bluuebunny/crossref_metadata_2025_split huggingface dataset:
Path to European quantum unicorns
Authors: Räsänen Markku , Mäkynen Henrikki , Möttönen Mikko , Goetz Jan 
Published: February 2021

AbstractQuantum computing holds the potential to deliver great economic prosperity to the European Union (EU). However, the creation of successful business in the field is challenging owing to the required extensive investments into postdoctoral-level workforce and sophisticated infrastructure without an existing market that can financially support these operations.This commentary paper reviews the recent efforts taken in the EU to foster the quantum-computing ecosystem together with its current status. Importantly, we propose concrete actions for the EU to take to enable future growth of this field towards the desired goals. In particular, we suggest ways to enable the creation of EU-based quantum-computing unicorns which may act as key crystallization points of quantum technology and its commercialization. These unicorns may provide stability to the otherwise scattered ecosystem, thus pushing forward global policies enabling the global spread of EU innovations and technologies.The unicorns may act as a conduit, through which the EU-based quantum ecosystem can stand out from similar ecosystems based in Asia and the United States. Such strong companies are required because of the level of investment currently required in the marketplace. This paper suggests methodologies and best practices that can enhance the probability of the creation of the unicorns.Furthermore, we explore future scenarios, in which the unicorns can operate from the EU and to support the EU quantum ecosystem. This exploration is conducted focusing on the steps to be taken and on the impact the companies may have in our opinion.
The Impact of COVID-19 Outbreak on Nosocomial Infection Rate: A Case of Iran
Authors: Jabarpour Maryam , Dehghan Mahlagha , Afsharipour Giti , Hajipour Abaee Elham , Mangolian Shahrbabaki Parvin , Ahmadinejad Mehdi , Maazallahi Mahboobeh 
Published: February 2021

Background. Coronavirus disease-19 (COVID-19) is a new type of coronavirus that has caused a global pandemic. The disease is highly contagious, and all people are susceptible to the disease. Therefore, extensive measures were taken to prevent the spread of the disease at the community and hospitals. This study aimed to investigate the impact of COVID-19 outbreak on nosocomial infection rate. Methods. This cross-sectional study was conducted in an educational hospital, southeast Iran. The nosocomial infection rates of critical/intensive care units (CCU/ICUs) and medical-surgical units were assessed during and before the COVID-19 outbreak. Results. There was a 19.75-point decrease in the total rate of nosocomial infection during the COVID-19 outbreak (

P

= 0.02). In addition, there was a 39.12-point decrease in the total rate of CCU/ICUs’ nosocomial infection during the COVID-19 outbreak (

P

< 0.001). A 19.23-point decrease was also observed in the total rate of medical-surgical units’ nosocomial infection during the COVID-19 outbreak (

P

= 0.13). All kinds of CCU/ICUs’ nosocomial infections had between 31.22- and 100-point decreases during the COVID-19 outbreak. Among medical-surgical units, 33.33- and 30.70-point decreases were observed only in UTI and SSI, respectively, during the COVID-19 outbreak, while BSI had a 40-point increase during the COVID-19 outbreak. Conclusions. Proper implementation of infection control protocols during the COVID-19 pandemic seems to reduce nosocomial infections.
Susceptibility-Associated Genetic Variation in NEDD9 Contributes to Prostate Cancer Initiation and Progression
Authors: Han Dong , Owiredu Jude N. , Healy Bridget M. , Li Muqing , Labaf Maryam , Steinfeld Jocelyn S. , Patalano Susan , Gao Shuai , Liu Mingyu , Macoska Jill A. , Zarringhalam Kourosh , Siegfried Kellee R. , Yuan Xin , Rebbeck Timothy R. , Cai Changmeng 
Published: February 2021

Abstract

Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (NEDD9) gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of NEDD9 by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis in vitro and in vivo. Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities.

Significance:
A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer.
See related commentary by Mavura and Huang, p. 3764
Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment
Authors: Borowsky Jennifer , Haruki Koichiro , Lau Mai Chan , Dias Costa Andressa , Väyrynen Juha P. , Ugai Tomotaka , Arima Kota , da Silva Annacarolina , Felt Kristen D. , Zhao Melissa , Gurjao Carino , Twombly Tyler S. , Fujiyoshi Kenji , Väyrynen Sara A. , Hamada Tsuyoshi , Mima Kosuke , Bullman Susan , Harrison Tabitha A. , Phipps Amanda I. , Peters Ulrike , Ng Kimmie , Meyerhardt Jeffrey A. , Song Mingyang , Giovannucci Edward L. , Wu Kana , Zhang Xuehong , Freeman Gordon J. , Huttenhower Curtis , Garrett Wendy S. , Chan Andrew T. , Leggett Barbara A. , Whitehall Vicki L.J. , Walker Neal , Brown Ian , Bettington Mark , Nishihara Reiko , Fuchs Charles S. , Lennerz Jochen K. , Giannakis Marios , Nowak Jonathan A. , Ogino Shuji 
Published: February 2021

Abstract

Purpose:
While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell–mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.

Experimental Design:
We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum–positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets.

Results:
The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28–0.79, for F. nucleatum–high vs. -negative category; Ptrend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32–0.85; Ptrend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.

Conclusions:
The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.
Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor–Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti–HER2-Based Therapy
Authors: Pascual Tomás , Fernandez-Martinez Aranzazu , Tanioka Maki , Dieci M. Vittoria , Pernas Sonia , Gavila Joaquin , Guarneri Valentina , Cortes Javier , Villagrasa Patricia , Chic Núria , Vidal Maria , Adamo Barbara , Muñoz Montserrat , Griguolo Gaia , Llombart Antonio , Conte Pierfranco , Oliveira Mafalda , Conte Benedetta , Paré Laia , Galvan Patricia , Carey Lisa A. , Perou Charles M. , Prat Aleix 
Published: February 2021

Abstract

Purpose:
We do not yet have validated biomarkers to predict response and outcome within hormone receptor–positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor–positive/HER2-negative (HR+/HER2−) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer.

Experimental Design:
Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS).

Results:
A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012).

Conclusions:
In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation
Authors: Pulte E. Dianne , Norsworthy Kelly J. , Wang Yaping , Xu Qing , Qosa Hisham , Gudi Ramadevi , Przepiorka Donna , Fu Wentao , Okusanya Olanrewaju O. , Goldberg Kirsten B. , De Claro R. Angelo , Farrell Ann T. , Pazdur Richard 
Published: February 2021

Abstract
On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8–15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%–29%), median duration of CR + CRh was 4.6 months (range, 0.1–15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49–0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.
FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non–small Cell Lung Cancer, A Collaborative Project Orbis Review
Authors: Vellanki Paz J. , Mulkey Flora , Jaigirdar Adnan A. , Rodriguez Lisa , Wang Yibo , Xu Yuan , Zhao Hong , Liu Jiang , Howe Grant , Wang Jian , Choo Qiuyi , Golding Sarah J. , Mansell Victoria , Korsah Kwadwo , Spillman Dianne , de Claro R. Angelo , Pazdur Richard , Beaver Julia A. , Singh Harpreet 
Published: February 2021

Abstract
On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2–16.2] compared with 10.7 months (95% CI, 9.5–12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55–0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit–risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.
Robust Antitumor Activity and Low Cytokine Production by Novel Humanized Anti-CD19 CAR T Cells
Authors: Dwivedi Alka , Karulkar Atharva , Ghosh Sarbari , Srinivasan Srisathya , Kumbhar Bajarang Vasant , Jaiswal Ankesh Kumar , Kizhakeyil Atish , Asija Sweety , Rafiq Afrin , Kumar Sushant , Nisar Albeena , Patil Deepali Pandit , Poojary Minal Vivek , Jain Hasmukh , Banavali Shripad D. , Highfill Steven L. , Stroncek David F. , Shah Nirali N. , Fry Terry J. , Narula Gaurav , Purwar Rahul 
Published: February 2021

Abstract
Recent studies have described the remarkable clinical outcome of anti-CD19 chimeric antigen receptor (CAR) T cells in treating B-cell malignancies. However, over 50% of patients develop life-threatening toxicities associated with cytokine release syndrome which may limit its utilization in low-resource settings. To mitigate the toxicity, we designed a novel humanized anti-CD19 CAR T cells by humanizing the framework region of single-chain variable fragment (scFv) derived from a murine FMC63 mAb and combining it with CD8α transmembrane domain, 4-1BB costimulatory domain, and CD3ζ signaling domain (h1CAR19-8BBζ). Docking studies followed by molecular dynamics simulation revealed that the humanized anti-CD19 scFv (h1CAR19) establishes higher binding affinity and has a flexible molecular structure with CD19 antigen compared with murine scFv (mCAR19). Ex vivo studies with CAR T cells generated from healthy donors and patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) expressing either h1CAR19 or mCAR19 showed comparable antitumor activity and proliferation. More importantly, h1CAR19-8BBζ T cells produced lower levels of cytokines (IFNγ, TNFα) upon antigen encounter and reduced the induction of IL6 cytokine from monocytes than mCAR19-8BBζ T cells. There was a comparable proliferation of h1CAR19-8BBζ T cells and mCAR19-8BBζ T cells upon repeated antigen encounter. Finally, h1CAR19-8BBζ T cells efficiently eliminated NALM6 tumor cells in a preclinical model. In conclusion, the distinct structural modification in CAR design confers the novel humanized anti-CD19 CAR with a favorable balance of efficacy to toxicity providing a rationale to test this construct in a phase I trial.
The Monoacylglycerol Lipase Inhibitor JZL184 Inhibits Lung Cancer Cell Invasion and Metastasis via the CB1 Cannabinoid Receptor
Authors: Prüser Jan Lukas , Ramer Robert , Wittig Felix , Ivanov Igor , Merkord Jutta , Hinz Burkhard 
Published: February 2021

AbstractA targeted modulation of the endocannabinoid system is currently discussed as a promising strategy for cancer treatment. An important enzyme for the endocannabinoid metabolism is the monoacylglycerol lipase (MAGL), which catalyzes the degradation of 2-arachidonoylglycerol (2-AG) to glycerol and free fatty acids. In this study, we investigated the influence of MAGL inhibition on lung cancer cell invasion and metastasis. Using LC-MS, significantly increased 2-AG levels were detected in A549 cells treated with the MAGL inhibitor JZL184. In athymic nude mice, JZL184 suppressed metastasis of A549 cells in a dose-dependent manner, whereby the antimetastatic effect was cancelled by the CB1 receptor antagonist AM-251. In vitro, JZL184 induced a time- and concentration-dependent reduction of A549 cell invasion through Matrigel-coated membranes, which was likewise reversed by AM-251. An MAGL inhibition–associated reduction of free fatty acids as a cause of the anti-invasive effect could be excluded by add-back experiments with palmitic acid. Both JZL184 and the MAGL substrate 2-AG led to an increased formation of the tissue inhibitor of metalloproteinase-1 (TIMP-1), whereby a TIMP-1 knockdown using siRNA significantly attenuated the anti-invasive effects of both substances. Decreased invasion and TIMP-1 upregulation was also caused by the MAGL inhibitors JW651 and MJN110 or transfection with MAGL siRNA. A CB1- and TIMP-1–dependent anti-invasive effect was further confirmed for JZL184 in H358 lung cancer cells. In conclusion, MAGL inhibition led to a CB1-dependent decrease in human lung cancer cell invasion and metastasis via inhibition of 2-AG degradation, with TIMP-1 identified as a mediator of the anti-invasive effect.
A Novel Antibody–IL15 Fusion Protein Selectively Localizes to Tumors, Synergizes with TNF-based Immunocytokine, and Inhibits Metastasis
Authors: Corbellari Riccardo , Stringhini Marco , Mock Jaqueline , Ongaro Tiziano , Villa Alessandra , Neri Dario , De Luca Roberto 
Published: February 2021

AbstractIL15 is an immunostimulatory cytokine that holds promises for cancer therapy, but its performance (alone or as partner for fusion proteins) has often been limited by suboptimal accumulation in the tumor and very rapid clearance from circulation. Most recently, the Sushi Domain (SD, the shortest region of IL15 receptor α, capable of binding to IL15) has been fused to IL15-based anticancer products to increase its biological activity. Here, we describe two novel antibody fusion proteins (termed F8-F8-IL15 and F8-F8-SD-IL15), specific to the alternatively spliced EDA domain of fibronectin (a marker of tumor neoangiogenisis, expressed in the majority of solid and hematologic tumors, but absent in normal healthy tissues) and featuring the F8 antibody in single-chain diabody format (with a short linker between VH and VL, thus allowing the domains to pair with the complementary ones of another chain). Unlike previously described fusions of the F8 antibody with human IL15, F8-F8-IL15 and F8-F8-SD-IL15 exhibited a preferential uptake in solid tumors, as evidenced by quantitative biodistribution analysis with radioiodinated protein preparations. Both products were potently active in vivo against mouse metastatic colon carcinomas and in sarcoma lesion in combination with targeted TNF. The results may be of clinical significance, as F8-F8-IL15 and F8-F8-SD-IL15 are fully human proteins, which recognize the cognate tumor-associated antigen with identical affinity in mouse and man.
Carotid Atherosclerosis in Predicting Coronary Artery Disease
Authors: Bytyçi Ibadete , Shenouda Rafik , Wester Per , Henein Michael Y. 
Published: February 2021

Objective:
This meta-analysis aims to compare the relationship between phenotypic manifestation of coronary and carotid atherosclerosis using available imaging techniques.

Approach and Results:

We searched all electronic databases until October 2020 for studies which reported relationship between carotid and coronary atherosclerosis. The primary end point was correlation between carotid intima-media thickness (CIMT) and carotid plaque features (calcification and lipid-rich necrotic core) with coronary artery disease (CAD). Secondary end points included carotid pathology that predicts CAD. Eighty-nine papers with 22 683 patients comparing carotid and coronary atherosclerosis were included in the analysis. CIMT was increased linearly with severity of CAD irrespective of its significance (
P
<0.001), mono versus 2 vessel disease (
P
=0.003), and 2 versus multivessel disease (
P
<0.001). Carotid plaque presence and calcification were less, and lipid-rich necrotic core was highly prevalent in nonsignificant versus significant CAD (
P
<0.001,
P
=0.03,
P
<0.001, respectively). Moderate correlation was found between CIMT and severity of CAD (
r
=0.60,
P
<0.001) and the number of diseased vessels (
r
=0.49,
P
<0.001). There was a moderate correlation between carotid and coronary stenosis (
r
=0.53,
P
<0.001) and between carotid and coronary calcification (
r
=0.61,
P
<0.001). CIMT ≥1.0 mm with a summary sensitivity of 77% and summary specificity of 72% and respective values of 80% and 67% for carotid plaque were the best predictors of CAD, irrespective of the technique used for its diagnosis.

Conclusions:
These results support the concept that atherosclerosis affects both carotid and coronary systems, although not always in identical phenotypic manner. These findings highlight the beneficial examination of carotid arteries whenever CAD is suspected.