niche is unresolved. Here we show that IL33 is upregulated in metastases-associated fibroblasts in mouse models of spontaneous breast cancer metastasis and in patients with breast cancer with lung metastasis. Upregulation of IL33 instigated type 2 inflammation in the metastatic microenvironment and mediated recruitment of eosinophils, neutrophils, and inflammatory monocytes to lung metastases. Importantly, targeting of IL33 in vivo resulted in inhibition of lung metastasis and significant attenuation of immune cell recruitment and type 2 immunity. These findings demonstrate a key function of IL33 in facilitating lung metastatic relapse by modulating the immune microenvironment. Our study shows a novel interaction axis between CAF and immune cells and reveals the central role of CAF in establishing a hospitable inflammatory niche in lung metastasis.Significance:This study elucidates a novel role for fibroblast-derived IL33 in facilitating breast cancer lung metastasis by modifying the immune microenvironment at the metastatic niche toward type 2 inflammation.
Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response
Authors: Karzai Fatima , Walker Stephanie M. , Wilkinson Scott , Madan Ravi A. , Shih Joanna H. , Merino Maria J. , Harmon Stephanie A. , VanderWeele David J. , Cordes Lisa M. , Carrabba Nicole V. , Bright John R. , Terrigino Nicolas T. , Chun Guinevere , Bilusic Marijo , Couvillon Anna , Hankin Amy , Williams Monique N. , Lis Rosina T. , Ye Huihui , Choyke Peter L. , Gulley James L. , Sowalsky Adam G. , Turkbey Baris , Pinto Peter A. , Dahut William L. 
Published: October 2020

Abstract

Purpose:
For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.

Patients and Methods:
Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.

Results:
Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated &gt;50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of &lt;0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology.

Conclusions:
Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.
A Space–Time Continuum for Immunotherapy Biomarkers in Gastroesophageal Cancer?
Authors: Klempner Samuel J. , Upadhyay Vivek , Chao Joseph 
Published: October 2020

Abstract
In an annotated series of gastroesophageal adenocarcinomas differences in PD-L1 expression and tumor mutation burden occur between both paired contemporaneous primary and metastatic biopsies and pre/posttreatment samples. This work has implications for optimizing patient selection, serial testing, need for mechanistic understanding, and may underlie variable responses to checkpoint inhibitors in gastroesophageal cancers.
See related article by Zhou et al., p. 6453
Inhibition of EZH2 Enhances the Antitumor Efficacy of Metformin in Prostate Cancer
Authors: Kong Yifan , Zhang Yanquan , Mao Fengyi , Zhang Zhuangzhuang , Li Zhiguo , Wang Ruixin , Liu Jinghui , Liu Xiaoqi 
Published: October 2020

Abstract
Upregulation of EZH2 is associated with advanced stage and poor prognosis of prostate cancer; therefore, it is likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type 2 diabetes, was found to have antineoplastic activity in different cancers. Herein, we report that the combination of metformin and the EZH2 inhibitor GSK126 exerts synergistic inhibition on prostate cancer cell growth, both in vitro and in vivo. Mechanistically, we identify that metformin can reduce EZH2 expression through upregulating miR-26a-5p, which is antagonized by androgen receptor (AR). Furthermore, we show that AR binds to the promoter of miR-26a-5p and suppresses its transcription. Although metformin can remove AR from the miR-26a-5p promoter, the interaction between AR and EZH2, which usually exists in androgen-refractory prostate cancer cells, strongly impedes the removal. However, GSK126 can inhibit the methyltransferase-dependent interaction between AR and EZH2, thus restoring metformin's efficacy in androgen-refractory prostate cancer cells. Collectively, our finding suggests that the combination of metformin and GSK126 would be an effective approach for future prostate cancer therapy, and particularly effective for AR-positive castration-resistant prostate cancer.
Assessment of and Interventions for Women at High Risk for Breast or Ovarian Cancer: A Survey of Primary Care Physicians
Authors: Samimi Goli , Heckman-Stoddard Brandy M. , Holmberg Christine , Tennant Bethany , Sheppard Bonny Bloodgood , Coa Kisha I. , Kay Shelley S. , Ford Leslie G. , Szabo Eva , Minasian Lori M. 
Published: October 2020

Abstract
As clinical guidelines for cancer prevention refer individuals to primary care physicians (PCP) for risk assessment and clinical management, PCPs may be expected to play an increasing role in cancer prevention. It is crucial that PCPs are adequately supported to assess an individual’s cancer risk and make appropriate recommendations. The objective of this study is to assess use, familiarity, attitude, and behaviors of PCPs regarding breast and ovarian cancer risk and prevention, to better understand the factors that influence their prescribing behaviors. We conducted a cross-sectional, web-based survey of PCPs in the United States, recruited from an opt-in healthcare provider panel. Invitations were sent in batches until the target sample size of 750 respondents (250 each for obstetrics/gynecology, internal medicine, and family medicine) was met. Self-reported use of breast/ovarian cancer risk assessments was low (34.7%–59.2%) compared with discussion of cancer family history (96.9%), breast exams (87.1%), and mammograms (92.8%). Although most respondents (48.0%–66.8%) were familiar with cancer prevention interventions, respondents who reported to be less familiar were more likely to report cautious attitudes. When presented with hypothetical cases depicting patients at different breast/ovarian cancer risks, up to 34.0% of respondents did not select any of the clinically recommended course(s) of action. This survey suggests that PCP use of breast/ovarian cancer risk assessment tools and ability to translate the perceived risks to clinical actions is variable. Improving implementation of cancer risk assessment and clinical management guidelines within primary care may be necessary to improve the appropriate prescribing of cancer prevention interventions.
Prevention Relevance: Primary care physicians are becoming more involved in cancer prevention management, so it is important that cancer risk assessment and medical society guideline recommendations for cancer prevention are better integrated into primary care to improve appropriate prescribing of cancer prevention interventions and help reduce cancer risk.
Immune Remodeling of the Extracellular Matrix Drives Loss of Cancer Stem Cells and Tumor Rejection
Authors: Pires Ana , Greenshields-Watson Alexander , Jones Emma , Smart Kathryn , Lauder Sarah N. , Somerville Michelle , Milutinovic Stefan , Kendrick Howard , Hindley James P. , French Rhiannon , Smalley Matthew J. , Watkins William J. , Andrews Robert , Godkin Andrew , Gallimore Awen 
Published: October 2020

AbstractThe nature of the tumor microenvironment (TME) influences the ability of tumor-specific T cells to control tumor growth. In this study, we performed an unbiased comparison of the TME of regulatory T-cell (Treg)–replete and Treg-depleted carcinogen-induced tumors, including Treg-depleted responding (regressing) and non-responding (growing) tumors. This analysis revealed an inverse relationship between extracellular matrix (ECM) and T-cell infiltrates where responding tumors were T-cell rich and ECM poor, whereas the converse was observed in non-responder tumors. For this reason, we hypothesized that the ECM acted as a barrier to successful T-cell infiltration and tumor rejection. However, further experiments revealed that this was not the case but instead showed that an effective T-cell response dramatically altered the density of ECM in the TME. Along with loss of ECM and high numbers of infiltrating T cells, responder tumors were distinguished by the development of lymphatic and blood vessel networks with specialized immune function. ECM-rich tumors exhibited a stem cell–like gene expression profile and superior tumor-initiating capacity, whereas such features were absent in responder tumors. Overall, these findings define an extended role for an effective immune response, not just in direct killing of tumor cells but in widescale remodeling of the TME to favor loss of ECM, elimination of cancer stem cells, and propagation of adaptive immunity.
The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment
Authors: Väyrynen Juha P. , Haruki Koichiro , Lau Mai Chan , Väyrynen Sara A. , Zhong Rong , Dias Costa Andressa , Borowsky Jennifer , Zhao Melissa , Fujiyoshi Kenji , Arima Kota , Twombly Tyler S. , Kishikawa Junko , Gu Simeng , Aminmozaffari Saina , Shi Shanshan , Baba Yoshifumi , Akimoto Naohiko , Ugai Tomotaka , Da Silva Annacarolina , Guerriero Jennifer L. , Song Mingyang , Wu Kana , Chan Andrew T. , Nishihara Reiko , Fuchs Charles S. , Meyerhardt Jeffrey A. , Giannakis Marios , Ogino Shuji , Nowak Jonathan A. 
Published: October 2020

Abstract
Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.