bluuebunny/crossref_metadata_2025_split huggingface dataset:
F-theory and heterotic duality, Weierstrass models from Wilson lines
Authors: Chabrol Lilian 
Published: October 2020

AbstractWe present how to construct elliptically fibered K3 surfaces via Weierstrass models which can be parametrized in terms of Wilson lines in the dual heterotic string theory. We work with a subset of reflexive polyhedras that admit two fibers whose moduli spaces contain the ones of the $$E_{8}\times E_{8}$$

E
8

×

E
8

or $$\frac{Spin(32)}{{\mathbb {Z}}_{2}}$$

S
p
i
n
(
32
)

Z
2

heterotic theory compactified on a two torus without Wilson lines. One can then interpret the additional moduli as a particular Wilson line content in the heterotic strings. A convenient way to find such polytopes is to use graphs of polytopes where links are related to inclusion relations of moduli spaces of different fibers. We are then able to map monomials in the defining equations of particular K3 surfaces to Wilson line moduli in the dual theories. Graphs were constructed developing three different programs which give the gauge group for a generic point in the moduli space, the Weierstrass model as well as basic enhancements of the gauge group obtained by sending coefficients of the hypersurface equation defining the K3 surface to zero.
Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma
Authors: Rusert Jessica M. , Juarez Edwin F. , Brabetz Sebastian , Jensen James , Garancher Alexandra , Chau Lianne Q. , Tacheva-Grigorova Silvia K. , Wahab Sameerah , Udaka Yoko T. , Finlay Darren , Seker-Cin Huriye , Reardon Brendan , Gröbner Susanne , Serrano Jonathan , Ecker Jonas , Qi Lin , Kogiso Mari , Du Yuchen , Baxter Patricia A. , Henderson Jacob J. , Berens Michael E. , Vuori Kristiina , Milde Till , Cho Yoon-Jae , Li Xiao-Nan , Olson James M. , Reyes Iris , Snuderl Matija , Wong Terence C. , Dimmock David P. , Nahas Shareef A. , Malicki Denise , Crawford John R. , Levy Michael L. , Van Allen Eliezer M. , Pfister Stefan M. , Tamayo Pablo , Kool Marcel , Mesirov Jill P. , Wechsler-Reya Robert J. 
Published: October 2020

Abstract

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.

Significance:
These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
Preclinical Activity of SAR408701: A Novel Anti-CEACAM5–maytansinoid Antibody–drug Conjugate for the Treatment of CEACAM5-positive Epithelial Tumors
Authors: Decary Stéphanie , Berne Pierre-François , Nicolazzi Céline , Lefebvre Anne-Marie , Dabdoubi Tarik , Cameron Béatrice , Rival Pierrick , Devaud Catherine , Prades Catherine , Bouchard Hervé , Cassé Alhassan , Henry Christophe , Amara Céline , Brillac Claire , Ferrari Paul , Maçon Laetitia , Lacoste Eric , Combeau Cecile , Beys Eric , Naimi Souad , García-Echeverría Carlos , Mayaux Jean-François , Blanc Véronique 
Published: October 2020

Abstract

Purpose:
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody–drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker.

Experimental Design:
The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey.

Results:
SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone.

Conclusions:
On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors.
Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non–small Cell Lung Cancer
Authors: Yu Helena A. , Paz-Ares Luis G. , Yang James Chih-Hsin , Lee Ki Hyeong , Garrido Pilar , Park Keunchil , Kim Joo-Hang , Lee Dae Ho , Mao Huzhang , Wijayawardana Sameera R. , Gao Ling , Hozak Rebecca R. , Chao Bo H. , Planchard David 
Published: October 2020

Abstract

Purpose:
We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non–small cell lung cancer (NSCLC).

Patients and Methods:
This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.

Results:
Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6–21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5–19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.

Conclusions:
Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.
See related commentary by Garon, p. 905
Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors
Authors: Janku Filip , Zhang Halle Huihong , Pezeshki Abdulmohammad , Goel Sanjay , Murthy Ravi , Wang-Gillam Andrea , Shepard Dale R. , Helgason Thorunn , Masters Tyler , Hong David S. , Piha-Paul Sarina A. , Karp Daniel D. , Klang Mark , Huang Steven Y. , Sakamuri Divya , Raina Anjali , Torrisi Jean , Solomon Stephen B. , Weissfeld Alice , Trevino Ernest , DeCrescenzo Gary , Collins Amanda , Miller Maria , Salstrom Jennifer L. , Korn Ronald L. , Zhang Linping , Saha Saurabh , Leontovich Alexey A. , Tung David , Kreider Brent , Varterasian Mary , Khazaie Khashayarsha , Gounder Mrinal M. 
Published: October 2020

Abstract

Purpose:
Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.

Patients and Methods:
This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.

Results:
Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors &gt;8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.

Conclusions:
Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.
A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma
Authors: Demajo Santiago , Albero Robert , Clot Guillem , Castellano Giancarlo , Navarro Alba , Capdevila Cristina , Enjuanes Anna , Nadeu Ferran , Giné Eva , Pinyol Magda , Jaffe Elaine S. , Ott German , Staudt Louis M. , Rosenwald Andreas , Scott David W. , Rimsza Lisa M. , López-Guillermo Armando , Beà Sílvia , Campo Elias , Jares Pedro 
Published: October 2020

Abstract

Purpose:
Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1–mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1–dependent gene expression program and analyze its prognostic value.

Experimental Design:
We integrated genome-wide expression analysis of cyclin D1–silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1–dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n = 53) and lymphoid tissues (n = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n = 81) by NanoString gene expression profiling to validate our findings.

Results:
We identified a cyclin D1–dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1–dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1–dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression.

Conclusions:
We identified a cyclin D1–dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.
Hybrid Coronary Revascularization Versus Conventional Coronary Artery Bypass Surgery
Authors: Hannan Edward L. , Wu Yifeng , Cozzens Kimberly , Sundt Thoralf M. , Girardi Leonard , Chikwe Joanna , Wechsler Andrew , Smith Craig R. , Gold Jeffrey P. , Lahey Stephen J. , Jordan Desmond 
Published: October 2020

Background:
Hybrid coronary revascularization (HCR) treats multivessel coronary artery disease by combining a minimally invasive surgical approach to the left anterior descending artery with percutaneous coronary intervention for non–left anterior descending diseased coronary arteries. The objective of this study is to compare HCR and conventional coronary artery bypass graft (CABG) surgery medium-term outcomes.

Methods:
Data from multivessel disease patients in New York’s cardiac surgery and percutaneous coronary intervention registries in 2010 to 2016 were used to compare mortality and repeat revascularization rates for HCR and conventional CABG after using propensity matching to reduce selection bias.

Results:
There was a total of 303 HCR (0.80%) patients and 37 556 conventional CABG patients after exclusions. After propensity matching, the respective median follow-up times were 3.72 years and 3.76 years. There was no difference between HCR and conventional CABG in survival at 6 years (80.9% versus 85.8%%, adjusted hazard ratio, 1.44 [0.90–2.31]), but HCR had higher mortality excluding deaths during the first year (adjusted hazard ratio, 1.88 [1.10–3.23]). Conventional CABG patients were more likely to be free from repeat revascularization at 6 years than HCR patients (88.2% versus 76.6%; hazard ratio, 2.22 [1.44–3.42]).

Conclusions:
HCR is rarely performed for patients with multivessel coronary artery disease. HCR and conventional CABG had no different 6-year mortality rates, but HCR had higher mortality after 1 year and higher rates of subsequent revascularization that were caused by both the need for repeat revascularization in the left anterior descending artery where minimally invasive CABG was performed, and in the coronary arteries where percutaneous coronary intervention was performed.

Graphic Abstract:

A
graphic abstract
is available for this article.
Large-Aspect-Ratio Structures in Simulated Ocean Surface Boundary Layer Turbulence under a Hurricane
Authors: Watkins Clifford , Whitt Daniel B. 
Published: October 2020

AbstractA large-eddy simulation (LES) initialized and forced using observations is used to conduct a process study of ocean surface boundary layer (OSBL) turbulence in a 2-km box of ocean nominally under Hurricane Irene (2011) in 35 m of water on the New Jersey shelf. The LES captures the observed deepening, cooling, and persistent stratification of the OSBL as the storm approaches and passes. As the storm approaches, surface-intensified Ekman-layer rolls, with horizontal wavelengths of about 200 m and horizontal-to-vertical aspect and velocity magnitude ratios of about 20, dominate the kinetic energy and increase the turbulent Prandtl number from about 1 to 1.5 due partially to their restratifying vertical buoyancy flux. However, as the storm passes, these rolls are washed away in a few hours due to the rapid rotation of the wind. In the bulk OSBL, the gradient Richardson number of the mean profiles remains just above (just below) 1/4 as the storm approaches (passes). At the base of the OSBL, large-aspect-ratio Kelvin–Helmholtz billows, with Prandtl number below 1, intermittently dominate the kinetic energy. Overall, large-aspect-ratio covariance modifies the net vertical fluxes of buoyancy and momentum by about 10%, but these fluxes and the analogous diffusivity and viscosity still approximately collapse to time-independent dimensionless profiles, despite rapid changes in the forcing and the large structures. That is, the evolutions of the mean temperature and momentum profiles, which are driven by the net vertical flux convergences, mainly reflect the evolution of the wind and the initial ocean temperature profile.
Rapid Scan Visible Imagery from the Geostationary Lightning Mapper (GLM) at 2.5-Minute Intervals
Authors: Cecil Daniel J. , Buechler Dennis E. , Mecikalski John R. , Li Xuanli 
Published: October 2020

AbstractThe Geostationary Lightning Mapper (GLM) is an instrument designed to continuously monitor lightning. It is on the GOES-16 and GOES-17 satellites, viewing much of the Western Hemisphere equatorward of 55°. Besides recording lightning-flash information, it transmits background visible-band images of its field of view every 2.5 min. The background images are not calibrated or geolocated, and they only have ~10-km grid spacing, but their 2.5-min sampling can potentially fill temporal gaps between full-disk imagery from the GOES satellites’ Advanced Baseline Imager. This paper applies an initial calibration and geolocation of the GLM background images and focuses on animations for two cases: a volcanic eruption in Guatemala and a severe thunderstorm complex in Argentina. Those locations typically have 10-min intervals between full-disk scans. Prior to April 2019, the interval was 15 min. Despite coarse horizontal resolution, the rapid updates from GLM background images appear to be useful in these cases. The 3 June 2018 eruption of Fuego Volcano appears in the GLM background imagery as an initial darkening of the pixels very near the volcano and then an outward expansion of the dark ash cloud. The GLM background imagery lacks horizontal textural detail but compensates for this lack with temporal detail. The ash cloud resembles a dark blob steadily expanding from frame to frame. Animation of the severe thunderstorm scene reveals vertical wind shear, with northerly low-level flow across a growing cumulus field and west-northwesterly upper-level flow at anvil level. Convective initiation is seen, as are propagating outflow boundaries and overshooting convective cloud tops.
Gene expression profiling reveals the effects of light on adventitious root formation in lotus seedlings (Nelumbo nucifera Gaertn.)
Authors: Libao Cheng , Yuyan Han , Minrong Zhao , Xiaoyong Xu , Zhiguang Shen , Chunfei Wang , Shuyan Li , Zhubing Hu 
Published: October 2020

Abstract
Background
Lotus is an aquatic horticultural crop that is widely cultivated in most regions of China and is used as an important off-season vegetable. The principal root of lotus is degenerated, and adventitious roots (ARs) are irreplaceable for plant growth. We found that no ARs formed under darkness and that exposure to high-intensity light significantly promoted the development of root primordia. Four differential expression libraries based on three light intensities were constructed to monitor metabolic changes, especially in indole-3-acetic acid (IAA) and sugar metabolism.

Results
AR formation was significantly affected by light, and high light intensity accelerated AR development. Metabolic changes during AR formation under different light intensities were evaluated using gene expression profiling by high-throughput tag-sequencing. More than 2.2 × 104 genes were obtained in each library; the expression level of most genes was between 0.01 and 100 (FPKF value). Libraries constructed from plants grown under darkness (D/CK), under 5000 lx (E/CK), and under 20,000 lx (F/CK) contained 1739, 1683, and 1462 upregulated genes and 1533, 995, and 834 downregulated genes, respectively, when compared to those in the initial state (CK). Additionally, we found that 1454 and 478 genes had altered expression in a comparison of libraries D/CK and F/CK. Gene transcription between libraries D/F ranged from a 5-fold decrease to a 5-fold increase. Twenty differentially expressed genes (DEGs) were involved in the signal transduction pathway, 28 DEGs were related to the IAA response, and 35 DEGs were involved in sugar metabolism. We observed that the IAA content was enhanced after seed germination, even in darkness; this was responsible for AR formation. We also observed that sucrose could eliminate the negative effect of 150 μMol IAA during AR development.

Conclusions
AR formation was regulated by IAA, even in the dark, where induction and developmental processes could also be completed. In addition, 36 genes displayed altered expression in carbohydrate metabolism and ucrose metabolism was involved in AR development (expressed stage) according to gene expression and content change characteristics.
Exogenous polyunsaturated fatty acids (PUFAs) promote changes in growth, phospholipid composition, membrane permeability and virulence phenotypes in Escherichia coli
Authors: Herndon Joshua L. , Peters Rachel E. , Hofer Rachel N. , Simmons Timothy B. , Symes Steven J. , Giles David K. 
Published: October 2020

Abstract
Background
The utilization of exogenous fatty acids by Gram-negative bacteria has been linked to many cellular processes, including fatty acid oxidation for metabolic gain, assimilation into membrane phospholipids, and control of phenotypes associated with virulence. The expanded fatty acid handling capabilities have been demonstrated in several bacteria of medical importance; however, a survey of the polyunsaturated fatty acid responses in the model organism Escherichia coli has not been performed. The current study examined the impacts of exogenous fatty acids on E. coli.

Results
All PUFAs elicited higher overall growth, with several fatty acids supporting growth as sole carbon sources. Most PUFAs were incorporated into membrane phospholipids as determined by Ultra performance liquid chromatography-mass spectrometry, whereas membrane permeability was variably affected as measured by two separate dye uptake assays. Biofilm formation, swimming motility and antimicrobial peptide resistance were altered in the presence of PUFAs, with arachidonic and docosahexaenoic acids eliciting strong alteration to these phenotypes.

Conclusions
The findings herein add E. coli to the growing list of Gram-negative bacteria with broader capabilities for utilizing and responding to exogenous fatty acids. Understanding bacterial responses to PUFAs may lead to microbial behavioral control regimens for disease prevention.