bluuebunny/crossref_metadata_2025_split huggingface dataset:
HUMAN EVOLUTION AND THE CHRISTIAN CALL TO LOVE
Authors: Poister David 
Published: December 2021

AbstractThis article will examine the Christian call to love as an invitation to participate in an ongoing evolutionary transformation of humanity. This interpretation recognizes that the ability to love others is both a product and driver of evolutionary change. Through natural selection, humans evolved the neurological capacity to benefit from the cooperation generated by empathy. Additionally, these evolutionary origins have created constraints on altruism such as the tendency to favor members of one's own group. Christianity and other religions are well‐suited to encourage the specific behaviors and cultural conditions that allow humans to overcome these constraints. Religions can provide consistent reinforcement of the symbolic and behavioral information that establishes empathy as a desirable trait and steers human evolution in a prosocial direction. Also, religious concepts such as the kingdom of God and Teilhard's Omega Point can inspire cooperation by associating even small acts of kindness with the evolutionary transformation to improve the human condition.
Impact of Sled Loads on Performance and Kinematics of Elite Sprinters and Rugby Players
Authors: Pareja-Blanco Fernando , Pereira Lucas A. , Reis Valter P. , Fernandes Victor , Arruda Ademir F.S. , Guerriero Aristide , Alcaraz Pedro E. , Freitas Tomás T. , Loturco Irineu 
Published: December 2021

Purpose: To examine the changes in resisted sprint performance and kinematics provoked by different sled loads in elite sprinters and rugby players. Methods: Eight elite male sprinters and 10 rugby union players performed 20-m sprints under 3 loading conditions (0%, 20%, and 60% body mass [BM]). Sprint time was measured in 0 to 5, 5 to 10, and 10 to 20 m, while stride length and hip, knee, and ankle angles were measured using an 8-sensor motion analysis system at the same distances. Results: Sprinters were significantly faster than rugby players in unresisted and resisted sprints using 20% BM (effect size, “ES” [90% confidence limit, CL] range: 0.65 [0.03 to 1.27]; 3.95 [3.10 to 4.81]), but these differences were not significant at 60% BM. Compared to rugby players, sprinters showed lower velocity decrement in resisted sprints using 20% BM (ES [90% CL] range: 0.75 [0.06 to 1.44]; 2.43 [0.83 to 4.02], but higher velocity decrement using 60% BM (ES [90% CL] range: 1.13 [0.43 to 1.82]; 1.46 [0.81 to 2.11]). No significant differences were detected in stride length between sprinters and rugby players for any sprint condition (ES [90% CL] range: 0.02 [−0.72 to 0.76]; 0.84 [0.13 to 1.54]). Rugby players showed higher hip flexion in resisted sprints (ES [90% CL] range: 0.30 [−0.54 to 1.14]; 1.17 [0.20 to 2.15]) and lower plantar flexion in both unresisted and resisted sprints (ES [90% CL] range: 0.78 [0.18 to 1.38]; 1.69 [1.00 to 2.38] than sprinters. Conclusions: The alterations induced by resisted sprints in sprint velocity and running technique differed between sprinters and rugby players. Some caution should be taken with general sled loads prescriptions, especially when relative loads are based on distinct percentages of BM, as training responses vary among sports and individuals.
Dense melt residues drive mid-ocean-ridge “hotspots”
Authors: Phethean* Jordan J.J. , Papadopoulou Martha , Peace Alexander L. 
Published: December 2021

ABSTRACT
The geodynamic origin of melting anomalies found at the surface, often referred to as “hotspots,” is classically attributed to a mantle plume process. The distribution of hotspots along mid-ocean-ridge spreading systems around the globe, however, questions the universal validity of this concept. Here, the preferential association of hotspots with slow- to intermediate-spreading centers and not fast-spreading centers, an observation contrary to the expected effect of ridge suction forces on upwelling mantle plumes, is explained by a new mechanism for producing melting anomalies at shallow (&lt;2.3 GPa) depths. By combining the effects of both chemical and thermal density changes during partial melting of the mantle (using appropriate latent heat and depth-dependent thermal expansivity parameters), we find that mantle residues experience an overall instantaneous increase in density when melting occurs at &lt;2.3 GPa. This controversial finding is due to thermal contraction of material during melting, which outweighs the chemical buoyancy due to melting at shallow pressures (where thermal expansivities are highest). These dense mantle residues are likely to locally sink beneath spreading centers if ridge suction forces are modest, thus driving an increase in the flow of fertile mantle through the melting window and increasing magmatic production. This leads us to question our understanding of sub–spreading center dynamics, where we now suggest a portion of locally inverted mantle flow results in hotspots. Such inverted flow presents an alternative mechanism to upwelling hot mantle plumes for the generation of excess melt at near-ridge hotspots, i.e., dense downwelling of mantle residue locally increasing the flow of fertile mantle through the melting window. Near-ridge hotspots, therefore, may not require the elevated temperatures commonly invoked to account for excess melting. The proposed mechanism also satisfies counterintuitive observations of ridge-bound hotspots at slow- to intermediate-spreading centers, yet not at fast-spreading centers, where large dynamic ridge suction forces likely overwhelm density-driven downwelling.
The lack of observations of such downwelling in numerical modeling studies to date reflects the generally high chemical depletion buoyancy and/or low thermal expansivity parameter values employed in simulations, which we find to be unrepresentative for melting at &lt;2.3 GPa. We therefore invite future studies to review the values used for parameters affecting density changes during melting (e.g., depletion buoyancy, latent heat of melting, specific heat capacity, thermal expansivity), which quite literally have the potential to turn our understanding of mantle dynamics upside down.
On the Schwarzschild-Anti-de Sitter black hole with an f(R) global monopole
Authors: Vieira H. S. 
Published: December 2021

AbstractIn this work, we follow the recently revisited f(R) theory of gravity for studying the interaction between quantum scalar particles and the gravitational field of a generalized black hole with an f(R) global monopole. This background has a term playing the role of an effective cosmological constant, which permits us to call it as Schwarzschild-Anti-de Sitter (SAdS) black hole with an f(R) global monopole. We examine the separability of the Klein–Gordon equation with a non-minimal coupling and then we discuss both the massless and massive cases for a conformal coupling. We investigate some physical phenomena related to the asymptotic behavior of the radial function, namely, the black hole radiation, the quasibound states, and the wave eigenfunctions.
Preparation, Characteristics, and Controlled Release Efficiency of the Novel PCL-PEG/EM Rod Micelles
Authors: Song Huiling , Yin Yu , Peng Jiahui , Du Zixiu , Bao Wei 
Published: December 2021

In order to achieve sustained and controlled release of the hydrophobic cargoes, improve the bioavailability, and reduce the side effects of antibiotics, the model drug erythromycin (EM) was used to prepare polycaprolactone-polyethylene glycol (PCL-PEG)/EM micelles. PCL-PEG, a biocompatible and biodegradable amphiphilic polymer, was used as carrier material of micelles to optimize the formulation and preparation process by orthogonal design. The morphology, stability, drug loading, and encapsulation efficiency and the in vitro release behavior of the micelles were investigated. In addition, activity assays of anti-Staphylococcus aureus were performed. The results indicated that PCL-PEG/EM were rod-like micelles with an average particle size of

220
±
2.6

nm and a zeta potential of +19 mV. The average drug loading and encapsulation efficiency were approximately 6.5% and 97.0%, respectively. The micelles were stable in the serum within three days. At the effective concentration of the drug, the formulation indicated no apparent toxicity to the cells. The micelles were able to rapidly enter Staphylococcus aureus (S. aureus) and to provide sustained release cargoes that effectively inhibited S. aureus proliferation. The present study provided a new platform for the rational and effective use of hydrophobic antibiotics to treat infections.
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Authors: Zhang Songfa , Yan Chuan , Millar David G. , Yang Qiqi , Heather James M. , Langenbucher Adam , Morton Laura T. , Sepulveda Sean , Alpert Eric , Whelton Lauren R. , Zarrella Dominique T. , Guo Mei , Minogue Eleanor , Lawrence Michael S. , Rueda Bo R. , Spriggs David R. , Lu Weiguo , Langenau David M. , Cobbold Mark 
Published: December 2021

Abstract

Antibody–peptide epitope conjugates (APEC) are a new class of modified antibody–drug conjugates that redirect T-cell viral immunity against tumor cells. APECs contain a tumor-specific protease cleavage site linked to a patient-specific viral epitope, resulting in presentation of viral epitopes on cancer cells and subsequent recruitment and killing by CD8+ T cells. Here we developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Using functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus (CMV) in patients with ovarian cancer, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. Each APEC was tested for in vitro cancer cell killing, and top candidates were screened for killing xenograft tumors grown in zebrafish and mice. These preclinical modeling studies identified EpCAM-MMP7-CMV APEC (EpCAM-MC) as a potential new immunotherapy for ovarian carcinoma. Importantly, EpCAM-MC also demonstrated robust T-cell responses in primary ovarian carcinoma patient ascites samples. This work highlights a robust, customizable platform to rapidly develop patient-specific APECs.

Significance:
This study develops a high-throughput preclinical platform to identify patient-specific antibody–peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma.
AMPK–mTOR–Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells
Authors: You Bo , Xia Tian , Gu Miao , Zhang Zhenxin , Zhang Qicheng , Shen Jianhong , Fan Yue , Yao Hui , Pan Si , Lu Yingna , Cheng Tianyi , Yang Zhiyuan , He Xin , Zhang Hao , Shi Muqi , Liu Dong , You Yiwen 
Published: December 2021

Abstract

Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer.

Significance:
Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.
The Effect of Corticosteroids on Prostate Cancer Outcome Following Treatment with Enzalutamide: A Multivariate Analysis of the Phase III AFFIRM Trial
Authors: Zhao Jimmy L. , Fizazi Karim , Saad Fred , Chi Kim N. , Taplin Mary-Ellen , Sternberg Cora N. , Armstrong Andrew J. , de Bono Johann S. , Duggan William T. , Scher Howard I. 
Published: December 2021

Abstract

Purpose:
The clinical impact of concurrent corticosteroid use (CCU) on enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) is unknown. We investigated the association of CCU with overall survival (OS), radiographic progression-free survival (rPFS), and time to prostate-specific antigen progression (TTPP) in post-chemotherapy, enzalutamide-treated patients with mCRPC.

Patients and Methods:
Post hoc analysis of AFFIRM (NCT00974311) with patients (n = 1,199) randomized 2:1 to enzalutamide 160 mg/day or placebo. Treatment group, CCU, and known prognostic factors were evaluated for impact on OS, rPFS, and TTPP using a multivariate Cox proportional hazards model. CCU was defined as “baseline” (use started at baseline) or “on-study” (baseline plus use that was started during the trial).

Results:
Enzalutamide significantly improved OS, rPFS, and TTPP independent of baseline CCU but was associated with inferior clinical outcomes when compared with no baseline CCU, including a shorter OS [10.8 months vs. not reached (NR); HR for use vs. no use, 2.13; 95% confidence interval (CI), 1.79–2.54], rPFS (5.2 months vs. 8.0 months; HR, 1.49; 95% CI, 1.29–1.72], and TTPP (4.6 months vs. 5.7 months; HR, 1.50; 95% CI, 1.25–1.81). These findings held in a multivariate analysis adjusting for baseline prognostic factors wherein baseline CCU was independently associated with decreased OS (HR, 1.71; 95% CI, 1.43–2.04; P &lt; 0.0001) and rPFS (HR, 1.28; 95% CI, 1.11–1.48; P = 0.0007).

Conclusions:
Patients with mCRPC benefited from enzalutamide treatment independent of CCU, but CCU was associated with worse baseline prognostic factors and outcomes.
Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial
Authors: Cohen Ezra E.W. , Nabell Lisle , Wong Deborah J. , Day Terry , Daniels Gregory A. , Milhem Mohammed , Deva Sanjeev , Jameson Michael , Guntinas-Lichius Orlando , Almubarak Mohammed , Strother Matthew , Whitman Eric , Chisamore Michael , Obiozor Cynthia , Bagulho Teresa , Gomez-Romo Jose , Guiducci Cristiana , Janssen Robert , Gamelin Erick , Algazi Alain P. 
Published: December 2021

Abstract

Purpose:
To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

Patients and Methods:
Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks.

Results:
A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to &lt; 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively.

Conclusions:
SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.
Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)
Authors: Nixon Andrew B. , Halabi Susan , Liu Yingmiao , Starr Mark D. , Brady John C. , Shterev Ivo , Luo Bin , Hurwitz Herbert I. , Febbo Phillip G. , Rini Brian I. , Beltran Himisha , Small Eric J. , Morris Michael J. , George Daniel J. 
Published: December 2021

AbstractPurpose:CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit.Patients and Methods:A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC).Results:A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P &lt; 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P &lt; 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0–13.8] and 34.3 (95% CI, 28.5–40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79).Conclusions:IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials.See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725
Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)
Authors: Nixon Andrew B. , Sibley Alexander B. , Liu Yingmiao , Hatch Ace J. , Jiang Chen , Mulkey Flora , Starr Mark D. , Brady John C. , Niedzwiecki Donna , Venook Alan P. , Baez-Diaz Luis , Lenz Heinz-Josef , O'Neil Bert H. , Innocenti Federico , Meyerhardt Jeffrey A. , O'Reilly Eileen M. , Owzar Kouros , Hurwitz Herbert I. 
Published: December 2021

Abstract

Purpose:
CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.

Patients and Methods:
In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.

Results:
In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097).

Conclusions:
In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.
See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725
Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
Authors: Bergamino Milana A. , Morani Gabriele , Parker Joel , Schuster Eugene F. , Leal Mariana F. , López-Knowles Elena , Tovey Holly , Bliss Judith M. , Robertson John F.R. , Smith Ian E. , Dowsett Mitch , Cheang Maggie C.U. 
Published: December 2021

Abstract

Purpose:
Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor–positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs.

Experimental Design:
Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors.

Results:
The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study.

Conclusions:
Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.