bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer
Authors: Schwede Matthew , Waldron Levi , Mok Samuel C. , Wei Wei , Basunia Azfar , Merritt Melissa A. , Mitsiades Constantine S. , Parmigiani Giovanni , Harrington David P. , Quackenbush John , Birrer Michael J. , Culhane Aedín C. 
Published: December 2019

AbstractBackground:Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.Methods:Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma.Results:Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11–1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content.Conclusions:Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important.Impact:Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.
FOXA1 Protein Expression in ER+ and ER− Breast Cancer in Relation to Parity and Breastfeeding in Black and White Women
Authors: Cheng Ting-Yuan David , Yao Song , Omilian Angela R. , Khoury Thaer , Buas Matthew F. , Payne-Ondracek Rochelle , Sribenja Sirinapa , Bshara Wiam , Hong Chi-Chen , Bandera Elisa V. , Davis Warren , Higgins Michael J. , Ambrosone Christine B. 
Published: December 2019

Abstract

Background:
Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor–negative (ER−) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER− tumors.

Methods:
We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status.

Results:
ER-positive (ER+) versus ER− tumors had higher FOXA1 protein expression (P &lt; 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple–negative cancer (both P &lt; 0.001), but not in those with ER− or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or β = −8.5; 95% confidence interval (CI), −15.1 to −2.0], particularly among parous women who never breastfed (β = −10.4; 95% CI, −19.7 to −1.0), but not among those who breastfed (β = −7.5; 95% CI, −16.9 to 1.8). The associations for ER− tumors were similar, although they were not statistically significant.

Conclusions:
In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence.

Impact:
These findings contribute to our understanding of FOXA1 methylation and breast cancer etiology.
Adherence to Dietary Recommendations among Long-Term Breast Cancer Survivors and Cancer Outcome Associations
Authors: Wang Fei , Cai Hui , Gu Kai , Shi Liang , Yu Danxia , Zhang Minlu , Zheng Wei , Zheng Ying , Bao Pingping , Shu Xiao-Ou 
Published: December 2019

Abstract

Background:
Adherence to dietary recommendations has been shown to be associated with reduced mortality in healthy populations. Little is known about the possible benefits of adherence to dietary recommendations among breast cancer survivors.

Methods:
Dietary information was collected using food frequency questionnaires at the 5-year postdiagnosis survey in 3,450 5-year breast cancer survivors from the Shanghai Breast Cancer Survival Study. Adherence scores to Chinese Food Pagoda (CHFP)-2007, CHFP-2016, modified Dietary Approaches to Stop Hypertension (DASH), and Healthy Eating Index 2015 (HEI-2015) were created. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality and breast cancer–specific events according to adherence scores.

Results:
Participants in the highest quartiles of CHFP-2007, CHFP-2016, and DASH had 25% to 34% lower risk of total mortality (HR, 0.66; 95% CI, 0.48–0.89 for CHFP-2007; HR, 0.75; 95% CI, 0.55–1.01 for CHFP-2016; HR, 0.66; 95% CI, 0.49–0.91 for DASH), and 36% to 40% lower risk of breast cancer–specific events (HR, 0.64; 95% CI, 0.44–0.93 for CHFP-2007; HR, 0.67; 95% CI, 0.45–0.99 for CHFP-2016; HR, 0.60; 95% CI, 0.40–0.90 for DASH) comparing with the lowest quartiles. Associations did not vary by known prognostic factors. HEI-2015 scores were not significantly associated with breast cancer outcomes.

Conclusions:
Higher adherence to CHFP and DASH dietary guidelines post-cancer diagnosis was associated with reduced risk of both overall death and breast cancer–specific recurrence or death among long-term breast cancer survivors.

Impact:
Our study highlights the importance of overall dietary quality among long-term breast cancer survivors.
Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein–Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial
Authors: Akutsu Taisuke , Okada Shinya , Hirooka Shinichi , Ikegami Masahiro , Ohdaira Hironori , Suzuki Yutaka , Urashima Mitsuyoshi 
Published: December 2019

Abstract

Background:
The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation.

Methods:
The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (&gt;10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles.

Results:
The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31–0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (Pinteraction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed.

Conclusions:
These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer.

Impact:
The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.
Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer
Authors: Goldstein Jennifer B. , Zhao Li , Wang Xuemei , Ghelman Yael , Overman Michael J. , Javle Milind M. , Shroff Rachna T. , Varadhachary Gauri R. , Wolff Robert A. , McAllister Florencia , Futreal Andrew , Fogelman David R. 
Published: December 2019

Abstract

Purpose:
Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer.

Experimental Design:
Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records.

Results:
Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival.

Conclusions:
We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers
Authors: Woroniecka Karolina I. , Rhodin Kristen E. , Dechant Cosette , Cui Xiuyu , Chongsathidkiet Pakawat , Wilkinson Daniel , Waibl-Polania Jessica , Sanchez-Perez Luis , Fecci Peter E. 
Published: December 2019

AbstractPurpose:The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti–PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM.Experimental Design:We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo.Results:Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell–dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous tumor location. Proffering 4-1BB expression to T cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective.Conclusions:Although poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti–PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.
Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential
Authors: Tivadar Silvana T. , McIntosh Richard S. , Chua Jia Xin , Moss Robert , Parsons Tina , Zaitoun Abed M. , Madhusudan Srinivasan , Durrant Lindy G. , Vankemmelbeke Mireille 
Published: December 2019

AbstractTumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1κ that targets sialyl-di-Lewisa–containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non–small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P = 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa–expressing solid tumors, as an antibody–drug conjugate or as an alternative cancer immunotherapy modality.
Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma
Authors: Flem-Karlsen Karine , McFadden Erin , Omar Nasrin , Haugen Mads H. , Øy Geir Frode , Ryder Truls , Gullestad Hans Petter , Hermann Robert , Mælandsmo Gunhild Mari , Flørenes Vivi Ann 
Published: December 2019

Abstract
Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.
Evaluating Lung Cancer Screening Across Diverse Healthcare Systems: A Process Model from the Lung PROSPR Consortium
Authors: Rendle Katharine A. , Burnett-Hartman Andrea N. , Neslund-Dudas Christine , Greenlee Robert T. , Honda Stacey , Elston Lafata Jennifer , Marcus Pamela M. , Cooley Mary E. , Vachani Anil , Meza Rafael , Oshiro Caryn , Simoff Michael J. , Schnall Mitchell D. , Beaber Elisabeth F. , Doria-Rose V. Paul , Doubeni Chyke A. , Ritzwoller Debra P. 
Published: December 2019

Abstract
Numerous organizations, including the United States Preventive Services Task Force, recommend annual lung cancer screening (LCS) with low-dose CT for high risk adults who meet specific criteria. Despite recommendations and national coverage for screening eligible adults through the Centers for Medicare and Medicaid Services, LCS uptake in the United States remains low (&lt;4%). In recognition of the need to improve and understand LCS across the population, as part of the larger Population-based Research to Optimize the Screening PRocess (PROSPR) consortium, the NCI (Bethesda, MD) funded the Lung PROSPR Research Consortium consisting of five diverse healthcare systems in Colorado, Hawaii, Michigan, Pennsylvania, and Wisconsin. Using various methods and data sources, the center aims to examine utilization and outcomes of LCS across diverse populations, and assess how variations in the implementation of LCS programs shape outcomes across the screening process. This commentary presents the PROSPR LCS process model, which outlines the interrelated steps needed to complete the screening process from risk assessment to treatment. In addition to guiding planned projects within the Lung PROSPR Research Consortium, this model provides insights on the complex steps needed to implement, evaluate, and improve LCS outcomes in community practice.
A preliminary checklist of the Coccinellidae of Bhutan (Insecta: Coleoptera)
Authors: DORJI CHETEN , LODAY PHUNTSHO , VORST OSCAR 
Published: December 2019

An annotated distributional checklist of the Coccinellidae of Bhutan is presented, enumerating 91 species, 17 of which are here recorded for the first time: Shirozuella tibetina Wang, Ge & Ren, 2012, Jauravia limbata (Motschulsky, 1858), Scymnus bourdilloni (Kapur, 1958), Illeis confusa Timberlake, 1943, Calvia albida Bielawski, 1972, Harmonia expalliata Sicard, 1913, H. octomaculata (Fabricius, 1781), H. sedecimnotata (Fabricius, 1801), Micraspis allardi (Mulsant, 1866), M. discolor (Fabricius, 1798), M. univittata (Hope, 1831), Oenopia adelgivora Poorani, 2002, O. billieti (Mulsant, 1853), O. smetanai Canepari, 1997, Afissula mysticoides (Sicard, 1913), Henosepilachna processa Li & Cook, 1961 and H. septima (Dieke, 1947). One species, Propylea japonica (Thunberg, 1781), has to be removed from the list. Nine species and two subspecies are hitherto only reported from the territory of Bhutan. The Bhutanese coccinellid fauna is still insufficiently known.
Facebook posts as performatives in Bulgarian political life: A sociolinguistic investigation
Authors: Tincheva Nelly 
Published: December 2019

Facebook posts as performatives in Bulgarian political life: A sociolinguistic investigationThe paper provides a snapshot of how the Bulgarian political public interprets the notion of ‘political action’. The paper argues there are two basic notions (‘performing’ and ‘performativity’) which are fundamental to present-day interpretations of ‘political action’, and that these two notions need to be approached through quantitative analysis of actual respondents’ interpretations. The paper addresses this analytical niche and in doing so draws on a previous sociolinguistic study which strongly suggests that the modern genre of the Facebook post has special social and political significance in pro-active Bulgarian political life. The paper systematizes and discusses the results from a questionnaire-based study on Bulgarian recipients’ expectations about the communicative and political effect of the Facebook post. The results of the study reveal that Bulgarian political audiences perceive the Facebook post not simply as a genre in Bulgarian political discourse but, crucially, as a vehicle for actual political performance in present-day Bulgarian political life. Posty na Facebooku jako performatywy w bułgarskim życiu politycznym. Ujęcie socjolingwistyczneArtykuł dotyczy tego, jak bułgarska społeczność pojmuje ideę „aktu politycznego”. Autorka broni tezy, że istnieją dwie kluczowe idee – „publiczne przedstawienie” i „performatywność” (tj. wypowiedzi performatywne) – które determinują współczesne bułgarskie interpretacje „aktu politycznego” oraz że obie te idee należy badać jakościowo, poprzez analizę danych wziętych od realnych respondentów, będących zarówno nosicielami języka, jak i aktywnymi politycznie obywatelami. Podejmując próbę zapełnienia analitycznej niszy, autorka wskazuje, że współczesny gatunek, jakim jest post na Facebooku, ma szczególne znaczenie w życiu codziennym aktywnych politycznie i społecznie Bułgarów. W artykule zostały usystematyzowane i omówione rezultaty badania, które dotyczyło nastawienia i oczekiwań bułgarskich recypientów w odniesieniu do efektu komunikacyjnego i politycznego postów na Facebooku. Okazuje się, że bułgarska społeczność polityczna pojmuje ten nowy gatunek nie tylko jako narzędzie do uczestnictwa w dyskursie politycznym, ale także jako sposób na realne działanie polityczne.