bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interplay of TP53 allelic state, blast count, and complex karyotype on survival of patients with AML and MDS
Authors: Stengel Anna , Meggendorfer Manja , Walter Wencke , Baer Constance , Nadarajah Niroshan , Hutter Stephan , Kern Wolfgang , Haferlach Torsten , Haferlach Claudia 
Published: July 2023

Abstract
Several clinical and genetic factors impact overall survival (OS) in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), including complex karyotype (CK), TP53 allelic state, and blast count. We analyzed the interplay of these factors by performing Cox regression analysis and by determining the frequency of TP53 single-hit (sh) and double-hit (dh) events and OS in MDS (n = 747) with &lt;5% blasts, with ≥5% but &lt;10% blasts, and ≥10% but &lt;20% blasts and AML (n = 772). MDS with &lt;5% blasts showed the best outcome, followed by with ≥5% but &lt;10% blasts, and ≥10% but &lt;20% blasts, and AML (median OS: 75, 54, 27, and 18 months, respectively). The same hierarchy was observed when each subgroup was divided into TP53sh, TP53dh, and without TP53 alterations (alt), revealing a dismal outcome of TP53dh in all subgroups (17, 10, 8, and 1 month[s], respectively). MDS with &lt;5% blasts differed from the other subgroups by showing predominantly TP53sh (76% of TP53alt cases), and by an independent adverse impact of CK on OS (hazard ratio, 5.2; P &lt; .001). The remaining subgroups displayed many similarities, with TP53dh found at high frequencies (67%, 91%, and 71%, respectively) and only TP53alt but not CK independently influencing OS, and TP53dh showing the strongest influence. When the total cohort was split based on TP53 state, only the blast count and not CK had an independent adverse impact on OS in all subgroups. Thus, TP53dh is the strongest prognostic factor, further supporting its integration into risk stratification guidelines and classification as a separate entity. However, the blast count also influences OS independent of TP53 state, whereas CK plays a minor prognostic role.
Differential effects of two phosphodiesterase 4 inhibitors against lipopolysaccharide-induced neuroinflammation in mice
Authors: Kang Dong Ho , Ahn Sunjoo , Chae Jung Woo , Song Jin Sook 
Published: July 2023

Abstract
Background
Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and zatolmilast, against lipopolysaccharide-induced neuroinflammation.

Results
In BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1β (IL-1β), and IL-6 levels in plasma and brain tissues. By contrast, zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and zatolmilast were high (> 23 × 10–6 cm/s) and moderate (3.72–7.18 × 10–6 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2–2.3 h and terminal half-lives of 7–20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively.

Conclusions
These findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.
Identifying discrepancies between clinical practice and evidence-based guideline in recurrent pregnancy loss care, a tool for clinical guideline implementation
Authors: Youssef A. , Lashley E.E.L.O. , Vermeulen N. , van der Hoorn M.L.P. 
Published: July 2023

Abstract
Background
Practice variation in recurrent pregnancy loss (RPL) care is common. International guidelines vary in their recommendations for the management of RPL couples, which could lead to an increase of cross border reproductive care. Currently, the Dutch RPL guideline is being adapted from the European Society for Human Reproduction and Embryology (ESHRE) guideline. We aim to identify discrepancies between RPL guidelines and RPL practice. These discrepancies could be considered in the development of a new guideline and implementation strategies to promote adherence to new recommendations.

Methods
A nationwide survey on the management of RPL patients was conducted across all 107 hospital-based obstetrics and gynaecology practices in the Netherlands. The survey was sent via the Dutch Society for Obstetricians and Gynaecologists to all affiliated clinicians. The questionnaire consisted of 36 questions divided in four sections: clinician’s demographics, RPL definition, investigations and therapy. The data were compared to the recommendations given by the Dutch national guideline and the most recent guideline of the ESHRE.

Results
All hospital-based practices (100%; n = 107) filled in the online questionnaire. The majority of respondents defined RPL similarly, as two or more pregnancy losses (87.4%), not obligatory consecutive (93.1%). More than half of respondents routinely perform thrombophilia screening ( 58%), although not advised by the ESHRE, while thyroid function (57%), thyroid auto-immunity (27%) and β2-glycoprotein antibodies (42%) in the context of antiphospholipid syndrome (APS) are recommended but investigated less often. Regarding parental karyotyping, 20% of respondents stated they always perform parental karyotyping, without prior risk assessment. because of RPL. Treatment for hereditary thrombophilia was frequently (43.8% (n = 137)) prescribed although not recommended. And finally, a considerable part (12–16%) of respondents prescribe medication in case of unexplained RPL.

Conclusion
While many clinicians perform investigations recommended by the ESHRE, there is a considerable variation of RPL practice in the Netherlands. We identified discrepancies between RPL guidelines and RPL practice, providing possibilities to focus on multifaceted implementation strategies, such as educational intervention, local consensus processes and auditing and feedback. This will improve the quality of care provided to RPL patients and may diminish the necessity felt by patients to turn to multiple opinions or cross border reproductive care.
Machine learning for prediction of asthma exacerbations among asthmatic patients: a systematic review and meta-analysis
Authors: Xiong Shiqiu , Chen Wei , Jia Xinyu , Jia Yang , Liu Chuanhe 
Published: July 2023

Abstract
Background
Asthma exacerbations reduce the patient’s quality of life and are also responsible for significant disease burdens and economic costs. Machine learning (ML)-based prediction models have been increasingly developed to predict asthma exacerbations in recent years. This systematic review and meta-analysis aimed to identify the prediction performance of ML-based prediction models for asthma exacerbations and address the uncertainty of whether modern ML methods could become an alternative option to predict asthma exacerbations.

Methods
PubMed, Cochrane Library, EMBASE, and Web of Science were searched for studies published up to December 15, 2022. Studies that applied ML methods to develop prediction models for asthma exacerbations among asthmatic patients older than five years and were published in English were eligible. The prediction model risk of bias assessment tool (PROBAST) was utilized to estimate the risk of bias and the applicability of included studies. Stata software (version 15.0) was used for the random effects meta-analysis of performance measures. Subgroup analyses stratified by ML methods, sample size, age groups, and outcome definitions were conducted.

Results
Eleven studies, including 23 prediction models, were identified. Most of the studies were published in recent three years. Logistic regression, boosting, and random forest were the most used ML methods. The most common important predictors were systemic steroid use, short-acting beta2-agonists, emergency department visit, age, and exacerbation history. The overall pooled area under the curve of the receiver operating characteristics (AUROC) of 11 studies (23 prediction models) was 0.80 (95% CI 0.77–0.83). Subgroup analysis based on different ML models showed that boosting method achieved the best performance, with an overall pooled AUROC of 0.84 (95% CI 0.81–0.87).

Conclusion
This study identified that ML was the potential tool to achieve great performance in predicting asthma exacerbations. However, the methodology within these models was heterogeneous. Future studies should focus on improving the generalization ability and practicability, thus driving the application of these models in clinical practice.
Development of a chemically defined medium for Paenibacillus polymyxa by parallel online monitoring of the respiration activity in microtiter plates
Authors: Goldmanns Jennifer , Röhling Georg Andreas , Lipa Marie Kristine , Scholand Theresa , Deitert Alexander , May Tobias , Haas Evangeline Priya , Boy Matthias , Herold Andrea , Büchs Jochen 
Published: July 2023

Abstract
Background
One critical parameter in microbial cultivations is the composition of the cultivation medium. Nowadays, the application of chemically defined media increases, due to a more defined and reproducible fermentation performance than in complex media. In order, to improve cost-effectiveness of fermentation processes using chemically defined media, the media should not contain nutrients in large excess. Additionally, to obtain high product yields, the nutrient concentrations should not be limiting. Therefore, efficient medium optimization techniques are required which adapt medium compositions to the specific nutrient requirements of microorganisms.

Results
Since most Paenibacillus cultivation protocols so far described in literature are based on complex ingredients, in this study, a chemically defined medium for an industrially relevant Paenibacillus polymyxa strain was developed. A recently reported method, which combines a systematic experimental procedure in combination with online monitoring of the respiration activity, was applied and extended to identify growth limitations for Paenibacillus polymyxa. All cultivations were performed in microtiter plates. By systematically increasing the concentrations of different nutrient groups, nicotinic acid was identified as a growth-limiting component. Additionally, an insufficient buffer capacity was observed. After optimizing the growth in the chemically defined medium, the medium components were systematically reduced to contain only nutrients relevant for growth. Vitamins were reduced to nicotinic acid and biotin, and amino acids to methionine, histidine, proline, arginine, and glutamate. Nucleobases/-sides could be completely left out of the medium. Finally, the cultivation in the reduced medium was reproduced in a laboratory fermenter.

Conclusion
In this study, a reliable and time-efficient high-throughput methodology was extended to investigate limitations in chemically defined media. The interpretation of online measured respiration activities agreed well with the growth performance of samples measured in parallel via offline analyses. Furthermore, the cultivation in microtiter plates was validated in a laboratory fermenter. The results underline the benefits of online monitoring of the respiration activity already in the early stages of process development, to avoid limitations of medium components, oxygen limitation and pH inhibition during the scale-up.
The effect of low-dose aspirin on aspirin triggered lipoxin, interleukin 1 beta, and prostaglandin E2 levels in periapical fluid: a double-blind randomized clinical trial
Authors: Khoshbin Elham , Salehi Razieh , Behroozi Rooholah , Sadr Soroush , Zamani Alireza , Farhadian Maryam , Karkehabadi Hamed 
Published: July 2023

AbstractBackgroundThe role of pro-resolving mediators in inflammation is a new concern in research. The effect of low-dose aspirin on production of a special kind of these mediators named aspirin triggered lipoxin (ATL) has been studied on different tissues. This randomized clinical trial evaluated the effect of low-dose aspirin on ATL and pro-inflammatory mediators’ level in periapical fluid of necrotic teeth with large lesions.MethodsTwenty-four patients with necrotic pulp and periapical lesion were randomly assigned to low-dose aspirin and placebo groups. In the first appointment, canals were shaped up to F3 size and #40 K-file and cleaned with 10 milliliters 2.5% sodium hypochlorite and 17% Ethylenediaminetetraacetic acid. Periapical fluid was sampled by a paper cone. The tooth was temporized without any intracanal medication. Tablets were administered for 7 days, then the teeth were re-opened and the sampling were repeated. Interleukin-1 beta (IL-1β), prostaglandin E2 (PGE2) and ATL were analyzed by enzyme-linked immunosorbent assay. Data were analyzed with paired t-test using SPSS statistical software, version 21 (α = 0.05).ResultsA significant reduction in PGE2 and IL-1β was noted in the aspirin-treated group while an increase in ATL was observed (P < 0.001). There was no significant difference in the mediator scores before and after in the placebo-treated group (P > 0.05).ConclusionLow-dose aspirin can influence the inflammatory process by reducing pro-inflammatory mediators such as PGE2 and IL-1β, as well as increasing the pro-resolving mediators such as ATL.Trial registrationIRCT20191211045702N1.
GEMIN4, a potential therapeutic targets for patients with basal-like subtype breast cancer
Authors: Wu Liang , Zhang Yue , Zheng Chunlei , Zhao Fuqiang , Lin Yan 
Published: July 2023

AbstractBackgroundBasal-like breast cancer (BLBC) takes up about 10–20% of all breast cancer(BC), what’s more, BLBC has the lowest survival rate among all BC subtypes because of lacks of efficient treatment methods. We aimed to explore the molecules that can be used as diagnostic maker for BLBC at early stage and provide optimized treatment strategies for BLBC patients in this study.MethodsApply weighted gene co-expression network analysis (WGCNA) to identify gene modules related to BLBC;The functional enrichment of candidate genes related to BLBC in the red module of Go data package and KEGG analysis;Overlapping cross analysis of URGs and WGCNA to identify candidate genes in each BC subtype;Divide BCBL patients into high-risk and low-risk groups, and analyze the two groups of overall survival (OS) and relapse free survival (RFS);Screening of GEMIN4 dependent cell lines; QRT PCR was used to verify the expression of GEMIN4 transfected with siRNA; CCK8 was used to determine the effect of GEMIN4 on cell viability; Positive cell count detected by BrdU staining;GO and KEGG enrichment analysis of GEMIN4.ResultsThe "red module" has the highest correlation with BLBC, with 913 promising candidate genes identified from the red module;913 red module candidate genes related to BLBC participated in multiple GO terms, and KEGG enrichment analysis results mainly enriched in estrogen signaling pathways and pathways in cancer;There are 386 overlapping candidate genes among the 913 "red module" genes identified by 1893 common URG and WGCNA;In BLBC patients, 9 highly expressed genes are associated with OS. Five highly expressed genes are associated with RFS. Kaplan Meier survival analysis suggests that high GEMIN4 expression levels are associated with poor prognosis in BLBC patients;The GEMIN4 gene dependency score in HCC1143 and CAL120 cell lines is negative and low; Si-GEMIN4-1 can significantly reduce the mRNA expression of GEMIN4; Si-GEMIN4 can inhibit cell viability; Si-GEMIN4 can reduce the number of positive cells;GO enrichment analysis showed that GEMIN4 is associated with DNA metabolism processes and adenylate binding; KEGG pathway enrichment analysis shows that GEMIN4 is related to ribosome biogenesis in eukaryotes.ConclusionWe hypothesized thatGEMIN4may be the potential target for the treatment of BLBC.
Functional polymorphism in miR-208 is associated with increased risk for ischemic stroke
Authors: Liu Chao , Luo Yan-Ping , Chen Jie , Weng Yin-Hua , Lan Yan , Liu Hong-Bo 
Published: July 2023

Abstract
Background
The miR-208 gene is one of the microRNAs now under active studies, and has been found to play significant roles in an array of cardiovascular diseases. Nevertheless, until now, no studies have examined the relationship between the susceptibility to ischemic stroke (IS) and genetic variations in miR-208. This study explored the association between the miR-208 polymorphisms (rs178642, rs8022522, and rs12894524) and the risk of IS.

Methods
A total of 205 cases of IS and 211 control subjects were included. The SNPscans genotyping test was employed to determine the genotypes of the three polymorphisms.

Results
Significant correlation was observed between rs8022522 polymorphism and risk of IS on the basis of analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 2.159, 95% CI: 1.052–4.430, P = 0. 036; AA vs. GG: adjusted OR = 5.154, 95% CI: 1.123–23.660, P = 0.035; dominant model: adjusted OR = 1.746, 95% CI, 1.075–2.838, P = 0.025; G vs. A: adjusted OR = 2.451, 95% CI: 1.374–4.370, P = 0.002).

Conclusions
The rs8022522 polymorphism of the miR-208 gene is significantly associated with an elevated risk of ischemic stroke in Chinese.
Generalisation of genomic findings and applications of polygenic risk scores
Authors: Corpas Manuel , Fatumo Segun 
Published: July 2023

AbstractPolygenic Risk Scores (PRS) (also known as polygenic scores, genetic risk scores or polygenic indexes) capture genetic contributions of a multitude of markers that characterise complex traits. Although their likely application to precision medicine remains to be established, promising advances have included their ability to stratify high risk individuals and targeted screening interventions. Current PRS have been mostly optimised for individuals of Northern European ancestries. If PRS are to become widespread as a tool for healthcare applications, more diverse populations and greater capacity for derived interventions need to be accomplished. In this editorial we aim to attract submissions from the research community that highlight current challenges in development of PRS applications at scale. We also welcome manuscripts that delve into the ethical, social and legal implications that the implementation of PRS may generate.
Biotransformation of triterpenoid ganoderic acids from exogenous diterpene dihydrotanshinone I in the cultures of Ganoderma sessile
Authors: Wang Xinwei , Wu Haibo , Wong Ka Hong , Wang Yixuan , Chen Baixiong , Feng Kun 
Published: July 2023

Abstract
Background
Triterpenoids have shown a wide range of biological activities including antitumor and antiviral effects. Typically, triterpenes are synthesized through the mevalonate pathway and are extracted from natural plants and fungi. In this work, triterpenoids, ganoderic acids (GAs) were discovered to be produced via biotransformation of a diterpene, 15,16-dihydrotanshinone I (DHT) in the liquid cultured Ganoderma sessile mycelium.

Results
Firstly, the biotransformation products, two rare GAs were isolated and purified by column chromatography, and characterized using HR-ESI-MS spectrometry and NMR spectrometry. The two compounds were Lanosta-7,9(11),24-trien-15α,22,β-diacetoxy-3β-hydroxy-26-oic acid (LTHA) and Lanosta-7,9(11),24-trien-15α,22,β-diacetoxy-3β-carbonyl-26-oic acid (LTCA). Then, transcriptome and proteome technologies were employed to measure the expression of mRNA and protein, which further confirmed that triterpenoid GAs could be transformed from exogenous diterpenoid DHT. At the molecular level, we proposed a hypothesis of the mechanism by which DHT converted to GAs in G. sessile mycelium, and the possible genes involved in biotransformation were verified by RT-qPCR.

Conclusions
Two rare GAs were obtained and characterized. A biosynthetic pathway of GAs from DHT was proposed. Although the synthetic route was not confirmed, this study provided important insights into omics resources and candidate genes for studying the biotransformation of diterpenes into triterpenes.
Erdheim-Chester disease with bilateral orbital masses and multi-systemic symptoms: two case reports
Authors: Qiao JunYi , Ma Ruixin , Peng Xiaolin , He Weimin 
Published: July 2023

Abstract
Background
Erdheim–Chester disease (ECD) is a rare histiocytic disorder characterized by multisystem xanthogranulomatous infiltration by lipid-laden histiocytes. We report two cases of ECD involving the orbit and describe their clinicopathologic factors, treatments, and prognosis. One was a rare case of ECD complicated with primary thrombocytosis.

Case presentation
This study describes two patients with bilateral orbital ECD. Both presented with proptosis and visual loss; imaging findings showed bilateral intraorbital masses. Both had different degrees of systemic symptoms (pleural effusion, pericardial effusion, ascites, and heart failure) before the ocular symptoms and did not find the cause before ophthalmic tumor resection and pathological biopsy. The diagnosis of ECD was confirmed after pathological biopsy and detection of BRAFV600E mutation. Patient 2 also with primary thrombocytosis and had a CALR mutation as well as the BRAFV600E mutation. Both patients were recommended to receive targeted therapy. Patient 1 refused targeted therapy for financial reasons and was discharged after local radiotherapy only. The patient had no light perception in either eye and no improvement in systemic symptoms. Patient 2 began targeted treatment after diagnosis and reached the discharge criteria 2 weeks later. He is in good condition at present, but unfortunately, his eyesight has not improved because of the irreversible damage to his visual function.

Conclusion
ECD is easily misdiagnosed and missed because of its rarity and diverse clinical manifestations. Orbital involvement is common in ECD, and surgery is the most frequently employed approach. Despite the surgical resection is not curative, its significance lies in biopsy to establish diagnosis and/or surgical debulking to relieve mass effect, minimizing further impairment of visual function. Targeted therapy is the most effective treatment for patients with a positive BRAF mutation gene. Evaluation of a concomitant myeloid neoplasm is also critical before initiating targeted therapies for refractory ECD.