bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low-dose arecoline regulates distinct core signaling pathways in oral submucous fibrosis and oral squamous cell carcinoma
Authors: Li Zhenming , Fu You , Hu Yuhua , Zhu Yun , Hu Longwei , Shi Chaoji , Zhang Yi , Zhang Jianjun , Zhou Shanghui 
Published: March 2023

Abstract
Background
Betel nut chewing plays a role in the pathogenesis of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC). As the major active ingredient of the betel nut, the effect of arecoline and its underlying mechanism to OSF and OSCC pathogenesis remain unclear.

Methods
Next-generation sequencing-based transcriptome and dRRBS analysis were performed on OSF and OSCC cells under low-dose arecoline exposure. Functional analyses were performed to compare the different roles of arecoline during OSF and OSCC pathogenesis, and key genes were identified.

Results
In this study, we identified that low-dose arecoline promoted cell proliferation of both NFs and OSCC cells via the acceleration of cell cycle progression, while high-dose arecoline was cytotoxic to both NFs and OSCC cells. We performed for the first time the transcriptome and methylome landscapes of NFs and OSCC cells under low-dose arecoline exposure. We found distinct transcriptome and methylome profiles mediated by low-dose arecoline in OSF and OSCC cells, as well as specific genes and signaling pathways associated with metabolic disorders induced by low-dose arecoline exposure. Additionally, low-dose arecoline displayed different functions at different stages, participating in the modulation of the extracellular matrix via Wnt signaling in NFs and epigenetic regulation in OSCC cells. After exposure to low-dose arecoline, the node roles of FMOD in NFs and histone gene clusters in OSCC cells were found. Meanwhile, some key methylated genes induced by arecoline were also identified, like PTPRM and FOXD3 in NFs, SALL3 and IRF8 in OSCC cells, indicating early molecular events mediated by arecoline during OSF and OSCC pathogenesis.

Conclusions
This study elucidated the contribution of low-dose arecoline to OSF and OSCC pathogenesis and identified key molecular events that could be targeted for further functional studies and their potential as biomarkers.
Antibiotic prescriptions for oral diseases in India: evidence from national prescription data
Authors: Mathur Manu Raj , Nagrath Deepti , Mishra Vijay Kumar , Harris Rebecca , Saeed Syed Saif , Selvaraj Sakthivel , Mehta Aashna , Farooqui Habib Hasan 
Published: March 2023

Abstract
Introduction
The key objective of this research was to describe the prescription rate of various antibiotics for dental problems in India and to study the relevance of the prescriptions by analysing antibiotic types associated with different dental diagnoses, using a large-scale nationally representative dataset.

Methods
We used a 12-month period (May 2015 to April 2016) medical audit dataset from IQVIA (formerly IMS Health). We coded the dental diagnosis provided in the medical audit data to the International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the prescribed antibiotics for the diagnosis to the Anatomic Therapeutic Chemical (ATC) -2020 classification of the World Health Organization. The primary outcome measure was the medicine prescription rate per 1,000 persons per year (PRPY1000).

Results
Our main findings were—403 prescriptions per 1,000 persons per year in the year 2015 -2016 for all dental ailments. Across all ATC level 1 classification, ‘Diseases of hard tissues’ made up the majority of the prescriptions. ‘Beta-lactam’, ‘Penicillin,’ and ‘Cephalosporins’ were the most commonly prescribed antibiotics for dental diagnoses followed by ‘Macrolides’ and ‘Quinolones’. ‘Dental caries’, ‘Discoloration of tooth’, and ‘Toothache’ were the most common reasons for ‘Beta-Lactams’ and ‘Penicillin’ prescriptions.

Conclusion
To conclude our study reports first ever country (India) level estimates of antibiotic prescription by antibiotic classes, age groups, and ICD-11 classification for dental ailments.
A qualitative study of influences on the uptake of contraceptive services among people of reproductive age in Uganda
Authors: Namanda Cissie , Atuyambe Lynn , Ssali Sarah , Mukose Aggrey , Tumwesigye Nazarius Mbona , Makumbi Frederick E. , Tweheyo Ritah , Gidudu Andrew , Sekimpi Carole , Hashim Catherine Verde , Nicholson Martha , Ddungu Peter 
Published: March 2023

Abstract
Background
Uganda has registered an increased investment in family planning (FP) programs, which has contributed to improvement in knowledge of modern contraceptive methods being nearly universal. However, this has not matched the uptake of modern methods or the reduction in the unmet need for FP. This may be explained by the different influences which include health workers, family, and friends. Due to the limited uptake of contraceptive methods, a program on improving awareness, access to, and uptake of modern contraceptives is being implemented in selected regions in Uganda. We, therefore, conducted a formative study to determine the influences on contraceptive uptake at the onset of this program.

Methods
Using a qualitative study design, we conducted thirty-two focus group discussions and twenty-one in-depth interviews involving men and women of reproductive age. We also carried out twenty-one key informant interviews with people involved in FP service delivery. Data was collected in four districts where implementation of the program was to take place. Audio recorders were used to collect data and tools were translated into local languages. A codebook was developed, and transcripts were coded in vivo using the computer software Atlas-ti version 7 before analysis. Ethical clearance was obtained from institutional review boards and informed consent was sought from all participants.

Results
From the study, most married people mentioned health workers as their main influence while adolescents reported their peers and friends. Religious leaders and mothers-in-law were reported to mainly discourage people from taking up modern contraceptive methods. The cultural value attached to having many children influenced the contraceptive use decision among people in rural settings. Other influences included a person’s experience and housing.

Conclusions
Health workers, religious leaders, and mothers determine the uptake of contraceptive services. The study recommends the consideration of the role of these influences in the design of FP program interventions as well as more involvement of health workers in sensitization of communities about contraceptive methods.
Two cases of bloodstream infections associated with opportunistic bacterial species (Enterococcus hirae and Enterobacter xiangfangensis) in companion animals
Authors: Scarpellini Raffaele , Giunti Massimo , Pontiero Alessandra , Savini Federica , Esposito Erika , Piva Silvia 
Published: March 2023

Abstract
Background
Bloodstream infections are a matter of concern in small animal veterinary practice. Few reports are avaiable, especially regarding the role of opportunistic bacteria in becoming infectious. This report aims to add to the current veterinary literature on two opportunistic bacterial species (Enterococcus hirae and Enterobacter xiangfangensis) associated with bloodstream infections in small animals admitted to the Bologna University Veterinary Hospital.

Case presentation
In the first case, a 15-year-old, immunocompromised, cardiopathic dog was admitted to the hospital for anorexia and diarrhea. The patient had a history of previous surgery and hospitalization. After three days, hyperthermia, leukopenia and hyperlactatemia were recorded, and blood culture revealed positivity for Enterococcus hirae, identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The patient’s general conditions progressively worsened, and the patient was euthanized. In the second case, a 2-year-old cat with chronic ocular herpesvirus infection and hypertrophic cardiomyopathy was admitted to the hospital for anorexia and hyperthermia. The cat was hospitalized one week before and received antimicrobial treatment for urinary tract infection by Staphylococcus felis. Hypokalemia and lymphopenia were also diagnosed. The patient progressively improved and was discharged after three days. On the same day, blood culture taken at admission revealed positivity for Enterobacter xiangfangensis, identified using MALDI-TOF MS. After five days, the patient returned with neurological symptoms, hypothermia and bradycardia, and was euthanized.

Conclusions
In small animal veterinary practice, the impact of opportunistic bacterial agents (such as E.hirae and E.xiangfangensis) on bloodstream infections remains unclear. As in human medicine, they can be contracted in every healthcare setting and considered hospital-acquired infections. In this report, we highlighted the threat they pose especially in patients with multiple risk factors. Rapid and accurate diagnostic tools (such as MALDI-TOF MS) could be particularly important for reducing the severity of the infections.
Insomnia in chronic obstructive pulmonary disease and associations with healthcare utilization and costs
Authors: Luyster Faith S. , Boudreaux-Kelly Monique Y. , Bon Jessica M. 
Published: March 2023

AbstractInsomnia has been linked to adverse chronic obstructive pulmonary disease (COPD) outcomes including exacerbations, yet its impact on COPD-related healthcare utilization and costs is unknown. In this study, we investigated the associations between insomnia and healthcare utilization and costs in patients with COPD. A retrospective cohort of veterans with COPD were identified from national Veterans Affairs administration data for fiscal years 2012–2017. Insomnia was operationalized as having an insomnia diagnosis based on International Classification of Disease codes or having a prescription of > 30 doses of a sedative-hypnotic medication in a given fiscal year. The index date for insomnia was the first date when dual criteria for COPD and insomnia was met. The index date for those without insomnia was set as the COPD index date. Our primary outcomes were 1-year healthcare utilization and costs related to outpatient visits and hospitalizations after index date. COPD-related healthcare utilization variables included number of prescription fills of corticosteroids and/or antibiotics and outpatient visits and hospitalizations with a primary diagnosis of COPD. Out of 1,011,646 patients (96% men, mean age 68.4 years) diagnosed with COPD, 407,363 (38.8%) had insomnia. After adjustment for confounders, insomnia was associated with higher rates of outpatient visits, hospitalizations, and fills for corticosteroids and/or antibiotics, longer hospital length of stay, and $10,344 higher hospitalization costs in the 12 months after index date. These findings highlight the importance of insomnia as a potentially modifiable target for reducing the burden of COPD on patients and healthcare systems.
Elevated urine albumin-to-creatinine ratio increases the risk of new-onset heart failure in patients with type 2 diabetes
Authors: Tao Jie , Sang Dasen , Zhen Libo , Zhang Xinxin , Li Yuejun , Wang Guodong , Chen Shuohua , Wu Shouling , Zhang Wenjuan 
Published: March 2023

Abstract
Background
Although albuminuria has been linked to heart failure in the general population, the relationship between urine albumin-to-creatinine ratio (uACR) and heart failure in type 2 diabetes patients is not well understood. We aimed to investigate the relationship between uACR and new-onset heart failure (HF) in type 2 diabetics.

Methods
We included 9287 Chinese participants with type 2 diabetes (T2D) but no heart failure (HF) who were assessed with uACR between 2014 and 2016. The participants were divided into three groups based on their baseline uACR: normal (< 3 mg/mmol), microalbuminuria (3–30 mg/mmol), and macroalbuminuria (≥ 30 mg/mmol). The relationship between uACR and new-onset HF was studied using Cox proportional hazard models and restricted cubic spline. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to see if incorporating uACR into existing models could improve performance.

Results
216 new-onset HF cases (2.33%) were recorded after a median follow-up of 4.05 years. When compared to normal uACR, elevated uACR was associated with a progressively increased risk of new-onset HF, ranging from microalbuminuria (adjusted HR, 2.21; 95% CI 1.59–3.06) to macroalbuminuria (adjusted HR, 6.02; 95% CI 4.11–8.80), and 1 standard deviation (SD) in ln (uACR) (adjusted HR, 1.89; 95% CI 1.68–2.13). The results were consistent across sex, estimated glomerular filtration rate, systolic blood pressure, and glycosylated hemoglobin subgroups. The addition of uACR to established HF risk models improved the HF risk prediction efficacy.

Conclusions
Increasing uACR, even below the normal range, is an independent risk factor for new-onset HF in a type 2 diabetic population. Furthermore, uACR may improve HF risk prediction in community-based T2D patients.
A novel feedback regulated loop of circRRM2-IGF2BP1-MYC promotes breast cancer metastasis
Authors: Hao Ran , Zhang Lei , Si Yangming , Zhang Peng , Wang Yipeng , Li Bangchao , Hu Jie , Qi Yixin 
Published: March 2023

Abstract
Background
Metastasis is the leading cause of mortality in patients with breast cancer (BC). Studies demonstrate that circular RNAs (circRNAs) were involved in BC progression, while the molecular mechanisms remain largely unclear.

Methods
The microArray circRNA profiles were used to explore the differential expression circRNAs in BC and paracancerous normal tissues, and the quantitative reverse transcription-polymerase chain reaction was used to validate their expression level in clinical samples and cell lines. Nuclear/cytosolic fractionation and fluorescence in situ hybridization (FISH) assays were performed to examine circRRM2 (hsa_circ_0052582) subcellular location. The scratch wound healing and transwell assays were conducted to evaluate the impact of circRRM2 on BC cell migration and invasion. We predicted miRNAs that might bind with cricRRM2 and the downstream target genes using bioinformatics analysis and explored their expression levels and prognostic value in BC. FISH, RNA immunoprecipitation, Co-immunoprecipitation, Western blot, and rescue experiments were implemented to figure out circRRM2 function and underlying mechanisms in BC.

Results
The present study revealed several aberrant circRNAs in BC tissues and observed that circRRM2 was upregulated in tumor tissues of 40 patients with BC. High circRRM2 was significantly associated with advanced N stage in patients with BC. Gain- and loss- of function experiments revealed that circRRM2 promoted the migration and invasion of cells and functioned as an oncogene in BC. Mechanism studies showed that circRRM2 competed with miR-31-5p/miR-27b-3p to upregulate the IGF2BP1 expression. Furthermore, IGF2BP1 upregulated the circRRM2 level via interacting with MYC, which functioned as the transcriptional factor of circRRM2. Thus, the positive feedback loop that was composed of circRRM2/IGF2BP1/MYC was identified.

Conclusion
This study confirms that upregulated circRRM2 functions an oncogenic role in BC metastasis. The positive feedback loop of circRRM2/IGF2BP1/MYC enforces the circRRM2 expression, which might offer a potential target for BC treatment.
The function and mechanisms of action of circular RNAs in Urologic Cancer
Authors: Zhang Zi-hao , Wang Yue , Zhang Ya , Zheng Sheng-Feng , Feng Tao , Tian Xi , Abudurexiti Mierxiati , Wang Zhen-Da , Zhu Wen-Kai , Su Jia-Qi , Zhang Hai-Liang , Shi Guo-Hai , Wang Zi-Liang , Cao Da-Long , Ye Ding-Wei 
Published: March 2023

AbstractKidney, bladder, and prostate cancer are the three major tumor types of the urologic system that seriously threaten human health. Circular RNAs (CircRNAs), special non-coding RNAs with a stabile structure and a unique back-splicing loop-forming ability, have received recent scientific attention. CircRNAs are widely distributed within the body, with important biologic functions such as sponges for microRNAs, as RNA binding proteins, and as templates for regulation of transcription and protein translation. The abnormal expression of circRNAs in vivo is significantly associated with the development of urologic tumors. CircRNAs have now emerged as potential biomarkers for the diagnosis and prognosis of urologic tumors, as well as targets for the development of new therapies. Although we have gained a better understanding of circRNA, there are still many questions to be answered. In this review, we summarize the properties of circRNAs and detail their function, focusing on the effects of circRNA on proliferation, metastasis, apoptosis, metabolism, and drug resistance in kidney, bladder, and prostate cancers.
Functionalization of curcumin nanomedicines: a recent promising adaptation to maximize pharmacokinetic profile, specific cell internalization and anticancer efficacy against breast cancer
Authors: Zhang Jinku , Sun Jirui , Li Chong , Qiao Haizhi , Hussain Zahid 
Published: March 2023

AbstractOwing to its diverse heterogeneity, aggressive nature, enormous metastatic potential, and high remission rate, the breast cancer (BC) is among the most prevalent types of cancer associated with high mortality. Curcumin (Cur) is a potent phytoconstituent that has gained remarkable recognition due to exceptional biomedical viability against a wide range of ailments including the BC. Despite exhibiting a strong anticancer potential, the clinical translation of Cur is restricted due to intrinsic physicochemical properties such as low aqueous solubility, chemical instability, low bioavailability, and short plasma half-life. To overcome these shortcomings, nanotechnology-aided developments have been extensively deployed. The implication of nanotechnology has pointedly improved the physicochemical properties, pharmacokinetic profile, cell internalization, and anticancer efficacy of Cur; however, majority of Cur-nanomedicines are still facing grandeur challenges. The advent of various functionalization strategies such as PEGylation, surface decoration with different moieties, stimuli-responsiveness (i.e., pH, light, temperature, heat, etc.), tethering of specific targeting ligand(s) based on the biochemical targets (e.g., folic acid receptors, transferrin receptors, CD44, etc.), and multifunctionalization (multiple functionalities) has revolutionized the fate of Cur-nanomedicines. This study ponders the biomedical significance of various Cur-nanomedicines and adaptable functionalizations for amplifying the physicochemical properties, cytotoxicity via induction of apoptosis, cell internalization, bioavailability, passive and active targeting to the tumor microenvironment (TME), and anticancer efficacy of the Cur while reversing the multidrug resistance (MDR) and reoccurrence in BC. Nevertheless, the therapeutic outcomes of Cur-nanomedicines against the BC have been remarkably improved after adaptation of various functionalizations; however, this evolving strategy still demands extensive research for scalable clinical translation.Graphical Abstract
Combining nanotechnology with monoclonal antibody drugs for rheumatoid arthritis treatments
Authors: Chi Xiao-Kai , Xu Xiao-Ling , Chen Bang-Yao , Su Jin , Du Yong-Zhong 
Published: March 2023

AbstractRheumatoid arthritis (RA) is a systemic immune disease characterized by synovial inflammation. Patients with RA commonly experience significant damage to their hand and foot joints, which can lead to joint deformities and even disability. Traditional treatments have several clinical drawbacks, including unclear pharmacological mechanisms and serious side effects. However, the emergence of antibody drugs offers a promising approach to overcome these limitations by specifically targeting interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and other cytokines that are closely related to the onset of RA. This approach reduces the incidence of adverse effects and contributes to significant therapeutic outcomes. Furthermore, combining these antibody drugs with drug delivery nanosystems (DDSs) can improve their tissue accumulation and bioavailability.Herein, we provide a summary of the pathogenesis of RA, the available antibody drugs and DDSs that improve the efficacy of these drugs. However, several challenges need to be addressed in their clinical applications, including patient compliance, stability, immunogenicity, immunosupression, target and synergistic effects. We propose strategies to overcome these limitations. In summary, we are optimistic about the prospects of treating RA with antibody drugs, given their specific targeting mechanisms and the potential benefits of combining them with DDSs.
Bioengineering of air-filled protein nanoparticles by genetic and chemical functionalization
Authors: Karan Ram , Renn Dominik , Nozue Shuho , Zhao Lingyun , Habuchi Satoshi , Allers Thorsten , Rueping Magnus 
Published: March 2023

Abstract
Background
Various bacteria and archaea, including halophilic archaeon Halobacterium sp. NRC-1 produce gas vesicle nanoparticles (GVNPs), a unique class of stable, air-filled intracellular proteinaceous nanostructures. GVNPs are an attractive tool for biotechnological applications due to their readily production, purification, and unique physical properties. GVNPs are spindle- or cylinder-shaped, typically with a length of 100 nm to 1.5 μm and a width of 30–250 nm. Multiple monomeric subunits of GvpA and GvpC proteins form the GVNP shell, and several additional proteins are required as minor structural or assembly proteins. The haloarchaeal genetic system has been successfully used to produce and bioengineer GVNPs by fusing several foreign proteins with GvpC and has shown various applications, such as biocatalysis, diagnostics, bioimaging, drug delivery, and vaccine development.

Results
We demonstrated that native GvpC can be removed in a low salt buffer during the GVNP purification, leaving the GvpA-based GVNP's shell intact and stable under physiological conditions. Here, we report a genetic engineering and chemical modification approach for functionalizing the major GVNP protein, GvpA. This novel approach is based on combinatorial cysteine mutagenesis within GvpA and genetic expansion of the N-terminal and C-terminal regions. Consequently, we generated GvpA single, double, and triple cysteine variant libraries and investigated the impact of mutations on the structure and physical shape of the GVNPs formed. We used a thiol–maleimide chemistry strategy to introduce the biotechnological relevant activity by maleimide-activated streptavidin–biotin and maleimide-activated SpyTag003-SpyCatcher003 mediated functionalization of GVNPs.

Conclusion
The merger of these genetic and chemical functionalization approaches significantly extends these novel protein nanomaterials' bioengineering and functionalization potential to assemble catalytically active proteins, biomaterials, and vaccines onto one nanoparticle in a modular fashion.

Graphical Abstract