bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing the $$H_0$$ tension with exponential acoustic dark energy
Authors: Yin Lu 
Published: January 2022

AbstractThe Hubble tension arises from different observations between the late-time and early Universe. We explore a new model with dark fluid, called the exponential acoustic dark energy (eADE) model, to relieve the Hubble tension. The eADE model gives an exponential form of the equation of state (EoS) in the acoustic dark energy, which is the first time to explore an exponential form for the EoS. In this model, the gravitational effects from the acoustic oscillations of the model can impact the CMB phenomena at the matter radiation equally epoch. We give the constraints of the eADE model by the current cosmological dataset. The comparison of the phenomena with the standard model can be shown through CMB and matter power spectra. The fitting results of our model have $$H_0 = 70.06^{+1.13}_{-1.09}$$

H
0

=
70
.

06

-
1.09

+
1.13

in 95$$\%$$
%
C.L. and a smaller best-fit value than $$\Lambda $$
Λ
CDM.
Survival of Adolescents and Young Adults with Prevalent Poor-Prognosis Metastatic Cancers: A Population-Based Study of Contemporary Patterns and Their Implications
Authors: Sheth Bhutada Jessica K. , Hwang Amie E. , Liu Lihua , Tsai Kai-Ya , Deapen Dennis , Freyer David R. 
Published: January 2022

Abstract

Background:
Although survival has improved dramatically for most adolescents and young adults (AYA; 15–39 years old) with cancer, it remains poor for those presenting with metastatic disease. To better characterize this subset, we conducted a landscape survival comparison with older adults (40–79 years).

Methods:
Using Surveillance, Epidemiology, and End Results Program data from 2000 to 2016, we examined incident cases of poor-prognosis metastatic cancers (5-year survival &lt; 50%) among AYAs (n = 11,518) and older adults (n = 345,681) and compared cause-specific survival by sociodemographic characteristics (race/ethnicity, sex, and socioeconomic status). Adjusted HRs (aHR) for death from metastatic disease [95% confidence intervals (95% CI)] were compared between AYAs and older adults (Pint).

Results:
AYAs had significantly better survival than older adults for every cancer site except kidney, where it was equivalent (range of aHRs = 0.91; 95% CI, 0.82–1.02 for kidney cancer to aHR = 0.33; 95% CI, 0.26–0.42 for rhabdomyosarcoma). Compared with their older adult counterparts, greater survival disparities existed for AYAs who were non-Hispanic Black with uterine cancer (aHR = 2.20; 95% CI, 1.25–3.86 versus aHR = 1.40; 95% CI, 1.28–1.54; Pint = 0.049) and kidney cancer (aHR = 1.51; 95% CI, 1.15–1.98 versus aHR = 1.10; 95% CI, 1.03–1.17; Pint = 0.04); non-Hispanic Asian/Pacific Islanders with ovarian cancer (aHR = 1.47; 95% CI, 1.12–1.93 versus aHR = 0.89; 95% CI, 0.84–0.95; Pint&lt;0.001); and males with colorectal cancer (aHR = 1.21; 95% CI, 1.10–1.32 versus aHR = 1.08; 95% CI, 1.06–1.10; Pint = 0.045).

Conclusions:
AYAs diagnosed with these metastatic cancers have better survival than older adults, but outcomes remain dismal.

Impact:
Overcoming the impact of metastasis in these cancers is necessary for continuing progress in AYA oncology. Sociodemographic disparities affecting AYAs within kidney, uterine, ovarian, and colorectal cancer could indicate plausible effects of biology, environment, and/or access and should be explored.
Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis
Authors: Harbs Justin , Rinaldi Sabina , Gicquiau Audrey , Keski-Rahkonen Pekka , Mori Nagisa , Liu Xijia , Kaaks Rudolf , Katzke Verena , Schulze Matthias B. , Agnoli Claudia , Tumino Rosario , Bueno-de-Mesquita Bas , Crous-Bou Marta , Sánchez Maria-Jose , Aizpurua Amaia , Chirlaque María-Dolores , Gurrea Aurelio Barricarte , Travis Ruth C. , Watts Eleanor L. , Christakoudi Sofia , Tsilidis Konstantinos K. , Weiderpass Elisabete , Gunter Marc J. , Van Guelpen Bethany , Murphy Neil , Harlid Sophia 
Published: January 2022

Abstract

Background:
Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking.

Methods:
We conducted a comprehensive nested case–control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men.

Results:
Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51–0.89) and SHBG (OR, 0.77; 95% CI, 0.62–0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58–1.18). In a dose–response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL = 0.98; 95% CI, 0.96–1.00; I2 = 22%] and free testosterone (RR per 1 ng/dL = 0.98; 95% CI, 0.95–1.00; I2 = 0%).

Conclusions:
Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development.

Impact:
Additional support for the involvement of sex hormones in male colon cancer.
Sleep Duration, Chronotype, and Insomnia and the Risk of Lung Cancer: United Kingdom Biobank Cohort
Authors: Peeri Noah C. , Tao Meng-Hua , Demissie Serkalem , Nguyen Uyen-Sa D.T. 
Published: January 2022

Abstract

Background:
Relationships between sleep duration, chronotype, insomnia, and lung cancer risk have not been comprehensively examined. Interrelations between sleep traits on the risk of lung cancer have not been assessed. We aimed to examine sleep traits with lung cancer risk.

Methods:
Participants were recruited between 2006 and 2010 and followed through November 30, 2020. We included 382,966 participants (3,664 incident lung cancer) in analysis. Cox proportional hazards models estimated HRs and 95% confidence intervals (CI) for associations between sleep duration, chronotype, and insomnia symptoms and lung cancer risk. Joint effects analyses were examined between sleep duration and three traits (chronotype, insomnia, and daytime napping). Nonlinear associations between sleep duration and lung cancer risk were assessed in restricted cubic spline analysis.

Results:
Longer sleep (&gt;8 hours) was positively associated with lung cancer risk compared with normal sleep duration (7–8 hours; HR = 1.22; 95% CI, 1.10–1.36). Frequent insomnia symptoms increased the risk of lung cancer compared with never/rarely experiencing symptoms (HR = 1.16; 95% CI, 1.05–1.28). Joint effects between sleep duration and chronotype, and sleep duration and insomnia symptoms were observed. In analysis excluding participants reporting shift work at baseline, evening chronotypes (“slight,” “definite”) were at a greater risk of lung cancer compared with definite morning chronotype (HR = 1.17; 95% CI, 1.06–1.28 and HR = 1.37; 95% CI, 1.21–1.54, respectively).

Conclusions:
Sleep traits such as long sleep duration, frequent insomnia symptoms, and definite evening chronotype may be risk factors for lung cancer. Joint effects should be further investigated.

Impact:
Sleep traits may be risk factors of lung cancer.
Tumor Targeting with Bacterial Shiga Toxin B Subunit in Genetic Porcine Models for Colorectal Cancer and Osteosarcoma
Authors: Ehrenfeld Maximilian , Schrade Anna , Flisikowska Tatiana , Perl Markus , Hirsch Noah-David , Sichler Anna , Geyer Laura , Flisikowski Krzysztof , Wilhelm Dirk , Schober Sebastian Johannes , Johannes Ludger , Schnieke Angelika , Janssen Klaus-Peter 
Published: January 2022

Abstract
The B subunit of bacterial Shiga toxin (STxB) is nontoxic and has low immunogenicity. Its receptor, the glycosphingolipid Gb3/CD77, is overexpressed on the cell surface of human colorectal cancer. We tested whether genetic porcine models, closely resembling human anatomy and pathophysiology, can be used to exploit the tumor-targeting potential of STxB. In accordance with findings on human colorectal cancer, the pig model APC1311 bound STxB in colorectal tumors, but not in normal colon or jejunum, except for putative enteroendocrine cells. In primary tumor cells from endoscopic biopsies, STxB was rapidly taken up along the retrograde intracellular route to the Golgi, whereas normal colon organoids did not bind or internalize STxB. Next, we tested a porcine model (TP53LSL-R167H) for osteosarcoma, a tumor entity with a dismal prognosis and insufficient treatment options, hitherto not known to express Gb3. Pig osteosarcoma strongly bound StxB and expressed the Gb3 synthase 1,4-galactosyltransferase (A4GALT). Primary osteosarcoma cells, but not normal osteoblasts, rapidly internalized fluorescently labeled STxB along the retrograde route to the Golgi. Importantly, six of eight human osteosarcoma cell lines expressed A4GALT mRNA and showed prominent intracellular uptake of STxB. The physiologic role of A4GALT was tested by CRISPR/Cas9 mutagenesis in porcine LLC-PK1 kidney epithelial cells and RNAi in MG-63 human osteosarcoma cells. A4GALT deficiency or knockdown abolished STxB uptake and led to significantly reduced cell migration and proliferation, hinting toward a putative tumor-promoting role of Gb3. Thus, pig models are suitable tools for STxB-based tumor targeting and may allow “reverse-translational” predictions on human tumor biology.
Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists
Authors: Grinkevitch Vera , Wappett Mark , Crawford Nyree , Price Stacey , Lees Andrea , McCann Christopher , McAllister Katherine , Prehn Jochen , Young Jamie , Bateson Jess , Gallagher Lewis , Michaut Magali , Iyer Vivek , Chatzipli Aikaterini , Barthorpe Syd , Ciznadija Daniel , Sloma Ido , Wesa Amy , Tice David A. , Wessels Lodewyk , Garnett Mathew , Longley Daniel B. , McDermott Ultan , McDade Simon S. 
Published: January 2022

Abstract
Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death. High-throughput drug screening failed to identify genomic alterations associated with response to MEDI3039; however, transcriptomics analysis revealed striking association between MEDI3039 sensitivity and expression of core components of the extrinsic apoptotic pathway, most notably its main apoptotic effector caspase-8 in solid tumor cell lines. Further analyses of colorectal cell lines and patient-derived xenografts identified caspase-8 expression ratio to its endogenous regulator FLIP(L) as predictive of sensitivity to MEDI3039 in several major solid tumor types and a further subset indicated by caspase-8:MCL-1 ratio. Subsequent MEDI3039 combination screening of TRAIL-R2, caspase-8, FADD, and BID knockout models with 60 compounds with varying mechanisms of action identified two inhibitor of apoptosis proteins (IAP) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8:MCL-1 as potential predictive biomarkers for second-generation TRAIL-R2 agonists and loss of key effectors such as FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.
Olaparib-Induced Senescence Is Bypassed through G2–M Checkpoint Override in Olaparib-Resistant Prostate Cancer
Authors: Lombard Alan P. , Armstrong Cameron M. , D'Abronzo Leandro S. , Ning Shu , Leslie Amy R. , Sharifi Masuda , Lou Wei , Evans Christopher P. , Dall'Era Marc , Chen Hong-Wu , Chen Xinbin , Gao Allen C. 
Published: January 2022

AbstractPARP inhibition represents the dawn of precision medicine for treating prostate cancer. Despite this advance, questions remain regarding the use of PARP inhibitors (PARPi) for the treatment of this disease, including (i) how specifically do PARPi-sensitive tumor cells respond to treatment, and (ii) how does PARPi resistance develop? To address these questions, we characterized response to olaparib in sensitive LNCaP and C4-2B cells and developed two olaparib-resistant derivative cell line models from each, termed LN-OlapR and 2B-OlapR, respectively. OlapR cells possess distinct morphology from parental cells and display robust resistance to olaparib and other clinically relevant PARPis, including rucaparib, niraparib, and talazoparib. In LNCaP and C4-2B cells, we found that olaparib induces massive DNA damage, leading to activation of the G2–M checkpoint, activation of p53, and cell-cycle arrest. Furthermore, our data suggest that G2–M checkpoint activation leads to both cell death and senescence associated with p21 activity. In contrast, both LN-OlapR and 2B-OlapR cells do not arrest at G2–M and display a markedly blunted response to olaparib treatment. Interestingly, both OlapR cell lines harbor increased DNA damage relative to parental cells, suggesting that OlapR cells accumulate and manage persistent DNA damage during acquisition of resistance, likely through augmenting DNA repair capacity. Further impairing DNA repair through CDK1 inhibition enhances DNA damage, induces cell death, and sensitizes OlapR cells to olaparib treatment. Our data together further our understanding of PARPi treatment and provide a cellular platform system for the study of response and resistance to PARP inhibition.
Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody–drug Conjugate Targeting AXL-expressing Cancers
Authors: Zammarchi Francesca , Havenith Karin EG. , Chivers Simon , Hogg Paul , Bertelli Francois , Tyrer Peter , Janghra Narinder , Reinert Halla W. , Hartley John A. , van Berkel Patrick H. 
Published: January 2022

Abstract
AXL, a tyrosine kinase receptor that is overexpressed in many solid and hematologic malignancies, facilitates cancer progression and is associated with poor clinical outcomes. Importantly, drug-induced expression of AXL results in resistance to conventional chemotherapy and targeted therapies. Together with its presence on multiple cell types in the tumor immune microenvironment, these features make it an attractive therapeutic target for AXL-expressing malignancies.
ADCT-601 (mipasetamab uzoptirine) is an AXL-targeted antibody–drug conjugate (ADC) comprising a humanized anti-AXL antibody site specifically conjugated using GlycoConnect technology to PL1601, which contains HydraSpace, a Val-Ala cleavable linker and the potent pyrrolobenzodiazepine (PBD) dimer cytotoxin SG3199. This study aimed to validate the ADCT-601 mode of action and evaluate its efficacy in vitro and in vivo, as well as its tolerability and pharmacokinetics.
ADCT-601 bound to both soluble and membranous AXL, and was rapidly internalized by AXL-expressing tumor cells, allowing release of PBD dimer, DNA interstrand cross-linking, and subsequent cell killing. In vivo, ADCT-601 had potent and durable antitumor activity in a wide variety of human cancer xenograft mouse models, including patient-derived xenograft models with heterogeneous AXL expression where ADCT-601 antitumor activity was markedly superior to an auristatin-based comparator ADC. Notably, ADCT-601 had antitumor activity in a monomethyl auristatin E–resistant lung-cancer model and synergized with the PARP inhibitor olaparib in a BRCA1-mutated ovarian cancer model. ADCT-601 was well tolerated at doses of up to 6 mg/kg and showed excellent stability in vivo.
These preclinical results warrant further evaluation of ADCT-601 in the clinic.
89Zr-ImmunoPET Shows Therapeutic Efficacy of Anti-CD20-IFNα Fusion Protein in a Murine B-cell Lymphoma Model
Authors: Zettlitz Kirstin A. , Salazar Felix B. , Yamada Reiko E. , Trinh K. Ryan , Vasuthasawat Alex , Timmerman John M. , Morrison Sherie L. , Wu Anna M. 
Published: January 2022

Abstract
Antibody-mediated tumor delivery of cytokines can overcome limitations of systemic administration (toxicity, short half-lives). Previous work showed improved antitumor potency of anti-CD20-IFNα fusion proteins in preclinical mouse models of B-cell lymphoma. Although tumor targeting is mediated by the antibody part of the fusion protein, the cytokine component might strongly influence biodistribution and pharmacokinetics, as a result of its affinity, size, valency, and receptor distribution.
Here, we used immunoPET to study the in vivo biodistribution and tumor targeting of the anti-CD20 rituximab-murine IFNα1 fusion protein (Rit-mIFNα) and compared it with the parental mAb (rituximab, Rit). Rit-mIFNα and Rit were radiolabeled with zirconium-89 (89Zr, t1/2 78.4 hours) and injected into C3H mice bearing syngeneic B-cell lymphomas (38C13-hCD20). Dynamic [(2 hours post injection (p.i.)] and static (4, 24, and 72 hours) PET scans were acquired. Ex vivo biodistribution was performed after the final scan.
Both 89Zr-Rit-mIFNα and 89Zr-Rit specifically target hCD20-expressing B-cell lymphoma in vivo. 89Zr-Rit-mIFNα showed specific uptake in tumors (7.6 ± 1.0 %ID/g at 75 hours p.i.), which was significantly lower than 89Zr-Rit (38.4 ± 9.9 %ID/g, P &lt; 0.0001). ImmunoPET studies also revealed differences in the biodistribution, 89Zr-Rit-mIFNα showed rapid blood clearance and high accumulation in the liver compared with 89Zr-Rit. Importantly, immunoPET clearly revealed a therapeutic effect of the single 89Zr-Rit-mIFNα dose, resulting in smaller tumors and fewer lymph node metastases compared with mice receiving 89Zr-Rit. Mice receiving 89Zr-Rit-mIFNα had enlarged spleens, suggesting that systemic immune activation contributes to therapeutic efficacy in addition to the direct antitumoral activity of IFNα.
In conclusion, immunoPET allows the noninvasive tracking and quantification of the antibody-cytokine fusion protein and helps understand the in vivo behavior and therapeutic efficacy.
Benchmarking functional connectivity by the structure and geometry of the human brain
Authors: Liu Zhen-Qi , Betzel Richard F. , Misic Bratislav 
Published: January 2022

Abstract
The brain’s structural connectivity supports the propagation of electrical impulses, manifesting as patterns of coactivation, termed functional connectivity. Functional connectivity emerges from the underlying sparse structural connections, particularly through polysynaptic communication. As a result, functional connections between brain regions without direct structural links are numerous, but their organization is not completely understood. Here we investigate the organization of functional connections without direct structural links. We develop a simple, data-driven method to benchmark functional connections with respect to their underlying structural and geometric embedding. We then use this method to reweigh and reexpress functional connectivity. We find evidence of unexpectedly strong functional connectivity among distal brain regions and within the default mode network. We also find unexpectedly strong functional connectivity at the apex of the unimodal-transmodal hierarchy. Our results suggest that both phenomena—functional modules and functional hierarchies—emerge from functional interactions that transcend the underlying structure and geometry. These findings also potentially explain recent reports that structural and functional connectivity gradually diverge in transmodal cortex. Collectively, we show how structural connectivity and geometry can be used as a natural frame of reference with which to study functional connectivity patterns in the brain.
Elective incisional hernia repair: lower risk of postoperative wound infection with laparoscopic versus open repair
Authors: Goh Serene Si Ning , Sanghvi Kaushal Amitbhai , Koura Aaryan Nath , Rao Jaideepraj Krishnaraj , Oo Aung Myint 
Published: January 2022

Introduction:
The superiority of laparoscopic repair over open repair of incisional hernias (IHs) in the elective setting is still controversial. Our study aimed to compare the postoperative outcomes of laparoscopic and open elective IH repair in an Asian population.

Methods:
This retrospective study was conducted in an acute general hospital in Singapore between 2010 and 2015. Inclusion criteria were IH repair in an elective setting, IHs with diameter of 3–15 cm, and location at the ventral abdominal wall. We excluded patients who underwent emergency repair, had recurrent hernias or had loss of abdominal wall domain (i.e. hernia sac containing more than 30% of abdominal contents or any solid organs). Postoperative outcomes within a year such as recurrence, pain, infection, haematoma and seroma formation were compared between the two groups.

Results:
There were 174 eligible patients. The majority were elderly Chinese women who were overweight. Open repair was performed in 49.4% of patients, while 50.6% underwent laparoscopic repair. The mean operation time for open repair was 116 minutes (116 ± 60.6 minutes) and 139 minutes (136 ± 64.1 minutes) for laparoscopic repair (P = 0.079). Within a year after open repair, postoperative wound infection occurred in 15.1% of the patients in the open repair group compared to 1.1% in the laparoscopic group (P = 0.0007). Postoperative pain, recurrence and haematoma/seroma formation were comparable.

Conclusion:
Elective laparoscopic IH repair has comparable outcomes with open repair and may offer the advantage of reduced postoperative wound infection rates.
The Philosophical Background of Yoḥanan Alemanno: Remarks on Logic and Psychology
Authors: Gentili Hanna 
Published: January 2022

Abstract
The convergence of philosophical and kabbalistic sources in the works of Yoḥanan Alemanno (ca. 1435–ca. 1504) attests to the richness of fifteenth-century scholarship in Italy, specifically its reception of sources that had characterized cultural debates across the Mediterranean for centuries. Beginning with a discussion of his personal notebook (Oxford, Bodleian Library, Ms Reggio 23), and focusing on his treatment of logic and psychology, this study demonstrates the extent to which Alemanno relied on the Jewish Aristotelian tradition based on the translations of Averroes’ Arabic commentaries. Moreover, it shows the relationship between this tradition and the kabbalistic themes addressed by the author in his works.