bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies
Authors: Nash Jennifer , Meah Mohammed N. , Whittington Beth , Debono Samuel , Raftis Jennifer , Miller Mark R. , Sorbie Andrew , Mills Nicholas L. , Nespoux Josselin , Bruce Lorraine , Duffin Rodger , Dhaun Neeraj , Brittan Mairi , Chao Longfei , Merali Samira , Kim Minji , Wang Zhaoqing , Zhang Yue , Jin Shiqiang , Wang Beqing , Kozinn Marc , Newby David E. 
Published: February 2024

BACKGROUND:
BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy.

METHODS:
Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants.

RESULTS:

BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)–induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (
P
≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (−21%;
P
=0.001) and in patients receiving ticagrelor alone (−28%;
P
=0.001), aspirin alone (−23%;
P
=0.018), or both in combination (−24%;
P
≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP–induced platelet responses (
P
≤0.001 for all) and total thrombus area under high shear stress conditions (
P
≤0.01 for all).

CONCLUSIONS:
PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05093790.
Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes
Authors: Sun Xiaojing , Lee Hon-Chi , Lu Tong 
Published: February 2024

BACKGROUND:

Vascular large conductance Ca
2+
-activated K
+
(BK) channel, composed of the α-subunit (BK-α) and the β1-subunit (BK-β1), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown.

METHODS:
The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis.

RESULTS:

Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-α mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-α subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-β1 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-α/BK-β1 channel current density. Additionally,
Sorbs2
is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of
Sorbs2
and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that
Sorbs2
knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca
2+
-sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice.

CONCLUSIONS:

Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of
Sorbs2
manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.
A Novel Necroptosis-Related Signature Can Predict Prognosis and Chemotherapy Sensitivity in Multiple Myeloma
Authors: Jiang Jun-Yao , Yao Fang-Yi , Liu Jing , Wang Xin-Lu , Huang Bo , Zhong Fang-Min , Wang Xiao-Zhong 
Published: February 2024

Background Necroptosis is an inflammatory cell death mode, and its association with multiple myeloma (MM) remains unclear. Methods This prospective study first analyzed the association between necroptosis-related signature as well as prognosis and chemotherapy sensitivity in MM using the necroptosis score. Consensus clustering was used to identify necroptosis-related molecular clusters. Least absolute shrinkage and selection operator analysis and multivariate Cox regression analysis were performed to establish the prognostic model of necroptosis-related genes (NRGs). Results A high necroptosis score was associated with poor prognosis and abundant immune infiltration. Two molecular clusters (clusters A and B) significantly differed in terms of prognosis and tumor microenvironment. Cluster B had a worse prognosis and higher tumor marker pathway activity than cluster A. The risk score model based on four NRGs can accurately predict the prognosis of patients with MM, which was validated in two validation cohorts. Receiver operating characteristic curve analysis showed that the area under the curves of the risk score in predicting the 1-, 3-, and 5-year survival rates were 0.710, 0.758, and 0.834, respectively. Further, the activity of pathways related to proliferation and genetic regulation in the high-risk group significantly increased. The drug prediction results showed that the low-risk score group was more sensitive to bortezomib, cytarabine, and doxorubicin than the high-risk score group. Meanwhile, the high-risk score group was more sensitive to lenalidomide and vinblastine than the low-risk score group. Finally, the upregulation of model genes CHMP1A, FAS, JAK3, and HSP90AA1 in clinical samples collected from patients with MM was validated via real-time polymerase chain reaction. Conclusion A systematic analysis of NRGs can help identify potential necroptosis-related mechanisms and provide novel biomarkers for MM prognosis prediction, tumor microenvironment evaluation, and personalized treatment planning.
Generic model to unravel the deeper insights of viral infections: an empirical application of evolutionary graph coloring in computational network biology
Authors: Kole Arnab , Bag Arup Kumar , Pal Anindya Jyoti , De Debashis 
Published: February 2024

Abstract
Purpose
Graph coloring approach has emerged as a valuable problem-solving tool for both theoretical and practical aspects across various scientific disciplines, including biology. In this study, we demonstrate the graph coloring’s effectiveness in computational network biology, more precisely in analyzing protein–protein interaction (PPI) networks to gain insights about the viral infections and its consequences on human health. Accordingly, we propose a generic model that can highlight important hub proteins of virus-associated disease manifestations, changes in disease-associated biological pathways, potential drug targets and respective drugs. We test our model on SARS-CoV-2 infection, a highly transmissible virus responsible for the COVID-19 pandemic. The pandemic took significant human lives, causing severe respiratory illnesses and exhibiting various symptoms ranging from fever and cough to gastrointestinal, cardiac, renal, neurological, and other manifestations.

Methods
To investigate the underlying mechanisms of SARS-CoV-2 infection-induced dysregulation of human pathobiology, we construct a two-level PPI network and employed a differential evolution-based graph coloring (DEGCP) algorithm to identify critical hub proteins that might serve as potential targets for resolving the associated issues. Initially, we concentrate on the direct human interactors of SARS-CoV-2 proteins to construct the first-level PPI network and subsequently applied the DEGCP algorithm to identify essential hub proteins within this network. We then build a second-level PPI network by incorporating the next-level human interactors of the first-level hub proteins and use the DEGCP algorithm to predict the second level of hub proteins.

Results
We first identify the potential crucial hub proteins associated with SARS-CoV-2 infection at different levels. Through comprehensive analysis, we then investigate the cellular localization, interactions with other viral families, involvement in biological pathways and processes, functional attributes, gene regulation capabilities as transcription factors, and their associations with disease-associated symptoms of these identified hub proteins. Our findings highlight the significance of these hub proteins and their intricate connections with disease pathophysiology. Furthermore, we predict potential drug targets among the hub proteins and identify specific drugs that hold promise in preventing or treating SARS-CoV-2 infection and its consequences.

Conclusion
Our generic model demonstrates the effectiveness of DEGCP algorithm in analyzing biological PPI networks, provides valuable insights into disease biology, and offers a basis for developing novel therapeutic strategies for other viral infections that may cause future pandemic.
In silico prediction of the metabolism of Blastocrithidia nonstop, a trypanosomatid with non-canonical genetic code
Authors: Opperdoes Fred R. , Záhonová Kristína , Škodová-Sveráková Ingrid , Bučková Barbora , Chmelová Ľubomíra , Lukeš Julius , Yurchenko Vyacheslav 
Published: February 2024

Abstract
Background
Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of Blastocrithidia nonstop, a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids.

Results
We in silico predicted the metabolism of B. nonstop and compared it with that of the well-studied human parasites Trypanosoma brucei and Leishmania major. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes.

Conclusions
In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of B. nonstop is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of B. nonstop has no significant repercussions on the metabolism of this flagellate.
Genome-wide identification, structural characterization and gene expression analysis of the WRKY transcription factor family in pea (Pisum sativum L.)
Authors: Xiong Ruiqi , Peng Zhonghua , Zhou Hui , Xue Guoxing , He Ailing , Yao Xin , Weng Wenfeng , Wu Weijiao , Ma Chao , Bai Qing , Ruan Jingjun 
Published: February 2024

Abstract
Background
The WRKY gene family is one of the largest families of transcription factors in higher plants, and WRKY transcription factors play important roles in plant growth and development as well as in response to abiotic stresses; however, the WRKY gene family in pea has not been systematically reported.

Results
In this study, 89 pea WRKY genes were identified and named according to the random distribution of PsWRKY genes on seven chromosomes. The gene family was found to have nine pairs of tandem duplicates and 19 pairs of segment duplicates. Phylogenetic analyses of the PsWRKY and 60 Arabidopsis WRKY proteins were performed to determine their homology, and the PsWRKYs were classified into seven subfamilies. Analysis of the physicochemical properties, motif composition, and gene structure of pea WRKYs revealed significant differences in the physicochemical properties within the PsWRKY family; however, their gene structure and protein-conserved motifs were highly conserved among the subfamilies. To further investigate the evolutionary relationships of the PsWRKY family, we constructed comparative syntenic maps of pea with representative monocotyledonous and dicotyledonous plants and found that it was most recently homologous to the dicotyledonous WRKY gene families. Cis-acting element analysis of PsWRKY genes revealed that this gene family can respond to hormones, such as abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin (GA), methyl jasmonate (MeJA), and salicylic acid (SA). Further analysis of the expression of 14 PsWRKY genes from different subfamilies in different tissues and fruit developmental stages, as well as under five different hormone treatments, revealed differences in their expression patterns in the different tissues and fruit developmental stages, as well as under hormone treatments, suggesting that PsWRKY genes may have different physiological functions and respond to hormones.

Conclusions
In this study, we systematically identified WRKY genes in pea for the first time and further investigated their physicochemical properties, evolution, and expression patterns, providing a theoretical basis for future studies on the functional characterization of pea WRKY genes during plant growth and development.
Frailty efficacy as a predictor of clinical and cognitive complications in patients undergoing coronary artery bypass grafting: a prospective cohort study
Authors: Bakhtiari Mehrnoosh , Shaker Farhad , Shirmard Fatemeh Ojaghi , Jalali Arash , Vakili-Basir Ahmad , Balabandian Mohammad , Khamene Sima Shamshiri , Mohammadkhawajah Izat , Shafiee Akbar , Badrkhahan Seyedeh Zahra , Hosseini Kaveh 
Published: February 2024

Abstract
Background
Frailty is proposed as a predictor of outcomes in patients undergoing major surgeries, although data on the association of frailty and coronary artery bypass grafting (CABG) are lacking. We assessed the association between frailty and cognitive and clinical complications following CABG.

Methods
This prospective study included patients aged over 60 years undergoing elective CABG at Tehran Heart Center from 2020 to 2022. Baseline and three-month follow-up data on frailty using the Frail scale and clinical Frail scale, functional status using the Lawton Instrumental Activities of Daily Living Scale (IADL), cognitive function by Montreal Cognitive Assessment (MoCA), and depression by the Geriatric Depression Scale (GDS) were obtained. The incidence of adverse outcomes was investigated at the three-month follow-up. Outcomes between frail and non-frail groups were compared utilizing T-tests and Mann-Whitney U tests, as appropriate.

Results
We included 170 patients with a median age of 66 ± 4 years (75.3% male). Of these, 58 cases were classified as frail, and 112 individuals were non-frail, preoperatively. Frail patients demonstrated significantly worse baseline MOCA scores (21.08 vs. 22.41, P = 0.045), GDS (2.00 vs. 1.00, P = 0.009), and Lawton IADL (8.00 vs. 6.00, P < 0.001) compared to non-frail. According to 3-month follow-up data, postoperative MOCA and GDS scores were comparable between the two groups, while Lawton IADL (8.00 vs. 6.00, P < 0.001) was significantly lower in frail cases. A significantly higher rate of readmission (1.8% vs. 12.1%), sepsis (7.1% vs. 19.0%), as well as a higher Euroscore (1.5 vs. 1.9), was observed in the frail group. A mildly significantly more extended ICU stay (6.00 vs. 5.00, p = 0.051) was shown in the frail patient.

Conclusion
Frailty showed a significant association with a worse preoperative independence level, cognitive function, and depression status, as well as increased postoperative complications.
The pertinence of gastric cancer and interleukin 10–819 single nucleotide polymorphisms: a meta-analysis and systematic review
Authors: Mao Qianqian , Liu Yanwen , Chen Xi , Liu Cheng Jiang 
Published: February 2024

Abstract
Purpose
Cytokines regulate the interaction between the immune system and malignant tumors. Among them, interleukin-10 (IL-10) is a multifunctional anti-inflammatory cytokine mainly produced by immune cells. The correlation between gastric cancer and T/C single nucleotide polymorphism (SNP) of interleukin-10 (IL-10) promoter−819(rs1800871)was opaque and remained to be determined. We aim to explore the pertinence of gastric cancer and SNP of interleukin 10–819 by meta-analysis via five statistical models.

Methods
Databases including PubMed, Cochrane Library, Embase, the Scopus, and Google Scholars were comprehensively retrieved for the eligible studies on the related topic from inception to March 2022. Odds ratios (ORs) were generated for dichotomous variants by meta-analysis in each model via STATA 17.0 MP. The statistical models comprised recessive model, over-dominant model, allele model, co-dominant model and dominant model. Subgroup analysis was performed to investigate the difference across races as well as the source of heterogeneity if necessary.

Results
Eventually a total of 15 articles reporting 7779 patients were enrolled in our study. There were 2383 patients and 5396 controls, collectively. There was no correlation between gastric cancer and IL-10 819 in recessive model, co-dominant model or dominant model, and subgroup analysis showed that Asian, Latin American and Caucasian had no correlation with the risk of gastric cancer. In the allelic model, there was significant correlation between gastric cancer and IL-10 819 (OR = 3.96%, 95%CI: 3.28 to 3.78). In the over-dominant model, there is no correlation between gastric cancer and IL-10 819, but subgroup analysis uncovered significant vulnerability of Asian people with regard to gastric cancer.

Conclusions
In our study, both Asians, Latin Americans, and Europeans showed an increased risk of gastric cancer in the allelic model, whereas only Asians showed significant susceptibility in the super dominant model. Of course, more large cohort studies are needed to confirm our results.
Safety and feasibility of minimally invasive gastrectomy following preoperative chemotherapy for highly advanced gastric cancer
Authors: Tanaka Tsuyoshi , Suda Koichi , Shibasaki Susumu , Serizawa Akiko , Akimoto Shingo , Nakauchi Masaya , Matsuoka Hiroshi , Inaba Kazuki , Uyama Ichiro 
Published: February 2024

Abstract
Background
This study aimed to determine the safety and feasibility of minimally invasive gastrectomy in patients who underwent preoperative chemotherapy for highly advanced gastric cancer.

Methods
Preoperative chemotherapy was indicated for patients with advanced large tumors (≥ cT3 and ≥ 5 cm) and/or bulky node metastasis (≥ 3 cm × 1 or ≥ 1.5 cm × 2). Between January 2009 and March 2022, 150 patients underwent preoperative chemotherapy followed by gastrectomy with R0 resection, including conversion surgery (robotic, 62; laparoscopic, 88). The outcomes of these patients were retrospectively examined.

Results
Among them, 41 and 47 patients had stage IV disease and underwent splenectomy, respectively. Regarding operative outcomes, operative time was 475 min, blood loss was 72 g, morbidity (grade ≥ 3a) rate was 12%, local complication rate was 10.7%, and postoperative hospital stay was 14 days (Interquartile range: 11–18 days). Fifty patients (33.3%) achieved grade ≥ 2 histological responses. Regarding resection types, total/proximal gastrectomy plus splenectomy (29.8%) was associated with significantly higher morbidity than other types (distal gastrectomy, 3.2%; total/proximal gastrectomy, 4.9%; P < 0.001). Specifically, among splenectomy cases, the rate of postoperative complications associated with the laparoscopic approach was significantly higher than that associated with the robotic approach (40.0% vs. 0%, P = 0.009). In the multivariate analysis, splenectomy was an independent risk factor for postoperative complications [odds ratio, 8.574; 95% confidence interval (CI), 2.584–28.443; P < 0.001].

Conclusions
Minimally invasive gastrectomy following preoperative chemotherapy was feasible and safe for patients with highly advanced gastric cancer. Robotic gastrectomy may improve surgical safety, particularly in the case of total/proximal gastrectomy combined with splenectomy.
Utility and predictive value of the CRAFITY score in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus tyrosine kinase inhibitors and PD-1 inhibitor
Authors: Zhang Lijie , Sun Tao , Sun Bo , Zhang Kailu , Zheng Yuting , Li Na , Chen Lei , Zheng Chuansheng , Liang Bin , Shi Heshui 
Published: February 2024

Abstract
Background
The prognostic significance of the CRAFITY score (CRP and AFP in ImmunoTherapY) has been demonstrated in hepatocellular carcinoma (HCC) patients receiving immunotherapy. The purpose of this study was to investigate the utility and the predictive value of CRAFITY score in HCC after transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) and immunotherapy.

Materials and methods
Data from patients with advanced HCC treated with TACE plus TKIs and PD-1 inhibitor from January 2019 to June 2022 were collected and analyzed retrospectively. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. Patients were divided into three groups according to their CRAFITY score (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). The differences in overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared among the three groups. Tumor response was evaluated at 3, 6 and 12 months after the first combination treatment. Risk factors for OS and PFS were assessed.

Results
A total of 70 patients were included. The patients were assigned CRAFITY scores of 0 points (CRAFITY-low, n = 25 [35.71%]), 1 point (CRAFITY-intermediate, n = 29 [41.42%]), and 2 points (CRAFITY-high, n = 16 [22.81%]). Multivariate analysis showed that lower CRAFITY score was an independent factor for the improved OS (P =.045) and PFS (P <.001). TACE session was also associated with the OS (P =.048) in the multivariate analysis. The CRAFITY-low cohort achieved a higher objective response rate (ORR) at the 3-month evaluation of tumor response. However, there was no significant difference in ORR and disease control rate (DCR) observed at the 6-month follow-up. DCR showed a statistically significant difference among three groups during the 12-month follow-up period. The percentage of patients with protein urea was highest in the CRAFITY-high group. No significance differences were observed in grade ≥ 3 AEs in three groups.

Conclusion
The CRAFITY score is simple and could be useful for predicting treatment outcomes, tumor response and AEs of the HCC patients receiving TACE plus TKIs and PD-1 inhibitor therapy.