bluuebunny/crossref_metadata_2025_split huggingface dataset:
TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas
Authors: Gonzalez-Buendia Edgar , Zhao Junfei , Wang Lu , Mukherjee Subhas , Zhang Daniel , Arrieta Víctor A. , Feldstein Eric , Kane J. Robert , Kang Seong Jae , Lee-Chang Catalina , Mahajan Aayushi , Chen Li , Realubit Ronald , Karan Charles , Magnuson Lisa , Horbinski Craig , Marshall Stacy A. , Sarkaria Jann N. , Mohyeldin Ahmed , Nakano Ichiro , Bansal Mukesh , James Charles D. , Brat Daniel J. , Ahmed Atique , Canoll Peter , Rabadan Raul , Shilatifard Ali , Sonabend Adam M. 
Published: August 2021

Abstract

Purpose:
The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors.

Experimental Design:
To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes.

Results:
We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA.

Conclusions:
Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.
Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
Authors: Even Caroline , Wang Hung-Ming , Li Shau-Hsuan , Ngan Roger K-C , Dechaphunkul Arunee , Zhang Li , Yen Chia-Jui , Chan Po Chung , Chakrabandhu Somvilai , Ma Brigette B.Y. , Tanasanvimon Suebpong , Lee Victor H.F. , Lou Pei-Jen , Li Zujun , Spira Alexander I. , Sukari Ammar , Guigay Joël , McCune Steven , Gonzalez-Maffe Juan , Szpakowski Sebastian , Yao Yao , Liang Hongzi , Mataraza Jennifer , Séchaud Romain , Manenti Luigi , Lim Darren W-T. 
Published: August 2021

AbstractPurpose:No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.Patients and Methods:Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice.Results:Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression.Conclusions:Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.
A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe 
Published: August 2021

Abstract

Purpose:
Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study.

Patients and Methods:
A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200–900 mg/day; arm B, LSZ102 200–600 mg/day plus ribociclib 300–600 mg/day; arm C, LSZ102 300–450 mg/day plus alpelisib 200–300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1).

Results:
The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0–7.0); arm B, 16.9% (9.3–27.1); and arm C, 7.0% (1.5–19.1), and clinical benefit rates 7.8% (2.9–16.2), 35.1% (24.5–46.8), and 20.9% (10.0–36.0), respectively.

Conclusions:
LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.
NEI-01-Induced Arginine Deprivation Has Potent Activity Against Acute Myeloid Leukemia Cells BothIn VitroandIn Vivo
Authors: Cai Yijun , Chow Jeremy P.H. , Leung Yu-On , Lu Xiaoxu , Yuen Chak-Ho , Lee Wing Lun , Chau Ka-Chun , Yang Liz L. , Wong Raymond M.H. , Lam Justin Y.T. , Chow Daniel T.L. , Chung Steven H.K. , Kwok Sui-Yi , Leung Yun-chung 
Published: August 2021

AbstractRecent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo. NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell-cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft, mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft. This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.
Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages
Authors: Smith Bryan D. , Kaufman Michael D. , Wise Scott C. , Ahn Yu Mi , Caldwell Timothy M. , Leary Cynthia B. , Lu Wei-Ping , Tan Gege , Vogeti Lakshminarayana , Vogeti Subha , Wilky Breelyn A. , Davis Lara E. , Sharma Maitreyi , Ruiz-Soto Rodrigo , Flynn Daniel L. 
Published: August 2021

Abstract
Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.
Evaluation of Racial and Ethnic Disparities in Cardiac Transplantation
Authors: Chouairi Fouad , Fuery Michael , Clark Katherine A. , Mullan Clancy W. , Stewart James , Caraballo Cesar , Clarke John‐Ross D. , Sen Sounok , Guha Avirup , Ibrahim Nasrien E. , Cole Robert T. , Holaday Louisa , Anwer Muhammed , Geirsson Arnar , Rogers Joseph G. , Velazquez Eric J. , Desai Nihar R. , Ahmad Tariq , Miller P. Elliott 
Published: August 2021

Background
Racial and ethnic disparities contribute to differences in access and outcomes for patients undergoing heart transplantation. We evaluated contemporary outcomes for heart transplantation stratified by race and ethnicity as well as the new 2018 allocation system.

Methods and Results

Adult heart recipients from 2011 to 2020 were identified in the United Network for Organ Sharing database and stratified into 3 groups: Black, Hispanic, and White. We analyzed recipient and donor characteristics, and outcomes. Among 32 353 patients (25% Black, 9% Hispanic, 66% White), Black and Hispanic patients were younger, more likely to be women and have diabetes mellitus or renal disease (all,
P
<0.05). Over the study period, the proportion of Black and Hispanic patients listed for transplant increased: 21.7% to 28.2% (
P
=0.003) and 7.7% to 9.0% (
P
=0.002), respectively. Compared with White patients, Black patients were less likely to undergo transplantation (adjusted hazard ratio [aHR], 0.87; CI, 0.84–0.90;
P
<0.001), but had a higher risk of post‐transplant death (aHR, 1.14; CI, 1.04–1.24;
P
=0.004). There were no differences in transplantation likelihood or post‐transplant mortality between Hispanic and White patients. Following the allocation system change, transplantation rates increased for all groups (
P
<0.05). However, Black patients still had a lower likelihood of transplantation than White patients (aHR, 0.90; CI, 0.79–0.99;
P
=0.024).

Conclusions
Although the proportion of Black and Hispanic patients listed for cardiac transplantation have increased, significant disparities remain. Compared with White patients, Black patients were less likely to be transplanted, even with the new allocation system, and had a higher risk of post‐transplantation death.
Recruitment of Black Adults into Cardiovascular Disease Trials
Authors: Prasanna Anagha , Miller Hailey N. , Wu Yingfei , Peeler Anna , Ogungbe Oluwabunmi , Plante Timothy B. , Juraschek Stephen P. 
Published: August 2021

Background
Although disproportionately affected by cardiovascular disease, Black adults remain underrepresented in clinical trials. The National Institutes of Health recommends that studies define goals for recruitment of underrepresented populations. However, the extent to which cardiovascular trials incorporate evidence‐based recruitment strategies in their protocols is understudied.

Methods and Results
We systematically reviewed National Institutes of Health‐funded cardiovascular clinical trials registered in ClinicalTrials.gov between 2000 and 2019. Based on publicly available or requested protocols, we focused on enrollment of Black adults as well as the following recruitment strategies: community‐based, electronic medical record‐based, and provider‐based recruitment. A total of 100 clinical trials focused on cardiovascular disease were included in our analysis, of which 62% had published protocols, and 46% of trials had enrolled populations that were <25% Black. In our analysis of available trial protocols, 21% of trials defined a recruitment target for underrepresented groups; however, only one study reported achieving its enrollment goal. While 13% of trial protocols referenced community‐based recruitment strategies, 5% explicitly mentioned involving community members in the trial design process. Defining recruitment targets was associated with higher enrollment of Black participants.

Conclusions
Black adults are underrepresented in National Institutes of Health‐funded cardiovascular trials, and the majority of these trials did not specify a Black enrollment target, did not meet targets, and largely did not report specific plans to enroll Black adults in their studies. Future interventions should target trial design and planning phases before study initiation to address these enrollment disparities.
Geographic and Socioeconomic Disparities in Major Lower Extremity Amputation Rates in Metropolitan Areas
Authors: Fanaroff Alexander C. , Yang Lin , Nathan Ashwin S. , Khatana Sameed Ahmed M. , Julien Howard , Wang Tracy Y. , Armstrong Ehrin J. , Treat‐Jacobson Diane , Glaser Julia D. , Wang Grace , Damrauer Scott M. , Giri Jay , Groeneveld Peter W. 
Published: August 2021

Background
Rates of major lower extremity amputation in patients with peripheral artery disease are higher in rural communities with markers of low socioeconomic status, but most Americans live in metropolitan areas. Whether amputation rates vary within US metropolitan areas is unclear, as are characteristics of high amputation rate urban communities.

Methods and Results

We estimated rates of major lower extremity amputation per 100 000 Medicare beneficiaries between 2010 and 2018 at the ZIP code level among ZIP codes with ≥100 beneficiaries. We described demographic characteristics of high and low amputation ZIP codes, and the association between major amputation rate and 3 ZIP code–level markers of socioeconomic status—the proportion of patients with dual eligibility for Medicaid, median household income, and Distressed Communities Index score—for metropolitan, micropolitan, and rural ZIP code cohorts. Between 2010 and 2018, 188 995 Medicare fee‐for‐service patients living in 31 391 ZIP codes with ≥100 beneficiaries had a major lower extremity amputation. The median (interquartile range) ZIP code–level number of amputations per 100 000 beneficiaries was 262 (75–469). Though nonmetropolitan ZIP codes had higher rates of major amputation than metropolitan areas, 78.2% of patients undergoing major amputation lived in metropolitan areas. Compared with ZIP codes with lower amputation rates, top quartile amputation rate ZIP codes had a greater proportion of Black residents (4.4% versus 17.5%,
P
<0.001). In metropolitan areas, after adjusting for clinical comorbidities and demographics, every $10 000 lower median household income was associated with a 4.4% (95% CI, 3.9–4.8) higher amputation rate, and a 10‐point higher Distressed Communities Index score was associated with a 3.8% (95% CI, 3.4%–4.2%) higher amputation rate; there was no association between the proportion of patients eligible for Medicaid and amputation rate. These findings were comparable to the associations identified across all ZIP codes.

Conclusions
In metropolitan areas, where most individuals undergoing lower extremity amputation live, markers of lower socioeconomic status and Black race were associated with higher rates of major lower extremity amputation. Development of community‐based tools for peripheral artery disease diagnosis and management targeted to communities with high amputation rates in urban areas may help reduce inequities in peripheral artery disease outcomes.
Cardiovascular Health Disparities in Racial and Other Underrepresented Groups: Initial Results From the All of Us Research Program
Authors: Acosta Julián N. , Leasure Audrey C. , Both Cameron P. , Szejko Natalia , Brown Stacy , Torres‐Lopez Victor , Abdelhakim Safa , Schindler Joseph , Petersen Nils , Sansing Lauren , Gill Thomas M. , Sheth Kevin N. , Falcone Guido J. 
Published: August 2021

Background
All of Us is a novel research program that aims to accelerate research in populations traditionally underrepresented in biomedical research. Our objective was to evaluate the burden of cardiovascular disease (CVD) in broadly defined underrepresented groups.

Methods and Results
We evaluated the latest data release of All of Us. We conducted a cross‐sectional analysis combining survey and electronic health record data to estimate the prevalence of CVD upon enrollment in underrepresented groups defined by race, ethnicity, age (>75 years), disability (not able to carry out everyday physical activities), sexual orientation and gender identity lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+), income (annual household income <$35 000 US dollars) and education (less than a high school degree). We used multivariate logistic regression to estimate the adjusted odds ratio (OR) and product terms to test for interaction. The latest All of Us data release includes 315 297 participants. Of these, 230 577 (73%) had information on CVD and 17 958 had CVD (overall prevalence, 7.8%; 95% CI, 7.7–7.9). Multivariate analyses adjusted by hypertension, hyperlipidemia, type 2 diabetes mellitus, body mass index, and smoking indicated that, compared with White participants, Black participants had a higher adjusted odds of CVD (OR, 1.21; 95% CI, 1.16–1.27). Higher adjusted odds of CVD were also observed in underrepresented groups defined by other factors, including age >75 years (OR, 1.90; 95% CI, 1.81–1.99), disability (OR, 1.60; 95% CI, 1.53–1.68), and income <$35 000 US dollars (OR, 1.22; 95% CI, 1.17–1.27). Sex significantly modified the odds of CVD in several of the evaluated groups.

Conclusions
Among participants enrolled in All of Us, underrepresented groups defined based on race, ethnicity and other factors have a disproportionately high burden of CVD. The All of Us research program constitutes a powerful platform to accelerate research focused on individuals in underrepresented groups.
Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke
Authors: Esenwa Charles , Cheng Natalie T. , Luna Jorge , Willey Joshua , Boehme Amelia K. , Kirchoff-Torres Kathryn , Labovitz Daniel , Liberman Ava L. , Mabie Peter , Moncrieffe Khadean , Soetanto Ainie , Lendaris Andrea , Seiden Johanna , Goldman Inessa , Altschul David , Holland Ryan , Benton Joshua , Dardick Joseph , Fernandez-Torres Jenelys , Flomenbaum David , Lu Jenny , Malaviya Avinash , Patel Nikunj , Toma Aureliana , Lord Aaron , Ishida Koto , Torres Jose , Snyder Thomas , Frontera Jennifer , Yaghi Shadi 
Published: August 2021

Background and Purpose:
We sought to determine if biomarkers of inflammation and coagulation can help define coronavirus disease 2019 (COVID-19)–associated ischemic stroke as a novel acute ischemic stroke (AIS) subtype.

Methods:
We performed a machine learning cluster analysis of common biomarkers in patients admitted with severe acute respiratory syndrome coronavirus 2 to determine if any were associated with AIS. Findings were validated using aggregate data from 3 large healthcare systems.

Results:

Clustering grouped 2908 unique patient encounters into 4 unique biomarker phenotypes based on levels of c-reactive protein, D-dimer, lactate dehydrogenase, white blood cell count, and partial thromboplastin time. The most severe cluster phenotype had the highest prevalence of AIS (3.6%,
P
<0.001), in-hospital AIS (53%,
P
<0.002), severe AIS (31%,
P
=0.004), and cryptogenic AIS (73%,
P
<0.001). D-dimer was the only biomarker independently associated with prevalent AIS with quartile 4 having an 8-fold higher risk of AIS compared to quartile 1 (
P
=0.005), a finding that was further corroborated in a separate cohort of 157 patients hospitalized with COVID-19 and AIS.

Conclusions:
COVID-19–associated ischemic stroke may be related to COVID-19 illness severity and associated coagulopathy as defined by increasing D-dimer burden.
A European Turn in Early American History?
Authors: Harris Tim , Beneke Chris , Kaplan Benjamin J. , Brake Wayne Te , Haefeli Evan 
Published: August 2021

Abstract
From the nineteenth century onwards, Americans have naturalized their colonial origins into a consensual nationalist history, emphasizing America’s perceived role as a refuge for the persecuted, while smoothing out a myriad of complexities in the process. Evan Haefeli attempts to overturn the assumptions underpinning this narrative and is convinced that many important aspects of early America need to be understood within a broader European context. In Accidental Pluralism, he argues that the collapse of religious unity in England lies at the root of the emergence of pluralism in colonial America, in which he includes Canada and the Caribbean. Relationships among states, churches, and publics were contested from the earliest decades of colonization and created a pluralistic religious landscape that no one had anticipated. The four reviewers are fulsome in their praise, calling it an impressive, important, powerful, and sweeping book that few scholars could have written. The reviewers also raise questions, for instance by problematizing the incorporation of the colonial American dimension into early British history, criticizing the validity of the chosen end date, and questioning his definitions of diversity, pluralism, and religious toleration. In his response Evan Haefeli takes the opportunity to reflect on what drove him to write the book and to organize it in this way. He acknowledges that connecting early American history with its broader European context was more difficult than it should have been, as the dominant questions in the two historiographies are an ocean apart. While the argument of the book is aimed at early Americanists, Haefeli is grateful that the reviewers situate the story he tells within the broader early modern European history of toleration.