bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wormhole solutions in embedding class 1 space–time
Authors: Sarkar Nayan , Sarkar Susmita , Rahaman Farook , Islam Safiqul 
Published: January 2021

The present work looks for new spherically symmetric wormhole solutions of the Einstein field equations based on the well-known embedding class 1, i.e. Karmarkar condition. The embedding theorems have an interesting property that connects an [Formula: see text]-dimensional space–time to the higher-dimensional Euclidean flat space–time. The Einstein field equations yield the wormhole solution by violating the null energy condition (NEC). Here, wormholes solutions are obtained corresponding to three different redshift functions: rational, logarithm, and inverse trigonometric functions, in embedding class 1 space–time. The obtained shape function in each case satisfies the flare-out condition after the throat radius, i.e. good enough to represents wormhole structure. In cases of WH1 and WH2, the solutions violate the NEC as well as strong energy condition (SEC), i.e. here the exotic matter content exists within the wormholes and strongly sustains wormhole structures. In the case of WH3, the solution violates NEC but satisfies SEC, so for violating the NEC wormhole preserve due to the presence of exotic matter. Moreover, WH1 and WH2 are asymptotically flat while WH3 is not asymptotically flat. So, indeed, WH3 cutoff after some radial distance [Formula: see text], the Schwarzschild radius, and match to the external vacuum solution.
The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
Authors: Deegen Petra , Thomas Oliver , Nolan-Stevaux Olivier , Li Shyun , Wahl Joachim , Bogner Pamela , Aeffner Famke , Friedrich Matthias , Liao Michael Z. , Matthes Katja , Rau Doris , Rattel Benno , Raum Tobias , Kufer Peter , Coxon Angela , Bailis Julie M. 
Published: January 2021

Abstract

Purpose:
Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.

Experimental Design:
We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated.

Results:
AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6–42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68–labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs.

Conclusions:
The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.
See related commentary by Kamat et al., p. 2675
Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032
Authors: Yu Alice L. , Gilman Andrew L. , Ozkaynak M. Fevzi , Naranjo Arlene , Diccianni Mitchell B. , Gan Jacek , Hank Jacquelyn A. , Batova Ayse , London Wendy B. , Tenney Sheena C. , Smith Malcolm , Shulkin Barry L. , Parisi Marguerite , Matthay Katherine K. , Cohn Susan L. , Maris John M. , Bagatell Rochelle , Park Julie R. , Sondel Paul M. 
Published: January 2021

Abstract

Purpose:
Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers.

Patients and Methods:
Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing.

Results:
For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively (P = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS.

Conclusions:
Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth
Authors: Lam Hubert , McNeil Lisa K. , Starobinets Hanna , DeVault Victoria L. , Cohen Roger B. , Twardowski Przemyslaw , Johnson Melissa L. , Gillison Maura L. , Stein Mark N. , Vaishampayan Ulka N. , DeCillis Arthur P. , Foti James J. , Vemulapalli Vijetha , Tjon Emily , Ferber Kyle , DeOliveira Daniel B. , Broom Wendy , Agnihotri Parul , Jaffee Elizabeth M. , Wong Kwok-Kin , Drake Charles G. , Carroll Pamela M. , Davis Thomas A. , Flechtner Jessica Baker 
Published: January 2021

AbstractNeoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens.Significance:Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521
Metabolic Codependencies in the Tumor Microenvironment
Authors: Dey Prasenjit , Kimmelman Alec C. , DePinho Ronald A. 
Published: January 2021

AbstractMetabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell–intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription factors that in turn increase expression of metabolic regulators. Extrinsic signaling mechanisms involve host-derived factors that further promote and amplify metabolic reprogramming in cancer cells. This review describes intrinsic and extrinsic mechanisms driving cancer metabolism in the tumor microenvironment and how such mechanisms may be targeted therapeutically.Significance:Cancer cell metabolic reprogramming is a consequence of the converging signals originating from both intrinsic and extrinsic factors. Intrinsic signaling maintains the baseline metabolic state, whereas extrinsic signals fine-tune the metabolic processes based on the availability of metabolites and the requirements of the cells. Therefore, successful targeting of metabolic pathways will require a nuanced approach based on the cancer's genotype, tumor microenvironment composition, and tissue location.
Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia
Authors: Egan Grace , Khan Dilshad H. , Lee Jong Bok , Mirali Sara , Zhang Li , Schimmer Aaron D. 
Published: January 2021

Abstract

Mitochondria are involved in many biological processes including cellular homeostasis, energy generation, and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation, and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin-modifying enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promote cancer development, progression, and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation, and immune response in leukemia.

Significance:
Emerging evidence demonstrates that mitochondrial and metabolic pathways influence gene expression to promote tumor development, progression, and immune evasion. These data highlight new areas of cancer biology and potential new therapeutic strategies.
Is Bombus pomorum (Panzer, 1805) (Hymenoptera: Apidae) a new bumblebee for Siberia or an indigenous species?
Authors: Byvaltsev Alexandr , Knyazev Svyatoslav , Afinogenov Anatoly 
Published: January 2021

Bombus pomorum (Panzer, 1805) is known from Europe, Anatolia, the Caucasus, and to the Urals in Russia. Two specimens have been collected in the south of western Siberia for the first time. It is possible that the species is indigenous to Siberia but was not discovered until regular observations were made. There is also a possibility that this observation results from an expansion of the range of B. pomorum. We consider the evidence that our study coincided with a range expansion of the bumblebee species B. pomorum and B. sylvarum (Linnaeus,1761) near the end of 20th century. The distribution and abundance of B. pomorum in Russia and conservation efforts are also discussed.
An assessment of the population status of the threatened medicinal plant Illicium griffithii Hook.f. & Thomson in West Kameng District of Arunachal Pradesh, India
Authors: Bapu Tashi Dorjee , Nimasow Gibji 
Published: January 2021

Illicium griffithii Hook.f. & Thomson, a medicinal plant of the family Schisandraceae, is an Endangered species listed by the IUCN. A decline in population of this plant due to climate change as well as increasing human influences on the natural resources has been a matter of great concern among the researchers. In order to estimate the existing population of this plant, a field-based study employing linear transect method was conducted in four phases, May–June 2017, May–June 2018, April–May 2019, October–November 2019 covering an area of 700km² (approx.) in West Kameng District of Arunachal Pradesh that lies within the Himalayan biodiversity hotspot. The study recorded 3,044 live individuals of I. griffithii including 1,372 seedlings, 1,358 saplings, and only 314 mature trees. Additionally, 126 dead trees were also recorded. The study confirmed that the plant has a good regeneration rate but with a poor survival rate of saplings. Besides, large-scale collection of its fruits for trade and anthropogenic disturbances in the study area appears to be the major threat to its existing population. Therefore, proper training of the local people on large-scale cultivation of this plant together with awareness towards judicious harvesting of fruits from the wild may be the significant approach to conservation.
Heart Disease and Stroke Statistics—2021 Update
Authors: Virani Salim S. , Alonso Alvaro , Aparicio Hugo J. , Benjamin Emelia J. , Bittencourt Marcio S. , Callaway Clifton W. , Carson April P. , Chamberlain Alanna M. , Cheng Susan , Delling Francesca N. , Elkind Mitchell S.V. , Evenson Kelly R. , Ferguson Jane F. , Gupta Deepak K. , Khan Sadiya S. , Kissela Brett M. , Knutson Kristen L. , Lee Chong D. , Lewis Tené T. , Liu Junxiu , Loop Matthew Shane , Lutsey Pamela L. , Ma Jun , Mackey Jason , Martin Seth S. , Matchar David B. , Mussolino Michael E. , Navaneethan Sankar D. , Perak Amanda Marma , Roth Gregory A. , Samad Zainab , Satou Gary M. , Schroeder Emily B. , Shah Svati H. , Shay Christina M. , Stokes Andrew , VanWagner Lisa B. , Wang Nae-Yuh , Tsao Connie W. ,   On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Published: January 2021

Background:
The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

Methods:
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year’s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year’s edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.

Results:
Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

Conclusions:
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching
Authors: Hartman Robin J.G. , Owsiany Katie , Ma Lijiang , Koplev Simon , Hao Ke , Slenders Lotte , Civelek Mete , Mokry Michal , Kovacic Jason C. , Pasterkamp Gerard , Owens Gary , Björkegren Johan L.M. , den Ruijter Hester M. 
Published: January 2021

Background:
Although sex differences in coronary artery disease are widely accepted with women developing more stable atherosclerosis than men, the underlying pathobiology of such differences remains largely unknown. In coronary artery disease, recent integrative systems biological studies have inferred gene regulatory networks (GRNs). Within these GRNs, key driver genes have shown great promise but have thus far been unidentified in women.

Methods:
We generated sex-specific GRNs of the atherosclerotic arterial wall in 160 women and age-matched men in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task). We integrated the female GRNs with single-cell RNA-sequencing data of the human atherosclerotic plaque and single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic smooth muscle cell (SMC) lineage-tracing mice.

Results:
By comparing sex-specific GRNs, we observed clear sex differences in network activity within the atherosclerotic tissues. Genes more active in women were associated with mesenchymal cells and endothelial cells, whereas genes more active in men were associated with the immune system. We determined that key drivers of GRNs active in female coronary artery disease were predominantly found in (SMCs by single-cell sequencing of the human atherosclerotic plaques, and higher expressed in female plaque SMCs, as well. To study the functions of these female SMC key drivers in atherosclerosis, we examined single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic SMC lineage-tracing mice. The female key drivers were found to be expressed by phenotypically modulated SMCs and affected by Klf4, suggesting that sex differences in atherosclerosis involve phenotypic switching of plaque SMCs.

Conclusions:
Our systems approach provides novel insights into molecular mechanisms that underlie sex differences in atherosclerosis. To discover sex-specific therapeutic targets for atherosclerosis, an increased emphasis on sex-stratified approaches in the analysis of multi-omics data sets is warranted.
Association Between Sex and Treatment Outcomes of Atrial Fibrillation Ablation Versus Drug Therapy
Authors: Russo Andrea M. , Zeitler Emily P. , Giczewska Anna , Silverstein Adam P. , Al-Khalidi Hussein R. , Cha Yong-Mei , Monahan Kristi H. , Bahnson Tristram D. , Mark Daniel B. , Packer Douglas L. , Poole Jeanne E. ,   For the CABANA Investigators
Published: January 2021

Background:
Among patients with atrial fibrillation (AF), women are less likely to receive catheter ablation and may have more complications and less durable results. Most information about sex-specific differences after ablation comes from observational data. We prespecified an examination of outcomes by sex in the 2204-patient CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).

Methods:
CABANA randomized patients with AF age ≥65 years or <65 years with ≥1 risk factor for stroke to a strategy of catheter ablation with pulmonary vein isolation versus drug therapy with rate/rhythm control agents. The primary composite outcome was death, disabling stroke, serious bleeding, or cardiac arrest, and key secondary outcomes included AF recurrence.

Results:

CABANA randomized 819 (37%) women (ablation 413, drug 406) and 1385 men (ablation 695, drug 690). Compared with men, women were older (median age, 69 years versus 67 years for men), were more symptomatic (48% Canadian Cardiovascular Society AF Severity Class 3 or 4 versus 39% for men), had more symptomatic heart failure (42% with New York Heart Association Class ≥II versus 32% for men), and more often had a paroxysmal AF pattern at enrollment (50% versus 39% for men) (
P
<0.0001 for all). Women were less likely to have ancillary (nonpulmonary vein) ablation procedures performed during the index procedure (55.7% versus 62.2% in men,
P
=0.043), and complications from treatment were infrequent in both sexes. For the primary outcome, the hazard ratio for those who underwent ablation versus drug therapy was 1.01 (95% CI, 0.62–1.65) in women and 0.73 (95% CI, 0.51–1.05) in men (interaction
P
value=0.299). The risk of recurrent AF was significantly reduced in patients undergoing ablation compared with those receiving drug therapy regardless of sex, but the effect was greater in men (hazard ratio, 0.64 [95% CI, 0.51–0.82] for women versus hazard ratio, 0.48 [95% CI, 0.40–0.58] for men; interaction
P
value=0.060).

Conclusions:
Clinically relevant treatment-related strategy differences in the primary and secondary clinical outcomes of CABANA were not seen between men and women, and there were no sex differences in adverse events. The CABANA trial results support catheter ablation as an effective treatment strategy for both women and men.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00911508.
Willingness to Coexist with Jaguars and Pumas in Costa Rica
Authors: Schauer Jennifer Rebecca 
Published: January 2021

Abstract
Shrinking habitat, depleted prey sources, and hunting increase conflict between humans and jaguars in Latin America. Participant observation was used for 131 open-ended interviews in the Mesoamerican Biological Corridor of Costa Rica to describe and provide recommendations for Panthera’s rancher outreach program. Changing husbandry practices is different than wanting to relocate jaguars or pumas, which suggests willingness to coexist is based on geo-physical proximities. Further, perceived attacks on livestock may be unreliable creating a perception of more predation, villainizing large felines, and challenging coexistence. This study urges wildlife managers to evaluate the effectiveness of relocation; suggests systematic recordkeeping of jaguar and puma attacks; encourages researchers to measure willingness to co-exist with large carnivores based on geo-physical distance; suggests strategies of coexistence may have both cultural and regional differences; and recommends a communication strategy through a citizen science approach, in order to educate ranchers and create social investment among communities.