bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model
Authors: Liu Qinwen , Luo Qian , Fan Qiling , Li Yi , Lu Aiping , Guan Daogang
Published: January 2024

Background

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the destruction of synovial tissue and articular cartilage. Huangqi-Guizhi-Wuwu-Decoction (HGWD), a formula of Traditional Chinese Medicine (TCM), has shown promising clinical efficacy in the treatment of RA. However, the synergistic effects of key response components group (KRCG) in the treatment of RA have not been well studied.

Methods

The components and potential targets of HGWD were extracted from published databases. A novel node influence calculation model that considers both the node control force and node bridging force was designed to construct the core response space (CRS) and obtain key effector proteins. An increasing coverage coefficient (ICC) model was employed to select the KRCG. The effectiveness and potential mechanism of action of KRCG were confirmed using CCK-8, qPCR, and western blotting.

Results

A total of 796 key effector proteins were identified in CRS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses confirmed their effectiveness and reliability. In addition, 59 components were defined as KRCG, which contributed to 85.05% of the target coverage of effective proteins. Of these, 677 targets were considered key reaction proteins, and their enriched KEGG pathways accounted for 84.89% of the pathogenic genes and 87.94% of the target genes. Finally, four components (moupinamide, 6-Paradol, hydrocinnamic acid, and protocatechuic acid) were shown to inhibit the inflammatory response in RA by synergistically targeting the cAMP, PI3K-Akt, and HIF-1α pathways.

Conclusions

We have introduced a novel model that aims to optimize and analyze the mechanisms behind herbal formulas. The model revealed the KRCG of HGWD for the treatment of RA and proposed that KRCG inhibits the inflammatory response by synergistically targeting cAMP, PI3K-Akt, and HIF-1α pathways. Overall, the novel model is plausible and reliable, offering a valuable reference for the secondary development of herbal formulas.
Multi-criteria decision making to validate performance of RBC-based formulae to screen $$\beta$$-thalassemia trait in heterogeneous haemoglobinopathies
Authors: Jain Atul Kumar , Sharma Prashant , Saleh Sarkaft , Dolai Tuphan Kanti , Saha Subhas Chandra , Bagga Rashmi , Khadwal Alka Rani , Trehan Amita , Nielsen Izabela , Kaviraj Anilava , Das Reena , Saha Subrata
Published: January 2024

Background

India has the most significant number of children with thalassemia major worldwide, and about 10,000-15,000 children with the disease are born yearly. Scaling up e-health initiatives in rural areas using a cost-effective digital tool to provide healthcare access for all sections of people remains a challenge for government or semi-governmental institutions and agencies.

Methods

We compared the performance of a recently developed formula SCS$$_{BTT}$$

BTT

and its web application SUSOKA with 42 discrimination formulae presently available in the literature. 6,388 samples were collected from the Postgraduate Institute of Medical Education and Research, Chandigarh, in North-Western India. Performances of the formulae were evaluated by eight different measures: sensitivity, specificity, Youden’s Index, AUC-ROC, accuracy, positive predictive value, negative predictive value, and false omission rate. Three multi-criteria decision-making (MCDM) methods, TOPSIS, COPRAS, and SECA, were implemented to rank formulae by ensuring a trade-off among the eight measures.

Results

MCDM methods revealed that the Shine & Lal and SCS$$_{BTT}$$

BTT

were the best-performing formulae. Further, a modification of the SCS$$_{BTT}$$

BTT

formula was proposed, and validation was conducted with a data set containing 939 samples collected from Nil Ratan Sircar (NRS) Medical College and Hospital, Kolkata, in Eastern India. Our two-step approach emphasized the necessity of a molecular diagnosis for a lower number of the population. SCS$$_{BTT}$$

BTT

along with the condition MCV$$\le$$
≤
80 fl was recommended for a higher heterogeneous population set. It was found that SCS$$_{BTT}$$

BTT

can classify all BTT samples with 100% sensitivity when MCV$$\le$$
≤
80 fl.

Conclusions

We addressed the issue of how to integrate the higher-ranked formulae in mass screening to ensure higher performance through the MCDM approach. In real-life practice, it is sufficient for a screening algorithm to flag a particular sample as requiring or not requiring further specific confirmatory testing. Implementing discriminate functions in routine screening programs allows early identification; consequently, the cost will decrease, and the turnaround time in everyday workflows will also increase. Our proposed two-step procedure expedites such a process. It is concluded that for mass screening of BTT in a heterogeneous set of data, SCS$$_{BTT}$$

BTT

and its web application SUSOKA can provide 100% sensitivity when MCV$$\le$$
≤
80 fl.
Multiple machine-learning tools identifying prognostic biomarkers for acute Myeloid Leukemia
Authors: Cheng Yujing , Yang Xin , Wang Ying , Li Qi , Chen Wanlu , Dai Run , Zhang Chan
Published: January 2024

Background

Acute Myeloid Leukemia (AML) generally has a relatively low survival rate after treatment. There is an urgent need to find new biomarkers that may improve the survival prognosis of patients. Machine-learning tools are more and more widely used in the screening of biomarkers.

Methods

Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), lrFuncs, IdaProfile, caretFuncs, and nbFuncs models were used to screen key genes closely associated with AML. Then, based on the Cancer Genome Atlas (TCGA), pan-cancer analysis was performed to determine the correlation between important genes and AML or other cancers. Finally, the diagnostic value of important genes for AML was verified in different data sets.

Results

The survival analysis results of the training set showed 26 genes with survival differences. After the intersection of the results of each machine learning method, DNM1, MEIS1, and SUSD3 were selected as key genes for subsequent analysis. The results of the pan-cancer analysis showed that MEIS1 and DNM1 were significantly highly expressed in AML; MEIS1 and SUSD3 are potential risk factors for the prognosis of AML, and DNM1 is a potential protective factor. Three key genes were significantly associated with AML immune subtypes and multiple immune checkpoints in AML. The results of the verification analysis show that DNM1, MEIS1, and SUSD3 have potential diagnostic value for AML.

Conclusion

Multiple machine learning methods identified DNM1, MEIS1, and SUSD3 can be regarded as prognostic biomarkers for AML.
Nurse-led intervention in the management of patients with cardiovascular diseases: a brief literature review
Authors: Qiu Xiaoqin
Published: January 2024

Coronary artery disease (CAD) is one among the major causes of mortality in patients all around the globe. It has been reported by the World Health Organization (WHO) that approximately 80% of cardiovascular diseases could be prevented through lifestyle modifications. Management of CAD involves the prevention and control of cardiovascular risk factors, invasive and non-invasive treatments including coronary revascularizations, adherence to proper medications and regular outpatient follow-ups. Nurse-led clinics were intended to mainly provide supportive, educational, preventive measures and psychological support to the patients, which were completely different from therapeutic clinics. Our review focuses on the involvement and implication of nurses in the primary and secondary prevention and management of cardiovascular diseases. Nurses have a vital role in Interventional cardiology. They also have major roles during the management of cardiac complications including congestive heart failure, atrial fibrillation and heart transplantation. Today, the implementation of a nurse-led tele-consultation strategy is also gaining positive views. Therefore, a nurse-led intervention for the management of patients with cardiovascular diseases should be implemented in clinical practice. Based on advances in therapy, more research should be carried out to further investigate the effect of nurse-led clinics during the long-term treatment and management of patients with cardiovascular diseases.
Supportive care needs of adults living with a peripherally inserted central catheter (PICC) at home: a qualitative content analysis
Authors: Sharp Rebecca , Xu Qunyan , Pumpa ‬‬‬‬‬‬‬‬‬‬‬Robyn , Elliott Lisa , Corsini Nadia , Marker Julie , Altschwager Jodie , Ortmann Alanna , Turner Lisa , Jin Lili , Ullman Amanda , Esterman Adrian
Published: January 2024

Background

Peripherally inserted central catheters (PICCs) are common vascular access devices inserted for adults undergoing intravenous treatment in the community setting. Individuals with a PICC report challenges understanding information and adapting to the device both practically and psychologically at home. There is a lack of research investigating the supportive care needs of individuals with a PICC to inform nursing assessment and the provision of additional supports they may require to successfully adapt to life with a PICC. The aim of this study was to identify the supportive care needs of adults with cancer or infection living with a PICC at home.

Method

Qualitative, semi-structured interviews were used to identify supportive care needs of adults living with a PICC at home. Participants were recruited from cancer and infectious diseases outpatient units. Two researchers independently analysed transcripts using content analysis.

Results

A total of 15 participants were interviewed (30–87 years old). There were 5 males and 10 females interviewed, 9 participants had a cancer diagnosis and most lived in a metropolitan area. Many participants lived with a partner/spouse at home and three participants had young children. Participants identified supportive care needs in the following eight categories (i (i) Adapting daily life (ii) Physical comfort (iii) Self-management (iv) Emotional impact (v) Information content (vi) Understanding information (vii) Healthcare resources and (viii) Social supports.

Conclusions

Adults living with a PICC at home report a broad range of supportive care needs. In addition to practical and information needs, health consumers may also require support to accept living with a device inside their body and to assume responsibility for the PICC. These findings may provide nurses with a greater understanding of individual needs and guide the provision of appropriate supports.
“Discovering shine through feedback seeking”---feedback seeking among new graduate nurses: a qualitative study
Authors: Song Ziling , Shen Yuanyuan , Yao Xin , Wen Siqi , Wang Jing , Chen Yanyan , Zhang Peihua , Huang Xiaoqiong
Published: January 2024

Background

Feedback is critical to improving practitioners’ clinical practice and professional growth. Although they are still considered junior practitioners, their feedback-seeking experiences have yet to be investigated. This study aimed to understand the fundamental thoughts and experiences of new graduate nurses regarding feedback-seeking and to identify the main factors that influence their feedback-seeking behaviors.

Methods

Conducting a descriptive phenomenological study, semi-structured in-depth interviews with newly graduated nurses from four hospitals in Zhejiang Province, China, face-to-face or via video call in the hospital conference room through purposive and snowball sampling. Interview data were evaluated using Colaizzi’s 7-step phenomenological data analysis. The COREQ checklist was followed.

Results

A total of 15 new graduate nurses were interviewed as a sample, and 13 categories emerged from our data. They were categorized into four central elements: (1) perceptions and attitudes, (2) drivers, (3) dilemmas and needs, and (4) transformation and growth.

Conclusions

This study found that new graduate nurses have various needs but face dilemmas in the feedback-seeking process. Nursing managers should be proficient at providing positive leadership, collaborating with clinical mentors to foster an atmosphere where new graduate nurses may obtain honest, transparent, and fair feedback, and exercising caution when providing negative feedback.
Association between game metrics in a simulation game and nursing students’ surgical nursing knowledge – a quasi-experimental study
Authors: Koivisto Jaana-Maija , Buure Tuija , Engblom Janne , Rosqvist Kristiina , Haavisto Elina
Published: January 2024

Background

Simulation games are effective for acquiring surgical nursing knowledge during education by offering possibilities to learn theoretical knowledge through practical patient scenarios, thus preparing students for demanding surgical nursing care. Game metrics stored in the game system enable assessment of students’ behaviour while gameplaying. Combining game metrics with the assessment of a student’s surgical nursing knowledge allows versatile information to be obtained about the student’s learning outcomes. However, studies on game metrics stored in systems and their relationship with learning outcomes are scarce.

Methods

The aim here was to evaluate the association between game metrics in a simulation game and nursing students’ surgical nursing knowledge. Nursing students from three universities of applied sciences in Finland participated in a one-week simulation gameplaying intervention that included five surgical nursing scenarios. Students’ surgical nursing knowledge was investigated with a quasi-experimental, one-group, pre- and post-test design using a surgical nursing knowledge test. In total, 280 students filled in the knowledge tests. In addition, cross-sectional game data were collected at a single time point between pre- and post-tests. The data were analysed with descriptive statistics and multivariate analysis methods.

Results

Students’ surgical nursing knowledge improved with the intervention. The total number of playthroughs was 3562. The mean maximum score was 126.2 (maximum score range 76–195). The mean playing time of all playthroughs by all players was 4.3 minutes (SD = 81.61). A statistically significant association was found between mean score and knowledge test total score (p < 0.0072), but no significant association emerged between mean playing time and knowledge test total score.

Conclusion

The results indicated that the higher the mean score the better the students’ surgical nursing knowledge in the knowledge test. This study did not show that the time spent playing had an impact on students’ post-playing knowledge. Our findings support the idea that game metrics can be used in performance evaluation and the results can be used to improve nursing students’ readiness for challenging preoperative and postoperative clinical situations.
Understanding the relationship of academic motivation and social support in graduate nursing education in Egypt
Authors: El-Sayed Mona Metwally , Taha Samah Mohamed , AbdElhay Eman Sameh , Hawash Manal Mohammed
Published: January 2024

Background

Obtaining a postgraduate nursing education in Egypt requires substantial resources, including a robust academic drive and supportive relationships. These resources help students overcome challenges and navigate their educational journey. This study examines the relationship between academic motivation and social support among nursing graduate students.

Design

A cross-sectional survey was conducted at two nursing colleges in Egypt, involving 410 randomly selected graduate students.

Measures

The Academic Motivation Scale—College Version (AMS-C 28) and the Multidimensional Scale of Perceived Social Support (MSPSS) were used.

Findings

Findings revealed a statistically significant positive relationship between academic motivation and perceived social support (r = 0.515, p < 0.001). Hierarchical regression analysis revealed that 12.9% (Adjusted R² = 0.129) of the variance in academic motivation could be explained by perceived social support and level of education.

Conclusion

This study pinpointed intrinsic motivation as the primary impetus for graduate nursing students. Robust social support and active participation in social and recreational activities were also significant motivators. Nursing education programs can enhance intrinsic motivation by integrating authentic learning experiences, providing empowering mentorship, offering condensed doctoral programs, and ensuring substantial peer support. The exploration of the role of novelty in graduate nursing education, facilitated by innovative teaching methods such as collaborative virtual reality simulations, gamification, and team-based research projects, can be advantageous. Building robust social networks is vital for establishing a supportive and motivating learning environment for nursing graduates in Egypt.
Health support of people with intellectual disability and the crucial role of support workers
Authors: Nijhof Kim , Boot Fleur H. , Naaldenberg Jenneken , Leusink Geraline L. , Bevelander Kirsten E.
Published: January 2024

Background

People with intellectual disability have a poorer health status than the general population. In The Netherlands, support workers play a key role in meeting health support needs of people with intellectual disability. Research on how people with intellectual disability and their support workers experience the support worker’s role in preventing, identifying, and following up health needs of people with intellectual disability is scarce. To enhance health support of people with intellectual disability it is crucial that we understand how health support is delivered in everyday practice. Therefore, this study investigated experiences of people with intellectual disability and support workers with the health support of people with intellectual disability.

Method

Data collection consisted of six focus group (FG) discussions with between four and six participants (N = 27). The FGs consisted of three groups with support workers (n = 15), two groups with participants with mild to moderate intellectual disability (n = 8), and one group with family members as proxy informants who represented their relative with severe to profound intellectual disability (n = 4). The data was analysed thematically on aspects relating to health support.

Results

We identified three main themes relevant to the health support of people with intellectual disability: 1) dependence on health support, 2) communication practices in health support, and 3) organizational context of health support. Dependence on health support adresses the way in which support workers meet a need that people with intellectual disability cannot meet themselves, and communication practices and organizational context are identified as systems in which health support takes place.

Conclusion

This study investigated experiences with the health support of people with intellectual disability from the perspectives of people with intellectual disability and support workers. We discuss the dependence of people with intellectual disability and the complexity of health support in everyday practice. We provide practical implications that can strengthen support workers in the provision of health support for people with intellectual disability in everyday practice. The findings of this study emphasize the need for intellectual disability care-provider organizations to establish policies around consistency in support staff to make it easier to identify and follow up health needs, and an environment where support staff can develop their expertise concerning communication practices, lifestyle choices, and identifying and following up health needs.
Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis
Authors: Tan Wei Jun , Hawley Hannah R. , Wilson Sarah J. , Fitzsimons Helen L.
Published: January 2024

Background

Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14–3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function.

Results

Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner.

Conclusions

We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.
Identification of potential biological processes and key genes in diabetes-related stroke through weighted gene co-expression network analysis
Authors: He Yong , Bai Yang , Huang Qin , Xia Jian , Feng Jie
Published: January 2024

Background

Type 2 diabetes mellitus (T2DM) is an established risk factor for acute ischemic stroke (AIS). Although there are reports on the correlation of diabetes and stroke, data on its pathogenesis is limited. This study aimed to explore the underlying biological mechanisms and promising intervention targets of diabetes-related stroke.

Methods

Diabetes-related datasets (GSE38642 and GSE44035) and stroke-related datasets (GSE16561 and GSE22255) were obtained from the Gene Expression omnibus (GEO) database. The key modules for stroke and diabetes were identified by weight gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses were employed in the key module. Genes in stroke- and diabetes-related key modules were intersected to obtain common genes for T2DM-related stroke. In order to discover the key genes in T2DM-related stroke, the Cytoscape and protein–protein interaction (PPI) network were constructed. The key genes were functionally annotated in the Reactome database.

Results

By intersecting the diabetes- and stroke-related crucial modules, 24 common genes for T2DM-related stroke were identified. Metascape showed that neutrophil extracellular trap formation was primarily enriched. The hub gene was granulin precursor (GRN), which had the highest connectivity among the common genes. In addition, functional enrichment analysis indicated that GRN was involved in neutrophil degranulation, thus regulating neutrophil extracellular trap formation.

Conclusions

This study firstly revealed that neutrophil extracellular trap formation may represent the common biological processes of diabetes and stroke, and GRN may be potential intervention targets for T2DM-related stroke.
A brief comparison of polygenic risk scores and Mendelian randomisation
Authors: Garfield Victoria , Anderson Emma L.
Published: January 2024

Mendelian randomisation and polygenic risk score analysis have become increasingly popular in the last decade due to the advent of large-scale genome-wide association studies. Each approach has valuable applications, some of which are overlapping, yet there are important differences which we describe here.
Novel compound heterozygous MYO15A splicing variants in autosomal recessive non-syndromic hearing loss
Authors: Zheng Kaifeng , Lin Sheng , Gao Jian , Chen Shiguo , Su Jindi , Liu Zhiqiang , Duan Shan
Published: January 2024

Background

Hereditary hearing loss is a highly heterogeneous disorder. This study aimed to identify the genetic cause of a Chinese family with autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL).

Methods

Clinical information and peripheral blood samples were collected from the proband and its parents. Two-step high-throughput next-generation sequencing on the Ion Torrent platform was applied to detect variants as follows. First, long-range PCR was performed to amplify all the regions of the GJB2, GJB3, SLC26A4, and MT-RNR1 genes, followed by next-generation sequencing. If no candidate pathogenetic variants were found, the targeted exon sequencing with AmpliSeq technology was employed to examine another 64 deafness-associated genes. Sanger sequencing was used to identify variants and the lineage co-segregation. The splicing of the MYO15A gene was assessed by in silico bioinformatics prediction and minigene assays.

Results

Two candidate MYO15A gene (OMIM, #602,666) heterozygous splicing variants, NG_011634.2 (NM_016239.3): c.6177 + 1G > T and c.9690 + 1G > A, were identified in the proband, and these two variants were both annotated as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Further bioinformatic analysis predicted that the c.6177 + 1G > T variant might cause exon skipping and that the c.9690 + 1G > A variant might activate a cryptic splicing donor site in the downstream intronic region. An in vitro minigene assay confirmed the above predictions.

Conclusions

We identified a compound heterozygous splicing variant in the MYO15A gene in a Han Chinese family with ARNSHL. Our results broaden the spectrum of MYO15A variants, potentially benefiting the early diagnosis, prevention, and treatment of the disease.
Identification and validation of iron metabolism genes in osteoporosis
Authors: Li Zutao , Xu Jiangbo , Shi Shouyin , Weng Youlin , Guo Bin , Che Lixin , Sun Jungang
Published: January 2024

Background

Osteoporosis is the most common metabolic bone disease in humans. Exploring the expression difference of iron metabolism-related genes in osteoporosis can provide a new target for diagnosis and treatment.

Methods

First, we used online databases to identify differentially expressed genes (DEGs) related to iron metabolism in patients with osteoporosis. The differential genes were comprehensively analyzed by bioinformatics method (GO, KEGG, GSEA, immune infiltration analysis, PPI). The expression levels of hub genes and important signaling pathways were verified by qRT-PCR and Western blotting.

Results

A total of 23 iron metabolism-related genes with significant differences were identified, which were enriched in “regulation of protein dephosphorylation” and “negative regulation of protein dephosphorylation”. The GSEA results, heme metabolism and Myc targets v1 were among the top two pathways, both upregulated. The immune infiltration analysis revealed that the expressions of genes such as ABCA5, D2HGDH, GNAI2, and CTSW were correlated with the infiltration degree of significantly different cells. The PPI network contained 12 differentially expressed iron metabolism-related genes. Additionally, YWHAE, TGFB1, PPP1R15A, TOP2A, and CALR were mined as hub genes using the Cytoscape software. qRT PCR showed that the expression of TGF-β1, YWHAE, TOP2A and CALR increased. We also verified the expression of related proteins and genes in the oxidative stress signaling pathway by qRT PCR and Western blotting. The results showed that Mob1, YAP and TAZ molecules were highly expressed at the gene and protein levels.

Conclusions

These differentially expressed iron metabolism-related genes could provide new potential targets for the diagnosis and treatment of osteoporosis.
Nano-modified viruses prime the tumor microenvironment and promote the photodynamic virotherapy in liver cancer
Authors: Ou Da-Liang , Liao Zi-Xian , Kempson Ivan M. , Li Lin , Yang Pan-Chyr , Tseng S.-Ja
Published: January 2024

Background

As of 2020, hepatocellular carcinoma (HCC), a form of liver cancer, stood as the third most prominent contributor to global cancer-related mortality. Combining immune checkpoint inhibitors (ICI) with other therapies has shown promising results for treating unresectable HCC, offering new opportunities. Recombinant adeno-associated viral type 2 (AAV2) virotherapy has been approved for clinical use but it efficacy is stifled through systemic administration. On the other hand, iron oxide nanoparticles (ION) can be cleared via the liver and enhance macrophage polarization, promoting infiltration of CD8+ T cells and creating a more favorable tumor microenvironment for immunotherapy.

Methods

To enhance the efficacy of virotherapy and promote macrophage polarization towards the M1-type in the liver, ION-AAV2 were prepared through the coupling of ION-carboxyl and AAV2-amine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)/N-hydroxysulfosuccinimide (Sulfo-NHS). Efficacy after systemic delivery of ION-AAV2 in an orthotopic HCC model was evaluated.

Results

After 28 days, the tumor weight in mice treated with ION-AAV2 was significantly reduced by 0.56-fold compared to the control group. The ION-AAV2 treatment led to an approximate 1.80-fold increase in the level of tumor associated M1-type macrophages, while the number of M2-type macrophages was reduced by 0.88-fold. Moreover, a proinflammatory response increased the population of tumor-infiltrating CD8+ T cells in the ION-AAV2 group. This transformation converted cold tumors into hot tumors.

Conclusions

Our findings suggest that the conjugation of ION with AAV2 could be utilized in virotherapy while simultaneously exploiting macrophage-modulating cancer immunotherapies to effectively suppress HCC growth.
PDGF-BB accelerates TSCC via fibroblast lactates limiting miR-26a-5p and boosting mitophagy
Authors: Xu Jianguo , Bian Li , You Dingyun , Li Ziliang , Wang Tingting , Li Yiting , Ren Xiaobin , He Yongwen
Published: January 2024

The tumor microenvironment and cancer-associated fibroblasts (CAFs) play crucial roles in tumor development, and their metabolic coupling remains unclear. Clinical data showed a positive correlation between PDGF-BB, CAFs, and glycolysis in the tumor microenvironment of oral tongue squamous cell carcinoma patients. In vitro, CAFs are derived from hOMF cells treated with PDGF-BB, which induces their formation and promotes aerobic glycolysis. Mitophagy increased the PDGF-BB-induced formation of CAF phenotypes and aerobic glycolysis, while autophagy inhibition blocked PDGF-BB-induced effects. Downregulation of miR-26a-5p was observed in CAFs; upregulation of miR-26a-5p inhibited the expression of mitophagy-related proteins ULKI, Parkin, PINK1, and LC3 and aerobic glycolysis in PDGF-BB-induced CAFs. PDGF-BB-induced CAFs promoted tumor cell proliferation, invasion, metastasis, NF-κB signaling pathway activation, and PDGF-BB secretion. Thus, PDGF-BB is associated with lactate-induced CAF formation and glucose metabolism reprogramming. These findings indicate potential therapeutic targets in oral tongue squamous cell carcinoma.
LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA
Authors: Ouyang Liu , Sun Min-min , Zhou Ping-sheng , Ren Yi-wei , Liu Xin-yu , Wei Wan-ying , Song Zhen-shun , Lu Kai , Yang Li-xue
Published: January 2024

Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.
Health-related quality of life and experience measures, to assess patients’ experiences of peripheral intravenous catheters: a secondary data analysis
Authors: Larsen Emily N. , Marsh Nicole , Rickard Claire M. , Mihala Gabor , Walker Rachel M. , Byrnes Joshua
Published: January 2024

Background

Peripheral intravenous catheters (PIVCs) are essential for successful administration of intravenous treatments. However, insertion failure and PIVC complications are common and negatively impact patients’ health-outcomes and experiences. We aimed to assess whether generic (not condition-specific) quality of life and experience measures were suitable for assessing outcomes and experiences of patients with PIVCs.

Methods

We undertook a secondary analysis of data collected on three existing instruments within a large randomised controlled trial, conducted at two adult tertiary hospitals in Queensland, Australia. Instruments included the EuroQol Five Dimension - Five Level (EQ5D-5L), the Functional Assessment of Chronic Illness Therapy – Treatment Satisfaction – General measure (FACIT-TS-G, eight items), and the Australian Hospital Patient Experience Question Set (AHPEQS, 12 items). Responses were compared against two clinical PIVC outcomes of interest: all-cause failure and multiple insertion attempts. Classic descriptives were reported for ceiling and floor effects. Regression analyses examined validity (discrimination). Standardised response mean and effect size (ES) assessed responsiveness (EQ5D-5L, only).

Results

In total, 685 participants completed the EQ5D-5L at insertion and 526 at removal. The FACIT-TS-G was completed by 264 and the AHPEQS by 262 participants. Two FACIT-TS-G items and one AHPEQS item demonstrated ceiling effect. Instruments overall demonstrated poor discrimination, however, all-cause PIVC failure was significantly associated with several individual items in the instruments (e.g., AHPEQS, ‘unexpected physical and emotional harm’). EQ5D-5L demonstrated trivial (ES < 0.20) responsiveness.

Conclusions

Initial investigation of an existing health-related quality of life measure (EQ5D-5L) and two patient-reported experience measures (FACIT-TS-G; AHPEQS) suggest they are inadequate (as a summary measure) to assess outcomes and experiences for patients with PIVCs. Reliable instruments are urgently needed to inform quality improvement and benchmark standards of care.
Follitropin delta combined with menotropin in patients at risk for poor ovarian response during in vitro fertilization cycles: a prospective controlled clinical study
Authors: Duarte-Filho Oscar Barbosa , Miyadahira Eduardo Hideki , Matsumoto Larissa , Yamakami Lucas Yugo Shiguehara , Tomioka Renato Bussadori , Podgaec Sergio
Published: January 2024

Background

The maximum daily dose of follitropin delta for ovarian stimulation in the first in vitro fertilization cycle is 12 μg (180 IU), according to the algorithm developed by the manufacturer, and based on patient’s ovarian reserve and weight. This study aimed to assess whether 150 IU of menotropin combined with follitropin delta improves the response to stimulation in women with serum antimullerian hormone levels less than 2.1 ng/mL.

Methods

This study involved a prospective intervention group of 44 women who received 12 μg of follitropin delta combined with 150 IU of menotropin from the beginning of stimulation and a retrospective control group of 297 women who received 12 μg of follitropin delta alone during the phase 3 study of this drug. The inclusion and exclusion criteria and other treatment and follow-up protocols in the two groups were similar. The pituitary suppression was achieved by administering a gonadotropin-releasing hormone (GnRH) antagonist. Ovulation triggering with human chorionic gonadotropin or GnRH agonist and the option of transferring fresh embryos or using freeze-all strategy were made according to the risk of developing ovarian hyperstimulation syndrome.

Results

Women who received follitropin delta combined with menotropin had higher estradiol levels on trigger day (2150 pg/mL vs. 1373 pg/mL, p < 0.001), more blastocysts (3.1 vs. 2.4, p = 0.003) and more top-quality blastocysts (1.8 vs. 1.3, p = 0.017). No difference was observed in pregnancy, implantation, miscarriage, and live birth rates after the first embryo transfer. The incidence of ovarian hyperstimulation syndrome did not differ between the groups. However, preventive measures for the syndrome were more frequent in the group using both drugs than in the control group (13.6% vs. 0.6%, p < 0.001).

Conclusions

In women with serum antimullerian hormone levels less than 2.1 ng/mL, the administration of 150 IU of menotropin combined with 12 μg of follitropin delta improved the ovarian response, making it a valid therapeutic option in situations where ovulation triggering with a GnRH agonist and freeze-all embryos strategy can be used routinely.

Trial registration

U1111-1247-3260 (Brazilian Register of Clinical Trials, available at https://ensaiosclinicos.gov.br/rg/RBR-2kmyfm).
Long pentraxin 3 and vitamin D receptor mRNA expression pattern of cumulus granulosa cells isolated from PCOS oocytes at different stages of nuclear maturation
Authors: Ersahin Aynur , Celik Onder , Gungor Nur D. , Celik Nilufer , Melil Sureyya , Yardim Meltem , Dalkilic Semih , Ersahin Cenk , Dogukargin Ece , Celik Sudenaz , Akkoc Ramazan F.
Published: January 2024

Background

A fine-tuned pro-inflammatory and anti-inflammatory balance in the follicular unit is essential for cumulus expansion and successful ovulation. While the long pentraxin 3 (PTX3) gene is required for the expansion of cumulus cells (CCs), ovulation, resumption of meiosis and fertilization, the vitamin D receptor gene (VDR-X2) is required for intra-follicle redox balance. This study was planned to determine the expression pattern of VDR-X2 and PTX3 mRNA in CCs isolated from germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) oocytes of PCOS patients with ovulatory dysfunction.

Methods

The relative expression of CC-PTX3 and CC-VDR-X2 mRNA were evaluated using qRT-PCR in a total of 79 CC samples collected from individual cumulus-oocyte complex of 40 infertile patients (20 PCOS and 20 non-PCOS normal responders) who underwent ovarian stimulation with the GnRH antagonist protocol.

Results

Relative PTX3 mRNA expressions of CCMI-control and CCMII-control showed 3- and 9-fold significant upregulation compared to CCGV-control, respectively. The relative PTX3 mRNA expression of CCMII-control increased approximately three fold compared to CCMI-control. Compared to CCGV-pcos, a 3-fold increase was noted in the relative PTX3 mRNA expression of CCMI-pcos and an approximately 4-fold increase in the PTX3 mRNA expression of CCMII-pcos. Relative PTX3 mRNA expression values of CCMII-pcos and CCMI-pcos were similar. A 6-fold upregulation of relative PTX3 mRNA and a 4-fold upregulation of VDR-X2 mRNA were detected in CCMII-control compared to CCMII-pcos. CC-VDR-X2 expression patterns of the PCOS and control groups overlapped with the CC-PTX3 pattern. Fertilization rates of the PCOS group exhibiting failed transcript expression were similar to normal responders.

Conclusion

The fact that relative CC-PTX3 and CC-VDR mRNA expression does not increase during the transition from MI to MII stage in PCOS as in normal responders suggests that PTX3 and VDR expression may be defective in cumulus cells of PCOS patients with ovulatory dysfunction.
The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation
Authors: Lyu Si-qi , Zhu Jun , Wang Juan , Wu Shuang , Zhang Han , Shao Xing-hui , Yang Yan-min
Published: January 2024

Background

The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) has not been well established yet. This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF.

Methods

PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. The primary endpoint was thromboembolic events. The relative risks and standard errors were pooled by random-effect models using the generic inverse variance method.

Results

Seven observational studies involving 9395 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a similar risk of thromboembolic events [RR (95%CI): 0.93 (0.73–1.20), p = 0.59] and ischemic stroke [RR (95%CI): 0.65 (0.33–1.28), p = 0.22]. The incidence of major bleeding was comparable between the two groups [RR (95%CI): 0.75 (0.49–1.15), p = 0.19]. Meanwhile, DOAC therapy was superior to VKA therapy in reducing the incidences of all-cause death [RR (95%CI): 0.44 (0.35–0.55), p < 0.001], cardiovascular death [RR (95%CI): 0.41 (0.22–0.75), p = 0.004], and intracranial hemorrhage [RR (95%CI): 0.42 (0.24–0.74), p = 0.003].

Conclusion

In patients with HCM and AF, DOAC therapy was similar to VKA therapy in reducing the risk of thromboembolic events, without increasing bleeding risk. In addition, the DOAC group displayed significant advantages in reducing mortality and intracranial hemorrhage compared with the VKA group. Further randomized controlled trials are needed to provide more evidence for DOAC therapy in this population.
CXXC5 mitigates P. gingivalis-inhibited cementogenesis by influencing mitochondrial biogenesis
Authors: Ma Li , Wang Huiyi , Huang Xin , Huang Hantao , Peng Yan , Liu Heyu , Wang Xiaoxuan , Cao Zhengguo
Published: January 2024

Background

Cementoblasts on the tooth-root surface are responsible for cementum formation (cementogenesis) and sensitive to Porphyromonas gingivalis stimulation. We have previously proved transcription factor CXXC-type zinc finger protein 5 (CXXC5) participates in cementogenesis. Here, we aimed to elucidate the mechanism in which CXXC5 regulates P. gingivalis-inhibited cementogenesis from the perspective of mitochondrial biogenesis.

Methods

In vivo, periapical lesions were induced in mouse mandibular first molars by pulp exposure, and P. gingivalis was applied into the root canals. In vitro, a cementoblast cell line (OCCM-30) was induced cementogenesis and submitted for RNA sequencing. These cells were co-cultured with P. gingivalis and examined for osteogenic ability and mitochondrial biogenesis. Cells with stable CXXC5 overexpression were constructed by lentivirus transduction, and PGC-1α (central inducer of mitochondrial biogenesis) was down-regulated by siRNA transfection.

Results

Periapical lesions were enlarged, and PGC-1α expression was reduced by P. gingivalis treatment. Upon apical inflammation, Cxxc5 expression decreased with Il-6 upregulation. RNA sequencing showed enhanced expression of osteogenic markers, Cxxc5, and mitochondrial biogenesis markers during cementogenesis. P. gingivalis suppressed osteogenic capacities, mitochondrial biogenesis markers, mitochondrial (mt)DNA copy number, and cellular ATP content of cementoblasts, whereas CXXC5 overexpression rescued these effects. PGC-1α knockdown dramatically impaired cementoblast differentiation, confirming the role of mitochondrial biogenesis on cementogenesis.

Conclusions

CXXC5 is a P. gingivalis-sensitive transcription factor that positively regulates cementogenesis by influencing PGC-1α-dependent mitochondrial biogenesis.
Liver damage profile in COVID-19 pregnant patients
Authors: Januszewski Marcin , Ziuzia-Januszewska Laura , Kudan Michal , Pluta Kamil , Klapaczyński Jakub , Wierzba Waldemar , Maciejewski Tomasz , Jakimiuk Alicja A. , Jakimiuk Artur J.
Published: January 2024

Introduction

SARS-CoV-2 unsparingly impacts all areas of medicine. Pregnant women are particularly affected by the pandemic and COVID-19 related liver damage seems to be another threat to maternal and fetal health. The aim of this study is to define liver damage profile including bile acids serum levels in COVID-19 pregnant patients and to determine predictors of disease aggravation and poor obstetrics outcomes.

Methods

This study has been carried out in the Obstetrics and Gynecology Department, at the National Medical Institute in Warsaw, Poland between 01.02.2021 and 01.11.2022 The study cohort comprises 148 pregnant patients with COVID-19 and 102 pregnant controls who has been tested negative for SARS-CoV-2.

Results

COVID-19 pregnant patients presented liver involvement at admission in 41,9%. Hepatotoxic damage accounted for 27 (19.85%), cholestatic type was diagnosed in 11 (8.09%) and mixed type of liver injury was presented in 19 (13.97%) of patients. Higher serum levels of AST, ALT, GGT, total bilirubin and bile acids as well as mixed type of liver injury at admission were correlated with severe form of an illness. AST and ALT above upper reference limit as well as hepatotoxic type of liver damage predisposed pregnant patients with COVID-19 to poor obstetrics outcomes.

Conclusion

Hepatic damage in pregnant women with COVID-19 is a common, mild, transaminase-dominant, or mixed type of injury, and often correlates with elevated inflammatory markers. SARS-CoV-2 test should be performed as a part of differential diagnosis in elevated liver function tests. Although bile acids serum levels were commonly elevated they seems to be clinically irrelevant in terms of pregnancy outcomes.