bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer
Authors: Saura Cristina , Matito Judit , Oliveira Mafalda , Wildiers Hans , Brufksy Adam M. , Waters Simon H. , Hurvitz Sara A. , Moy Beverly , Kim Sung-Bae , Gradishar William J. , Queiroz Geraldo Silva , Cronemberger Eduardo , Wallweber Gerald J. , Bebchuk Judith , Keyvanjah Kiana , Lalani Alshad S. , Bryce Richard , Vivancos Ana , Eli Lisa D. , Delaloge Suzette 
Published: August 2021

Abstract

Purpose:
Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS.

Patients and Methods:
Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models.

Results:
Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64–1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97–3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54–0.82); H-score ≥240 versus &lt;240, HR = 0.77 (0.63–0.93); HERmark positive vs. negative, HR = 0.76 (0.59–0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51–0.81); H-score ≥ 240, HR = 0.54 (0.41–0.72); HERmark positive, HR = 0.65 (0.50–0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50–0.86) vs. p95 &lt; 2.8 RF/mm2, HR = 0.91 (0.61–1.36)].

Conclusions:
PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.
T Cell–Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer
Authors: Li Dandan , Schaub Nicholas , Guerin Theresa M. , Bapiro Tashinga E. , Richards Frances M. , Chen Vicky , Talsania Keyur , Kumar Parimal , Gilbert Debra J. , Schlomer Jerome J. , Kim Seong-Jin , Sorber Rebecca , Teper Yaroslav , Bautista Wendy , Palena Claudia , Ock Chan-Young , Jodrell Duncan I. , Pate Nathan , Mehta Monika , Zhao Yongmei , Kozlov Serguei , Rudloff Udo 
Published: August 2021

Abstract
The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were coadministered with antistromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with coadministered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMM) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAF) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell–mediated antitumor activity. The antitumor activity was further improved by the addition of anti–PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined antistroma anticancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery.
KITlow Cells Mediate Imatinib Resistance in Gastrointestinal Stromal Tumor
Authors: Banerjee Sudeep , Yoon Hyunho , Ting Stephanie , Tang Chih-Min , Yebra Mayra , Wenzel Alexander T. , Yeerna Huwate , Mesirov Jill P. , Wechsler-Reya Robert J. , Tamayo Pablo , Sicklick Jason K. 
Published: August 2021

Abstract
Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34+KIThigh progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell–associated transcription factors (OCT4 and NANOG) and concomitant enrichment of the CD34+KITlow cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our in vitro findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets in vitro and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34+KITlow cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy.
Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor
Authors: Xie Yanqi , Zhang Wen , Guo Lichao , Kril Liliia M. , Begley Kristin L. , Sviripa Vitaliy M. , Chen Xi , Liu Xifu , Lee Eun Y. , He Daheng , Wang Chi , Gao Tianyan , Liu Xiaoqi , Evers B. Mark , Watt David S. , Liu Chunming 
Published: August 2021

Abstract
Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as N7,N7-dimethyl-3-(1-methyl-1H-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent in vitro inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy–homeostasis master regulator. We explored the effect of ISQs on cell metabolism. Seahorse assays measuring oxygen consumption rate (OCR) indicated that ISQ-1 inhibited complex I (i.e., NADH ubiquinone oxidoreductase) in the mitochondrial, electron transport chain (ETC). In addition, ISQ-1 treatment showed remarkable synergistic depletion of oncogenic c-Myc protein level in vitro and induced strong tumor remission in vivo when administered together with BI2536, a polo-like kinase-1 (Plk1) inhibitor. These studies point toward the potential value of dual drug therapies targeting the ETC and Plk-1 for the treatment of c-Myc–driven cancers.
Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor–Resistant Melanoma
Authors: Nassar Kelsey W. , Hintzsche Jennifer D. , Bagby Stacey M. , Espinoza Veronica , Langouët-Astrié Christophe , Amato Carol M. , Chimed Tugs-Saikhan , Fujita Mayumi , Robinson William , Tan Aik Choon , Schweppe Rebecca E. 
Published: August 2021

Abstract
There is a clear need to identify targetable drivers of resistance and potential biomarkers for salvage therapy for patients with melanoma refractory to the combination of BRAF and MEK inhibition. In this study, we performed whole-exome sequencing on BRAF-V600E–mutant melanoma patient tumors refractory to the combination of BRAF/MEK inhibition and identified acquired oncogenic mutations in NRAS and loss of the tumor suppressor gene CDKN2A. We hypothesized the acquired resistance mechanisms to BRAF/MEK inhibition were reactivation of the MAPK pathway and activation of the cell-cycle pathway, which can both be targeted pharmacologically with the combination of a MEK inhibitor (trametinib) and a CDK4/6 inhibitor (palbociclib). In vivo, we found that combination of CDK4/6 and MEK inhibition significantly decreased tumor growth in two BRAF/MEK inhibitor–resistant patient-derived xenograft models. In vitro, we observed that the combination of CDK4/6 and MEK inhibition resulted in synergy and significantly reduced cellular growth, promoted cell-cycle arrest, and effectively inhibited downstream signaling of MAPK and cell-cycle pathways in BRAF inhibitor–resistant cell lines. Knockdown of CDKN2A in BRAF inhibitor–resistant cells increased sensitivity to CDK4/6 inhibition alone and in combination with MEK inhibition. A key implication of our study is that the combination of CDK4/6 and MEK inhibitors overcomes acquired resistance to BRAF/MEK inhibitors, and loss of CDKN2A may represent a biomarker of response to the combination. Inhibition of the cell-cycle and MAPK pathway represents a promising strategy for patients with metastatic melanoma who are refractory to BRAF/MEK inhibitor therapy.
Hsp90 Inhibitor STA9090 Sensitizes Hepatocellular Carcinoma to Hyperthermia-Induced DNA Damage by Suppressing DNA-PKcs Protein Stability and mRNA Transcription
Authors: Liu Lixia , Deng Yaotang , Zheng Zhenming , Deng Zihao , Zhang Jinxin , Li Jieyou , Liang Manfeng , Zhou Xueqiong , Tan Wenchong , Yang Hongjun , Neckers Leonard M. , Zou Fei , Chen Xuemei 
Published: August 2021

Abstract
As a conserved molecular chaperone, heat shock protein 90 (Hsp90) maintains the stability and homeostasis of oncoproteins and helps cancer cells survive. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a pivotal role in the non-homologous end joining pathway for DNA double-strand breaks (DSB) repair. Tumor cells contain higher levels of DNA-PKcs to survive by the hostile tumor microenvironment and various antitumor therapies. Here, we showed that increased levels of Hsp90α, Hsp90β, and DNA-PKcs correlated with a poor overall survival in hepatocellular carcinoma (HCC). We revealed that Hsp90 N-terminal domain and C-terminal domain have different effects on DNA-PKcs protein and mRNA levels. The stability of DNA-PKcs depended on Hsp90α N-terminal nucleotide binding domain. Transcription factor SP1 regulates the transcription of PRKDC (gene name of DNA-PKcs) and is a client protein of Hsp90. Inhibition of Hsp90 N-terminal by STA9090 decreased the location of Hsp90α in nucleus, Hsp90α-SP1 interaction, SP1 level, and the binding of Hsp90α/SP1 at the proximal promoter region of PRKDC. Because hyperthermia induces DSBs with increases level of DNA-PKcs, combined STA9090 treatment with hyperthermia effectively delayed the tumor growth and significantly decreased DNA-PKcs levels in xenografts model. Consistently, inhibition of Hsp90 increased the number of heat shock–induced γ-H2AX foci and delayed the repair of DSBs. Altogether, our results suggest that Hsp90 inhibitor STA9090 decreases DNA-PKcs protein stability and PRKDC mRNA level, which provide a theoretical basis for the promising combination therapy of hyperthermia and Hsp90 inhibitor in HCC.
Exosomal Noncoding RNAs in Hepatobiliary Cancer: A Rising Star
Authors: Zheng Wangyang , Ji Daolin , Zhou Yongxu , Yu Liang , Huang Peng , Zheng Yuling , Meng Nanfeng , Wang Hang , Bai Xue , Huang ZiYue , Chen Wangming , Yam Judy W.P. , Xu Yi , Cui Yunfu 
Published: August 2021

AbstractHepatobiliary cancers are a heterogeneous group of malignancies with a dismal prognosis. Despite intensive research efforts focused on these tumors, methods for early diagnosis and effective targeted therapies are still lacking. Exosomes, released by most cells, exist in all kinds of body fluids and play an important role in cell-to-cell communication. They are small membranous vesicles containing biological molecules, such as noncoding RNAs (ncRNA), which are not translated into proteins, but they exert effects on the regulation of gene transcription and translation. There is growing evidence for the essential roles of ncRNAs in exosomes in both physiologic and pathologic conditions of hepatobiliary cancers. They have been identified as sensitive diagnostic biomarkers as well as potential therapeutic targets. The present review discusses recent findings in the cross-talk between hepatobiliary cancers cells and the surrounding cells of the microenvironment and discuss their potential clinical usage.
N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes
Authors: DelaCourt Andrew , Black Alyson , Angel Peggi , Drake Richard , Hoshida Yujin , Singal Amit , Lewin David , Taouli Bachir , Lewis Sara , Schwarz Myron , Fiel M. Isabel , Mehta Anand S. 
Published: August 2021

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically.

Implications:
Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.
Association of Subjective Social Status With Life's Simple 7s Cardiovascular Health Index Among Hispanic/Latino People: Results From the HCHS/SOL
Authors: Piedra Lissette M. , Andrade Flavia C. D. , Hernandez Rosalba , Perreira Krista M. , Gallo Linda C. , González Hector M. , Gonzalez Sara , Cai Jianwen , Chen Jinsong , Castañeda Sheila F. , Tabb K. M. , Talavera Gregory A. , Durazo‐Arvizu Ramon A. , Daviglus Martha L. 
Published: August 2021

Background
Evidence suggests that subjective (perceived) social status (SSS) may predict health outcomes more strongly than objective social status, but little is known about the relationship between SSS and cardiovascular health (CVH). This study focuses on this relationship among diverse Hispanic/Latino adults because while poor CVH profiles are prevalent in this population, immigration complicates attempts to measure their social status.

Methods and Results
We analyzed baseline HCHS/SOL (Hispanic Community Health Study/Study of Latinos) data on 15 374 Hispanic/Latino adults aged 18 to 74 years in 2008 to 2011. SSS was assessed using the McArthur Scale, a 10‐rung “social ladder.” CVH was based on levels of 7 metrics defined by the American Heart Association. Linear and logistic regressions were used to examine cross‐sectional associations of SSS with CVH (overall and single metrics) after adjusting for objective social status, demographic, and health factors. Less than half of the population (46%) had Ideal scores in ≥4 metrics of CVH. In multivariable‐adjusted models, an increase in SSS was associated with a higher overall CVH score (β=0.04; 95% CI, 0.01–0.06) and greater likelihood of Ideal levels of body mass index, physical activity, and fasting blood glucose levels. Nativity and time in the United States modified the association between SSS and Ideal smoking.

Conclusions
Subjective measures of social status can enhance an understanding of CVH among Hispanic/Latino people. Future studies should explore the stability of SSS over time in comparison with objective social status and the mechanisms through which SSS may influence CVH.
Suprasternal Versus Transfemoral Access for Transcatheter Aortic Valve Replacement: Insights From a Propensity Score Matched Analysis
Authors: Brener Michael I. , Olds Anna , Nemeth Samantha , Kurlansky Paul , Nazif Tamim M. , Vahl Torsten P. , Khalique Omar K. , Hamid Nadira B. , Patel Amisha , Ng Vivian G. , Chen Shmuel , Cahill Thomas J. , Rahim Hussein M. , Hahn Rebecca T. , Bapat Vinayak , Sarraf Mohammad , Ahmed Mustafa I. , Leon Martin B. , Kodali Susheel , Eudailey Kyle W. , George Isaac 
Published: August 2021

Background
Suprasternal access is an alternative access strategy for transcatheter aortic valve replacement (TAVR) where the innominate artery is cannulated from an incision above the sternal notch. To date, suprasternal access has never been compared with transfemoral TAVR. Thus, we sought to assess safety, feasibility, and early clinical outcomes between suprasternal and transfemoral access for patients undergoing TAVR.

Methods and Results

We evaluated patients from 2 institutional prospective, observational registries containing 1348 patients. Patients were selected in a 2:1 ratio (transfemoral:suprasternal) on the basis of propensity score matching. The primary outcome was in‐hospital mortality, and secondary outcomes included the incidence of ischemic stroke, major bleeding, vascular injury, left bundle‐branch block, and permanent pacemaker implantation at 30‐day follow‐up. Propensity score matching identified 89 patients undergoing suprasternal TAVR and 159 patients undergoing transfemoral TAVR suitable for analysis. There was no significant difference between suprasternal TAVR and transfemoral TAVR with respect to in‐hospital mortality (1.1% versus 0.6%; odds ratio [OR], 1.80; 95% CI, 0.11–29.06;
P
=0.680). No patients in either cohort suffered an ischemic stroke. The incidence of major bleeding (2.2% versus 2.5%; OR, 0.89; 95% CI, 0.16–4.96;
P
=0.895) and vascular injury (1.1% versus 1.9%; OR, 0.59; 95% CI, 0.06–5.77;
P
=0.651) did not differ significantly. The frequency of left bundle‐branch block (9.4% versus 15.8%; OR, 0.56; 95% CI, 0.24–1.30;
P
=0.177) and permanent pacemaker implantation (11.2% versus 5.9%; OR, 2.01; 95% CI, 0.75–5.45;
P
=0.169) were not statistically significantly different.

Conclusions
Suprasternal TAVR was safe and achieved promising short‐term clinical outcomes when compared with transfemoral TAVR. Future studies seeking to identify the optimal alternative access site should evaluate suprasternal TAVR access alongside other substitutes for transfemoral TAVR.
Bypassing the Social Distance: International Catholic Community, Friendship, and Homemaking among Expatriates in Brno
Authors: Fujda Milan , Ondrašinová Michaela , Vrzal Miroslav 
Published: August 2021

Abstract
We analyze the role of intimate social ties and community in the processes of homemaking and social integration of highly skilled migrants who are members of the local international Catholic community in Brno, Czech Republic. We use the concepts of bonding and bridging social capital developed by Michael W. Foley and Dean R. Hoge and follow their attention to the effects of the worship communities’ organizational culture on migrants’ integration. In the article, we show that the Catholic community mediates its members’ homemaking efficiently by providing them with rich bonding social capital, generated through close social ties in the community. However, it does not provide them with enough bridging social capital, and their social integration, thus, remains restricted to the company of international fellows. We compare it with the strategies of homemaking used by settling migrants who have integrated more successfully into the Czech social environment.
Proselytism and Ostentation: a Critical Discourse Analysis of the European Court of Human Rights’ Case Law on Religious Symbols
Authors: Evolvi Giulia , Gatti Mauro 
Published: August 2021

Abstract
This article focuses on the European Court of Human Rights’ (ECtHR) case law about religious symbols (N=27) from 2001 to 2018, exploring the following questions: What discourses does the ECtHR employ in cases about religious symbols? How do ECtHR’s discourses about religious symbols evolve in time? The data is innovatively analyzed through critical discourse analysis and leads to two findings: first, the ECtHR tends to endorse ‘Christian secularism,’ considering Christian symbols as compatible with secularism but not Muslim symbols; second, ECtHR discourses occasionally become more favorable to Muslim applicants over time, but the evolution of case law is not linear.
[RETRACTED] Modeling the Theory-Form: Beyond the Elements of Observational Postulation
Authors: Erkan Ekin 
Published: August 2021

Abstract
We formalize a theory of the subject by sketching a pragmatic functional hierarchy of sapient cognition. Our expanded framework attempts to articulate a normative understanding of discursive cognition by demarcating its functional propriety within a naturalist rejoinder, seeing in the functional development of cognition from pre-discursive to discursive abilities an increase and refinement in representational competence found in non-intentional systems. We therein explain how sapient cognitive systems not only engage in patterns of material and formal inference to map intensional relations between phenomena in nature through theoretical and practical reasonings, but also engage in practices of theoretical construction and systematic integration through techniques of formalization that make the unity of nature and thought progressively intelligible. We trace the development of mind in its representational function from barren discriminatory capacities, shared with inanimate objects, to complex theory-forming systematizing conceptual abilities enabling agents to theoretically map and intervene upon the world of which they are part, and to embed the informational indexes they register from the environment that makes globally explicit the objective modal structure of the world.