bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD71+erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
Authors: Bozorgmehr Najmeh , Okoye Isobel , Mashhouri Siavash , Lu Julia , Koleva Petya , Walker John , Elahi Shokrollah 
Published: May 2023

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. However, only a portion of patients respond to such treatments. Therefore, it remains a prevailing clinical need to identify factors associated with acquired resistance or lack of response to ICIs. We hypothesized that the immunosuppressive CD71+erythroid cells (CECs) within the tumor and/or distant ‘out-of-field’ may impair antitumor response.MethodsWe studied 38 patients with cancer through a phase II clinical trial investigating the effects of oral valproate combined with avelumab (anti-programmed death-ligand 1 (PD-L1)) in virus-associated solid tumors (VASTs). We quantified the frequency/functionality of CECs in blood and biopsies of patients. Also, we established an animal model of melanoma (B16-F10) to investigate the possible effects of erythropoietin (EPO) treatment on anti-PD-L1 therapy.ResultsWe found a substantial expansion of CECs in the blood of patients with VAST compared with healthy controls. We noted that the frequency of CECs in circulation was significantly higher at the baseline and throughout the study in non-responders versus responders to PD-L1 therapy. Moreover, we observed that CECs in a dose-dependent manner suppress effector functions of autologous T cells in vitro. The subpopulation of CD45+CECs appears to have a more robust immunosuppressive property compared with their CD45−counterparts. This was illustrated by a stronger expression of reactive oxygen species, PD-L1/PD-L2, and V-domain Ig suppressor of T-cell activation in this subpopulation. Lastly, we found a higher frequency of CECs in the blood circulation at the later cancer stage and their abundance was associated with anemia, and a poor response to immunotherapy. Finally, we report the expansion of CECs in the spleen and tumor microenvironment of mice with melanoma. We found that although CECs in tumor-bearing mice secret artemin, this was not the case for VAST-derived CECs in humans. Notably, our results imply that EPO, a frequently used drug for anemia treatment in patients with cancer, may promote the generation of CECs and subsequently abrogates the therapeutic effects of ICIs (eg, anti-PD-L1).ConclusionsOur results demonstrate that anemia by the expansion of CECs may enhance cancer progression. Notably, measuring the frequency of CECs may serve as a valuable biomarker to predict immunotherapy outcomes.
Low-energy constants in the chiral Lagrangian with baryon octet and decuplet fields from Lattice QCD data on CLS ensembles
Authors: Lutz Matthias F. M. , Heo Yonggoo , Guo Xiao-Yu 
Published: May 2023

AbstractWe perform an analysis of Lattice QCD data on baryon octet and decuplet masses based on the chiral SU(3) Lagrangian. Low-energy constants (LEC) are adjusted to describe baryon masses from a large set of CLS ensembles, where finite-box and discretization effects are considered. The set is successfully compared against previous Lattice QCD data from ensembles generated with distinct QCD actions by the ETMC, QCDSF-UKQCD and HSC groups. Discretization effects are modelled by the use of action and lattice-scale dependent leading orders LEC, where uniform values are imposed in the limit of vanishing lattice scales. From the CLS data set we extract a pion-nucleon sigma term, $$\sigma _{\pi N}= 58.7(1.2)$$

σ

π
N

=
58.7

(
1.2
)

MeV, compatible with its empirical value.
Constraining über gravity with recent observations and studying the $$H_0$$ problem
Authors: Valdez Gustavo A. Concha , Quintanilla Claudia , García-Aspeitia Miguel A. , Hernández-Almada A. , Motta V. 
Published: May 2023

AbstractThis paper studies both $$\Lambda $$
Λ
CDM and CDM models under the über gravity theory, named ü$$\Lambda $$
Λ
CDM and üCDM respectively. We report bounds over their parameter phase-space using several cosmological data, in particular, the recent Pantheon+ sample. Based on the joint analysis, the best fit value of the über characteristic parameter is $$z_\oplus = 0.046^{+0.047}_{-0.032}$$

z
⊕

=
0
.

046

-
0.032

+
0.047

and $$z_\oplus = 1.382^{+0.020}_{-0.021}$$

z
⊕

=
1
.

382

-
0.021

+
0.020

at 68% confidence level for ü$$\Lambda $$
Λ
CDM and üCDM respectively. Although über gravity can successfully mimics the cosmological constant, we find that the $$\mathbb {H}0(z)$$

H
0
(
z
)

diagnostic suggests the $$H_0$$

H
0

tension is not alleviated. Finally, both models are statistically compared with $$\Lambda $$
Λ
CDM through the Akaike and Bayesian information criteria. Both über gravity models and $$\Lambda $$
Λ
CDM are equally preferred for most of the single samples, in particular, ü$$\Lambda $$
Λ
CDM is not rejected by the CMB data. However, there is strong evidence against them for the joint analysis.
Improving Arabic Sentiment Analysis Using LSTM Based on Word Embedding Models
Authors: Zahidi Youssra , Al-Amrani Yassine , El Younoussi Yacine 
Published: May 2023

In recent times, online users freely express their sentiments in different life aspects because of the huge increase in social networks. Sentiment Analysis (SA) is one of the main Natural Language Processing (NLP) fields thanks to its important role in identifying sentiment polarities and making decisions from the public’s opinions. The Arabic language is one of the most challenging languages for SA due to its various dialects, and morphological and syntactic complexities. Deep Learning (DL) models have shown significant capabilities, especially in SA. In particular, Long Short-Term Memory (LSTM) networks have proven perfect abilities to learn sequential data. This paper proposes a comparative study result of Word2Vec and FastText word embedding models that are used to create two Arabic SA (ASA) LSTM-based approaches. The experimental results confirm that the LSTM model with FastText can significantly ameliorate the Arabic classification accuracy.
Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non–Small Cell Lung Cancer: The Piedmont Study
Authors: Eisner Joel R. , Mayhew Gregory M. , Davison James M. , Beebe Kirk D. , Shibata Yoichiro , Guo Yuelong , Farhangfar Carol , Farhangfar Farhang , Uronis Joshua M. , Conroy Jeffrey M. , Milburn Michael V. , Hayes David Neil , Mileham Kathryn F. 
Published: May 2023

Abstract

Purpose:
The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic nonsquamous (NS) non–small cell lung cancer (NSCLC) treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that AF-PRS identifies patients with NS-NSCLC who have a higher likelihood of responding positively to PMX-PDC. The goal was to gather clinical evidence supporting AF-PRS as a potential diagnostic test.

Experimental Design:
Residual pretreatment FFPE tumor samples and clinical data were analyzed from 105 patients treated with first-line (1L) PMX-PDC. Ninety-five patients had sufficient RNA sequencing (RNA-seq) data quality and clinical annotation for inclusion in the analysis. Associations between AF-PRS status and associate genes and outcome measures including progression-free survival (PFS) and clinical response were evaluated.

Results:
Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not overall survival, versus AF-PRS(−) (16.6 months vs. 6.6 months; P = 0.025). In patients who were stage I to III patients at the time of treatment, PFS was further extended in AF-PRS(+) versus AF-PRS(−) (36.2 months vs. 9.3 months; P = 0.03). Complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients stage I to III (six of seven) and stage IV (five of seven) at the time of treatment.

Conclusions:
AF-PRS identified a significant population of patients with extended PFS and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.
Sex-Specific Outcomes of Candidates Listed as the Highest Priority Status for Heart Transplantation
Authors: DeFilippis Ersilia M. , Masotti Maria , Blumer Vanessa , Maharaj Valmiki , Cogswell Rebecca 
Published: May 2023

Background:
While sex differences in heart transplantation (HT) waitlist mortality have been previously described, waitlist and HT outcomes by sex of patients in the highest urgency strata (Status 1) since implementation of the 2018 allocation system change in the United States are unknown. We hypothesized that women listed as Status 1 may have worse outcomes due to adverse events on temporary mechanical circulatory support.

Methods:
The analysis included adult, single-organ HT waitlist candidates listed as Status 1 at any time while listed, after the HT allocation system change (from October 18, 2018 through March 31, 2022). The primary outcome was the rate of HT by sex, assessed using multivariable competing risk analysis where waitlist removal for death or clinical deterioration was the competing event. Post-HT survival by sex of waitlist candidates transplanted as a Status 1 was also compared.

Results:

Of 1120 Status 1 waitlist candidates (23.8% women), women had a lower rate of HT compared to men (adjusted hazard ratio, 0.74 [95% CI, 0.62–0.88];
P
<0.001) and a higher rate of delisting for death or medical unsuitability (adjusted hazard ratio, 1.48 [95% CI, 1.05–2.09];
P
=0.026). Calculated panel reactive antibody did not account for all the harm observed. Post-HT survival of Status 1 candidates by sex was similar (adjusted hazard ratio, 1.13 [95% CI, 0.62–2.06];
P
=0.70).

Conclusions:
Women have a lower rate of HT and higher rate of delisting for death or clinical deterioration at the highest urgent status, which appears to be mediated but not fully explained by calculated panel reactive antibody levels. Further investigation into the safety profile of temporary mechanical circulatory support devices in women is needed.
LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts
Authors: Su Chi-Ting , See Daniel H.W. , Huang Yue-Jhu , Jao Tzu-Ming , Liu Shin-Yun , Chou Chih-Yi , Lai Chun-Fu , Lin Wei-Chou , Wang Chih-Yuan , Huang Jenq-Wen , Hung Kuan-Yu 
Published: May 2023

Background:
As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI.

Methods:

LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry.
LTBP4
was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed.

Results:

LTBP4 expression was upregulated in the renal tissues of patients with AKI.
Ltbp4
-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells.

Conclusions:
Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.
Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection
Authors: Zhang Xi , Xu Heng , Yu Jizhang , Cui Jikai , Chen Zhang , Li Yuan , Niu Yuqing , Wang Song , Ran Shuan , Zou Yanqiang , Wu Jie , Xia Jiahong 
Published: May 2023

BACKGROUND:
PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, is not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in the immune regulation of infections and tumors. However, the role of PCSK9 and the liver in heart transplant rejection (HTR) and the underlying mechanisms remain unclear.

METHODS:

We assessed serum PCSK9 expression in both murine and human recipients during HTR and investigated the effect of PCSK9 ablation on HTR by using global knockout mice and a neutralizing antibody. Moreover, we performed multiorgan histological and transcriptome analyses, and multiomics and single-cell RNA-sequencing studies of the liver during HTR, as well. We further used hepatocyte-specific
Pcsk9
knockout mice to investigate whether the liver regulated HTR through PCSK9. Last, we explored the regulatory effect of the PCSK9/CD36 pathway on the phenotype and function of macrophages in vitro and in vivo.

RESULTS:
Here, we report that murine and human recipients have high serum PCSK9 levels during HTR. PCSK9 ablation prolonged cardiac allograft survival and attenuated the infiltration of inflammatory cells in the graft and the expansion of alloreactive T cells in the spleen. Next, we demonstrated that PCSK9 was mainly produced and significantly upregulated in the recipient liver, which also showed a series of signaling changes, including changes in the TNF-α (tumor necrosis factor α) and IFN-γ (interferon γ) signaling pathways and the bile acid and fatty acid metabolism pathways. We found mechanistically that TNF-α and IFN-γ synergistically promoted PCSK9 expression in hepatocytes through the transcription factor SREBP2 (sterol regulatory element binding protein 2). Moreover, in vitro and in vivo studies indicated that PCSK9 inhibited CD36 expression and fatty acid uptake by macrophages and strengthened the proinflammatory phenotype, which facilitated their ability to promote proliferation and IFN-γ production by donor-reactive T cells. Last, we found that the protective effect of PCSK9 ablation against HTR is dependent on the CD36 pathway in the recipient.

CONCLUSIONS:
This study reveals a novel mechanism for immune regulation by the liver through the PCSK9/CD36 pathway during HTR, which influences the phenotype and function of macrophages and suggests that the modulation of this pathway may be a potential therapeutic target to prevent HTR.
Midterm Outcomes in Patients With Aortic Stenosis Treated With Contemporary Balloon‐Expandable and Self‐Expanding Valves: Does Valve Size Have an Impact on Outcome?
Authors: Kalogeras Konstantinos , Jabbour Richard J. , Pracon Radoslaw , Kabir Tito , Shannon Joanne , Duncan Alison , Quarto Cesare , Heng Ee‐Ling , Rahbi Hazim , Oikonomou Evangelos , Katsianos Efstratios , Patel Niket , Chandra Navin , Vavuranakis Michael‐Andrew , Cadiz Suzane , Bougiakli Maria , Smith Robert D. , Siasos Gerasimos , Vavuranakis Manolis , Davies Simon , Dalby Miles , Panoulas Vasileios 
Published: May 2023

Background
No data currently exist comparing the contemporary iterations of balloon‐expandable (BE) Edwards SAPIEN 3/Ultra and the self‐expanding (SE) Medtronic Evolut PRO/R34 valves. The aim of the study was the comparison of these transcatheter heart valves with emphasis on patients with small aortic annulus.

Methods and Results

In this retrospective registry, periprocedural outcomes and midterm all‐cause mortality were analyzed. A total of 1673 patients (917 SE versus 756 BE) were followed up for a median of 15 months. A total of 194 patients died (11.6%) during follow‐up. SE and BE groups showed similar survival at 1 (92.6% versus 90.6%) and 3 (80.3% versus 85.2%) years (
P
log‐rank
=0.136).

Compared with the BE group, patients treated with the SE device had lower peak (16.3±8 mm Hg SE versus 21.9±8 mm Hg BE) and mean (8.8±5 mm Hg SE versus 11.5±5 mm Hg BE) gradients at discharge. Conversely, the BE group demonstrated lower rates of at least moderate paravalvular regurgitation postoperatively (5.6% versus 0.7% for SE and BE valves, respectively;
P
<0.001). In patients treated with small transcatheter heart valves (≤26 mm for SE and ≤23 mm for BE; N=284 for SE and N=260 for BE), survival was higher among patients treated with SE valves at both 1 (96.7% SE versus 92.1% BE) and 3 (91.8% SE versus 82.2% BE) years (
P
log‐rank
=0.042). In propensity‐matched patients treated with small transcatheter heart valve, there remained a trend for higher survival among the SE group at both 1 (97% SE versus 92.3% BE) and 3 years (91.8% SE versus 78.7% BE),
P
log‐rank
=0.096).

Conclusions
Real‐world comparison of the latest‐generation SE and BE devices demonstrated similar survival up to 3 years’ follow‐up. In patients with small transcatheter heart valves, there may be a trend for improved survival among those treated with SE valves.
Reducing Long‐Term Mortality Post Transcatheter Aortic Valve Replacement Requires Systemic Differentiation of Patient‐Specific Coronary Hemodynamics
Authors: Khodaei Seyedvahid , Garber Louis , Abdelkhalek Mohamed , Maftoon Nima , Emadi Ali , Keshavarz‐Motamed Zahra 
Published: May 2023

Background
Despite the proven benefits of transcatheter aortic valve replacement (TAVR) and its recent expansion toward the whole risk spectrum, coronary artery disease is present in more than half of the candidates for TAVR. Many previous studies do not focus on the longer‐term impact of TAVR on coronary arteries, and hemodynamic changes to the circulatory system in response to the anatomical changes caused by TAVR are not fully understood.

Methods and Results
We developed a multiscale patient‐specific computational framework to examine the effect of TAVR on coronary and cardiac hemodynamics noninvasively. Based on our findings, TAVR might have an adverse impact on coronary hemodynamics due to the lack of sufficient coronary blood flow during diastole phase (eg, maximum coronary flow rate reduced by 8.98%, 16.83%, and 22.73% in the left anterior descending, left circumflex coronary artery, and right coronary artery, respectively [N=31]). Moreover, TAVR may increase the left ventricle workload (eg, left ventricle workload increased by 2.52% [N=31]) and decrease the coronary wall shear stress (eg, maximum time averaged wall shear stress reduced by 9.47%, 7.75%, 6.94%, 8.07%, and 6.28% for bifurcation, left main coronary artery, left anterior descending, left circumflex coronary artery, and right coronary artery branches, respectively).

Conclusions
The transvalvular pressure gradient relief after TAVR might not result in coronary flow improvement and reduced cardiac load. Optimal revascularization strategy pre‐TAVR and progression of coronary artery disease after TAVR could be determined by noninvasive personalized computational modeling.
A new perspective on the molecular dating of the brown trout complex with an extended phylogeographic information on the species in Serbia
Authors: Veličković Tijana , Snoj Aleš , Simić Vladica , Šanda Radek , Vukić Jasna , Barcytė Dovilė , Stanković David , Marić Saša 
Published: May 2023

Abstract
To elucidate the historical biogeography of a species, the patterns of population divergence must be understood, and the evolutionary history of the species must be accurately known. For brown trout (Salmo trutta complex), estimating divergence times remains a challenge due to the lack of well-defined time calibration points and insufficient phylogeographic coverage in previous studies. The present work aims to improve molecular dating of mitochondrial control region sequences by using a multicalibration framework based on the latest paleogeological evidence for dating the origin of Lake Ohrid and two available Salmo fossils, including the overlooked Salmo immigratus. Our results clearly show that, contrary to common belief, the major divisions within the brown trout occurred in the Late Pliocene, not the Pleistocene. The Pliocene origin suggests that the brown trout lineages did not form because of geo(hydro)morphological changes during glaciation cycles but may be the result of orogeny and drainage evolution. In addition, increased sampling, particularly in Serbia, led to the identification of a new haplogroup (da-int) occupying an intermediate position with respect to da-es and da-bs haplogroups. While the control region can delineate brown trout lineages, its phylogenetic resolution is limited, so even extensive sampling could not further resolve the lineage level polytomies.
Estrogen modulation of cortical spreading depression
Authors: Kudo Chiho , Harriott Andrea M. , Moskowitz Michael A. , Waeber Christian , Ayata Cenk 
Published: May 2023

AbstractBackground and aimsCortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD.MethodsTo determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography.ResultsThe CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAAreceptor binding density after estrogen treatment and withdrawal.ConclusionsThese data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura.