bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response
Authors: Sarkar Soumyadeep , Elliott Emily C. , Henry Hayden R. , Ludovico Ivo Díaz , Melchior John T. , Frazer-Abel Ashley , Webb-Robertson Bobbie-Jo , Davidson W. Sean , Holers V. Michael , Rewers Marian J. , Metz Thomas O. , Nakayasu Ernesto S.
Published: September 2023

Background

Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development.

Methods

This systematic review was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria.

Results

A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development.

Conclusions

Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.
An improved transmissibility model to detect transgenerational transmitted environmental effects
Authors: David Ingrid , Ricard Anne
Published: September 2023

Background

Evolutionary studies have reported that non-genetic information can be inherited across generations (epigenetic marks, microbiota, cultural inheritance). Non-genetic information is considered to be a key element to explain the adaptation of wild species to environmental constraints because it lies at the root of the transgenerational transmission of environmental effects. The “transmissibility model” was proposed several years ago to better predict the transmissible potential of each animal by taking these diverse sources of inheritance into account in a global transmissible potential. We propose to improve this model to account for the influence of the environment on the global transmissible potential as well. This extension of the transmissibility model is the “transmissibility model with environment” that considers a covariance between transmissibility samplings of animals sharing the same environment. The null hypothesis of “no transmitted environmental effect” can be tested by comparing the two models using a likelihood ratio test (LRT).

Results

We performed simulations that mimicked an experimental design consisting of two lines of animals with one exposed to a particular environment at a given generation. This enabled us to evaluate the performances of the transmissibility model with environment so as to detect and quantify transgenerational transmitted environmental effects. The power and the realized type I error of the LRT were compared to those of a T-test comparing the phenotype of the two lines, three generations after the environmental exposure for different sets of parameters. The power of the LRT ranged from 45 to 94%, whereas that of the T-test was always lower than 26%. In addition, the realized type I error of the T-test was 15% and that of the LRT was 5%, as expected. Variances, the covariance between transmissibility samplings, and path coefficients of transmission estimated with the transmissibility model with environment were close to their true values for all sets of parameters.

Conclusions

The transmissibility model with environment is effective in modeling vertical transmission of environmental effects.
A bioinformatics screen reveals hox and chromatin remodeling factors at the Drosophila histone locus
Authors: Hodkinson Lauren J. , Smith Connor , Comstra H. Skye , Ajani Bukola A. , Albanese Eric H. , Arsalan Kawsar , Daisson Alvaro Perez , Forrest Katherine B. , Fox Elijah H. , Guerette Matthew R. , Khan Samia , Koenig Madeleine P. , Lam Shivani , Lewandowski Ava S. , Mahoney Lauren J. , Manai Nasserallah , Miglay JonCarlo , Miller Blake A. , Milloway Olivia , Ngo Nhi , Ngo Vu D. , Oey Nicole F. , Punjani Tanya A. , SiMa HaoMin , Zeng Hollis , Schmidt Casey A. , Rieder Leila E.
Published: September 2023

Background

Cells orchestrate histone biogenesis with strict temporal and quantitative control. To efficiently regulate histone biogenesis, the repetitive Drosophila melanogaster replication-dependent histone genes are arrayed and clustered at a single locus. Regulatory factors concentrate in a nuclear body known as the histone locus body (HLB), which forms around the locus. Historically, HLB factors are largely discovered by chance, and few are known to interact directly with DNA. It is therefore unclear how the histone genes are specifically targeted for unique and coordinated regulation.

Results

To expand the list of known HLB factors, we performed a candidate-based screen by mapping 30 publicly available ChIP datasets of 27 unique factors to the Drosophila histone gene array. We identified novel transcription factor candidates, including the Drosophila Hox proteins Ultrabithorax (Ubx), Abdominal-A (Abd-A), and Abdominal-B (Abd-B), suggesting a new pathway for these factors in influencing body plan morphogenesis. Additionally, we identified six other factors that target the histone gene array: JIL-1, hormone-like receptor 78 (Hr78), the long isoform of female sterile homeotic (1) (fs(1)h) as well as the general transcription factors TBP associated factor 1 (TAF-1), Transcription Factor IIB (TFIIB), and Transcription Factor IIF (TFIIF).

Conclusions

Our foundational screen provides several candidates for future studies into factors that may influence histone biogenesis. Further, our study emphasizes the powerful reservoir of publicly available datasets, which can be mined as a primary screening technique.
Risk factors associated with acute kidney injury in a pediatric intensive care unit in Addis Ababa Ethiopia: case-control study
Authors: Keneni Mulualem , Murugan Rajalakshmi , Bizuwork Ketema , Asfaw Tesfaye , Tekle Sosina , Tolosa Gadissa , Desalew Assefa
Published: September 2023

Background

Acute kidney injury (AKI) is a serious health problem in critically ill children. It is associated with poor treatment outcomes and high morbidity and mortality rates. Globally, one in three critically ill children suffers from acute kidney injury. However, limited data are available in Africa, particularly Ethiopia, which highlighting the risk factors related to acute kidney injury. Therefore, this study aimed to identify the risk factors associated with acute kidney injury among critically ill children admitted to the pediatric intensive care unit (PICU) at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia.

Methods

A facility-based unmatched case-control study was carried out on 253 (85 cases and 168 controls) critically ill children admitted to the pediatric intensive care unit from January 2011 to December 2021. Participants were selected using a systematic random sampling technique for the control group and all cases consecutively. Data were collected using a structured checklist. Data were entered using Epi data version 4.6 and analyzed using SPSS version 25. Multivariable analysis was carried out using the adjusted odds ratio (aOR) with a 95% confidence interval (CI) to identify associated factors with acute kidney injury. Statistical significance was set at P < 0.05.

Results

The median age of the participants was two years. Approximately 55.6% of cases and 53.1% of controls were females. The diagnosis of hypertension (aOR = 5.36; 95% CI: 2.06–13.93), shock (aOR = 3.88, 95% CI: 1.85–8.12), exposure to nephrotoxic drugs (aOR = 4.09; 95% CI: 1. 45- 11.59), sepsis or infection aOR = 3.36; 95% CI: 1.42–7.99), nephritic syndrome (aOR = 2.97; 95% CI:1.19, 7.43), and use of mechanical ventilation aOR = 2.25, 95% CI: 1.12, 4.51) were significantly associated factors with acute kidney injury.

Conclusion

The diagnosis of sepsis or infection, hypertension, shock, nephrotoxic drugs, demand for mechanical ventilation support, and nephritic syndrome increased the risk of AKI among critically ill children. Multiple risk factors for AKI are associated with illness and severity. All measures that ensure adequate renal perfusion must be taken in critically ill children with identified risk factors to prevent the development of AKI.
“Border closure only increased precariousness”: a qualitative analysis of the effects of restrictive measures during the COVID-19 pandemic on Venezuelan’s health and human rights in South America
Authors: Rocha-Jimenez Teresita , Olivari Carla , Martínez Alejandra , Knipper Michael , Cabieses Báltica
Published: September 2023

Background

In 2010, a political and social crisis pushed thousands of Venezuelans out of their country; today, seven million Venezuelans live abroad. In addition, during the COVID-19 pandemic, border closure increased and affected specific vulnerable migration flows, such as Venezuelans trying to migrate to Chile through the Northern borders. In this context, there is little evidence of migrants’ health status and needs, their access to health services, and other basic needs (e.g., housing) from a human rights perspective. Therefore, we qualitatively explored the effects of border closure due to the COVID-19 pandemic on Venezuelan migrants’ health and human rights, focusing on access to healthcare in the Northern Chilean border that adjoins Peru and Bolivia.

Methods

Following a case-study qualitative design, we conducted an ethnography that included participatory observation of relevant sites (e.g., hospitals, main squares, migrant shelters) in Antofagasta, Iquique, and Arica and 30 in-depth interviews with actors in the health sector (n = 7), experts from the non-governmental sector (n = 16), and governmental actors (n = 7) in three large cities close to the Northern border.

Results

We found four main dimensions: (i) border and migration processes, (ii) specific groups and intersectionality, (iii) barriers to healthcare services, and (iv) regional and local responses to the crisis during the COVID-19 pandemic. Programs characterized by the presence of healthcare providers in the field were essential to attend to migrants’ health needs at borders.

Conclusions

Coordination between actors is crucial to implement regional protocols that respond to current migration phenomena and migrants’ health needs. Health policies using a human rights approach are urgently required to respond to migrants’ healthcare needs at borders in South America.
Reliability and validity of the Chinese version of the achievement emotions questionnaire for physical education in university students
Authors: Tian Jianing , Liu Peifeng , Zhang Qianqian , Song Shun , An Shicheng , Yu Hongyan
Published: September 2023

Background

Achievement emotions have a significant impact on both the learning process and outcomes. However, there is currently no brief and effective questionnaire available to evaluate Chinese university students' achievement emotions in physical education courses. This study aimed to examine the reliability and validity of the Achievement Emotions for Physical Education Questionnaire (AEQ-PE) in a sample of Chinese university students, while also investigating its measurement invariance across gender and grade levels.

Methods

A cluster randomization sampling method was used to select 694 first- and second-year university students in Shanghai, China for the survey. Descriptive statistics, item analysis, reliability testing, and measurement invariance testing were conducted on the full sample (n = 694). Subsequently, the full sample was randomly divided into two groups, with Sample 1 (n = 347) undergoing exploratory factor analysis (EFA), and Sample 2 (n = 347) undergoing confirmatory factor analysis (CFA) to test the structural validity, convergent validity, and discriminant validity of the Chinese version of the Achievement Emotions Questionnaire for Physical Education (AEQ-PE-C). Finally, Sample 3 (n = 45), which was retested one month later, was used to evaluate test–retest reliability.

Results

The Chinese version of the Achievement Emotions Questionnaire for Physical Education consists of 6 dimensions and 24 items, with good item discrimination. The EFA supported a 6-factor structure model, while the CFA demonstrated good model fit indices (χ2/df = 3.086, CFI = 0.928, TLI = 0.916, RMSEA = 0.078) and good convergent and discriminant validity. The questionnaire exhibits high internal consistency reliability (0.794) and excellent test–retest reliability (0.792). Furthermore, the multi-group analysis confirms that the AEQ-PE-C questionnaire has measurement invariance across gender and grade levels.

Conclusion

The Chinese version of the Achievement Emotions Questionnaire for Physical Education has good reliability and validity, as well as measurement invariance across gender and grade levels, making it an effective tool for measuring achievement emotions in physical education among Chinese university students.
Deliberate practice of diagnostic clinical reasoning reveals low performance and improvement of diagnostic justification in pre-clerkship students
Authors: Staal Justine , Waechter Jason , Allen Jon , Lee Chel Hee , Zwaan Laura
Published: September 2023

Purpose

Diagnostic errors are a large burden on patient safety and improving clinical reasoning (CR) education could contribute to reducing these errors. To this end, calls have been made to implement CR training as early as the first year of medical school. However, much is still unknown about pre-clerkship students’ reasoning processes. The current study aimed to observe how pre-clerkship students use clinical information during the diagnostic process.

Methods

In a prospective observational study, pre-clerkship medical students completed 10–11 self-directed online simulated CR diagnostic cases. CR skills assessed included: creation of the differential diagnosis (Ddx), diagnostic justification (DxJ), ordering investigations, and identifying the most probable diagnosis. Student performances were compared to expert-created scorecards and students received detailed individualized formative feedback for every case.

Results

121 of 133 (91%) first- and second-year medical students consented to the research project. Students scored much lower for DxJ compared to scores obtained for creation of the Ddx, ordering tests, and identifying the correct diagnosis, (30–48% lower, p < 0.001). Specifically, students underutilized physical exam data (p < 0.001) and underutilized data that decreased the probability of incorrect diagnoses (p < 0.001). We observed that DxJ scores increased 40% after 10–11 practice cases (p < 0.001).

Conclusions

We implemented deliberate practice with formative feedback for CR starting in the first year of medical school. Students underperformed in DxJ, particularly with analyzing the physical exam data and pertinent negative data. We observed significant improvement in DxJ performance with increased practice.
Student nurses as a future general practice nursing workforce. Implementing collaborative learning in practice: implications for placement learning and patient access. A mixed methods study
Authors: Williamson Graham R , Kane Adele , Evans Sharon , Attrill Lisa , Cook Fiona , Nash Katy
Published: September 2023

Background

There is a global shortage of nurses, with particularly acute shortfall in General Practice Nursing in the United Kingdom estimated at as high as 50% vacancy rate by 2031 by some sources. There has previously been reluctance for General Practices to host student nurses on placement, but it has become imperative to increase placement capacity if practices are to be able to recruit a future workforce. Collaborative Learning in Practice is a means of organising placement learning for student nurses using a coaching model, that allows for leadership development, peer support and earlier engagement in patient care, and increases placement capacity.

Methods

This was a mixed methods study using qualitative data from focus groups to evaluate the implementation of Collaborative Learning in Practice, and routinely collected audit data on numbers of clinic appointments to investigate the potential impact an increased capacity of student nurses might have on patient access to services. The aims of this study were: to implement and evaluate Collaborative Learning in Practice in General Practice Nursing settings; to explore issues of interprofessional learning; to explore patient access to services related to increased student nurse capacity.

Results

Our qualitative data indicated the following themes as important to students and staff: Peer Support; Interprofessional Learning; and the Importance of ‘own clinics’ for students to see patients. The audit data indicated that having students leading their own clinics increased the clinic numbers available by approximately 20% compared to when students were not in placement.

Conclusions

This study shows that student nurses increased clinic capacity and improved access for patients. Students valued their placement, felt that they were more ‘part of the team’ than in other placements and consequently had a greater sense of belonging. This was multifaceted, coming in part from the welcoming practice staff, in part from the opportunities for peer support engendered by the collaborative learning in practice model, and in part from the interprofessional learning opportunities available. General Practice Nursing placements for students are important for future workforce recruitment and can help meet Quality and Outcomes Framework targets for General Practices.
Evaluation of treatment patterns, healthcare resource utilization and cost of illness for sickle cell disease in Ghana: a private medical insurance claims database study
Authors: Marfo Kwaku , Dei-Adomakoh Yvonne , Segbefia Catherine , Dwomoh Duah , Edgal Adeline , Ampah Nancy , Ramachandrachar Badarinath Chickballapur , Subramanyam Kumaresan , Natarajan Ashok , Egbujo Olufolake , Ataga Kenneth I.
Published: September 2023

Background

Sickle cell disease (SCD) is a major public health concern in sub-Saharan Africa, accounting for nearly 75% of the global disease burden. The current analysis evaluated patient characteristics, treatment patterns, healthcare resource utilization (HCRU) and associated costs in patients with SCD based on a Private Medical Insurance Database in Ghana.

Methods

This retrospective longitudinal cohort study was conducted using an e-claims database from Ghana (01 January 2015 to 31 March 2021). Patients were stratified by age (0 month to < 2 years, ≥ 2 years to ˂6 years, ≥ 6 years to < 12 years, ≥ 12 years to < 16 years; ≥16 years), vaso-occlusive crisis (VOC) (< 1, ≥ 1 to < 3, and ≥ 3 per year), and continuous enrolment. Study outcomes related to patient characteristics, comorbidities, treatment pattern, HCRU were evaluated for pre- and post-index period (index period was between July 2015 to March 2020). Descriptive analysis was used to analyse different study variables.

Results

The study included 2,863 patients (mean age: 20.1 years; Min age: 0; Max age: 83; females 56.1%). Overall, 52.2% (n = 1,495) of SCD patients were ≥ 16 years and 17.0% (n = 486) were in the ≥ 2 to ˂6-years age group. The majority of patients aged ≥ 16 years (62.5%) in the database did not have reported VOC episodes, 35.9% of patients had 1 to 3 VOCs per year and 1.5% had ≥ 3 VOCs per year during the follow-up period. Consultation-based prevalence of SCD was 0.5% [95% confidence interval (CI): 0-1.3%] − 1.4% [CI: 0.6-2.2%]. Malaria, upper respiratory tract infection (URTI) and sepsis were the common complications of SCD. Analgesics were the most frequently prescribed medications followed by anti-infectives, hematinics, and antimalarials. Hydroxyurea, a routine standard of care for SCD was under-utilized. SCD patients had median cost incurred for consultation/hospital services of $11.3 (Interquartile range [IQR] $6.2 - $27.2). For patients with VOC, maximum median cost was incurred for medications ($10.9 [IQR $5.0-$32.6]). Overall median healthcare cost was highest for individuals with ≥ 3 VOCs per year during the follow-up period ($166.8 [IQR $70.3-$223.5]).

Conclusion

In this retrospective private insurance claims database analysis, SCD imposes a significant healthcare burden, especially in patients with VOC. There is a need for reimbursed treatment options that could reduce the long-term burden associated with SCD and VOC.
Nuclear receptor RXRα binds the precursor of miR-103 to inhibit its maturation
Authors: Ye Xiaohong , Yang Yun , Yao Jiayue , Wang Mo , Liu Yixin , Xie Guobin , Zeng Zhiping , Zhang Xiao-kun , Zhou Hu
Published: September 2023

Background

The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute ˗mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known.

Results

In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer.

Conclusions

Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.
Identification of the expression patterns and potential prognostic role of m6A-RNA methylation regulators in Wilms Tumor
Authors: Jia Changlin , Gao Hongjie , Ma Wenyue , Liu Xiaoya , Chang Mengmeng , Sun Fengyin
Published: September 2023

Background

To explore the potential role of m6A methylation modification in Wilms Tumor (WT) by m6A-RNA Methylation (m6A) regulators.

Methodology

The association of m6A modification patterns with immune and prognostic characteristics of tumors was systematically evaluated using 19 m6A regulators extracted from Wilms Tumor’s samples in public databases. A comprehensive model of “m6Ascore” was constructed using principal component analysis, and its prognostic value was evaluated.

Results

Almost all m6A regulators were differentially expressed between WT and normal tissues. Unsupervised clustering identified three distinct m6A clusters that differed in both immune cell infiltration and biological pathways. The m6Ascore was constructed to quantify m6A modifications in individual patients. Our analysis suggests that m6Ascore is an independent prognostic factor for WT and can be used as a novel predictor of WT prognosis.

Conclusions

This study comprehensively explored and systematically characterized m6A modifications in WT. m6A modification patterns play a critical role in the tumor immune microenvironment (TIME) and WT prognosis. m6Ascore provides a more comprehensive understanding of m6A modifications in WT and offers a practical tool for predicting WT prognosis. This study will help clinicians to identify valid indicators of WT to improve the poor prognosis of this disease.

Supplementary Information

The online version contains supplementary material available at https://www.aliyundrive.com/drive/folder/64be739cd6956a741fb24670baeea53422be6024.
Diabetes- versus smoking-related thrombo-inflammation in peripheral artery disease
Authors: Alnima T. , Meijer R. I. , Spronk H. M.H. , Warlé M. , Cate H. ten
Published: September 2023

Peripheral artery disease (PAD) is a major health problem with increased cardiovascular mortality, morbidity and disabling critical limb threatening ischemia (CLTI) and amputation. Diabetes mellitus (DM) and cigarette smoke are the main risk factors for the development of PAD. Although diabetes related PAD shows an accelerated course with worse outcome regarding complications, mortality and amputations compared with non-diabetic patients, current medical treatment does not make this distinction and includes standard antiplatelet and lipid lowering drugs for all patients with PAD. In this review we discuss the pathophysiologic mechanisms of PAD, with focus on differences in thrombo-inflammatory processes between diabetes-related and smoking-related PAD, and hypothesize on possible mechanisms for the progressive course of PAD in DM. Furthermore, we comment on current medical treatment and speculate on alternative medical drug options for patients with PAD and DM.
Catastrophic health expenditure and its association with socioeconomic status in China: evidence from the 2011-2018 China Health and Retirement Longitudinal Study
Authors: Li Xi , Mohanty Itismita , Zhai Tiemin , Chai Peipei , Niyonsenga Theo
Published: September 2023

Background

An increase in healthcare utilization in response to universal health coverage may leave massive economic burden on individuals and households. Identifying catastrophic health expenditure helps us understand such burden. This study aims to examine the incidence of catastrophic health expenditure at various thresholds, explore its trend over years, and investigate whether it varies across socioeconomic status (SES).

Methods

Data used in this study were from four waves of the China Health and Retirement Longitudinal Study (CHARLS): 2011, 2013, 2015, and 2018. SES was measured by annual per-capita household expenditure, which was then divided into quintiles (Quintile 1 (Q1): the poorest - Quintile 5 (Q5): the wealthiest). Catastrophic health expenditure was measured at both a fixed threshold (40%) and a set of variable thresholds, where the thresholds for other quintiles were estimated by multiplying 40% by the ratio of average food expenditure in certain quintile to that in the index quintile. Multilevel mixed-effects logistic regression models were used to analyze the determinants of catastrophic health expenditure at various thresholds.

Results

A total of 6,953 households were included in our study. The incidence of catastrophic health expenditure varied across the thresholds set. At a fixed threshold, 10.90%, 9.46%, 13.23%, or 24.75% of households incurred catastrophic health expenditure in 2011, 2013, 2015, and 2018, respectively, which were generally lower than those at variable thresholds. Catastrophic health expenditure often decreased from 2011 to 2013, and an increasing trend occurred afterwards. Compared to households in Q5, those in lower quintiles were more likely to suffer catastrophic health expenditure, irrespective of the thresholds set. Similarly, having chronic diseases and healthcare utilization increased the odds of catastrophic health expenditure.

Conclusions

The financial protection against catastrophic health expenditure shocks remains a challenge in China, especially for the low-SES and those with chronic diseases. Concerted efforts are needed to further expand health insurance coverage across breadth, depth, and height, optimize health financing mechanism, redesign cost-sharing arrangements and provider payment methods, and develop more efficient expenditure control strategies.
Nano-immunotherapy: overcoming delivery challenge of immune checkpoint therapy
Authors: Kiaie Seyed Hossein , Salehi-Shadkami Hossein , Sanaei Mohammad Javad , Azizi Marzieh , Shokrollahi Barough Mahdieh , Nasr Mohammad Sadegh , Sheibani Mohammad
Published: September 2023

Immune checkpoint (ICP) molecules expressed on tumor cells can suppress immune responses against tumors. ICP therapy promotes anti-tumor immune responses by targeting inhibitory and stimulatory pathways of immune cells like T cells and dendritic cells (DC). The investigation into the combination therapies through novel immune checkpoint inhibitors (ICIs) has been limited due to immune-related adverse events (irAEs), low response rate, and lack of optimal strategy for combinatorial cancer immunotherapy (IMT). Nanoparticles (NPs) have emerged as powerful tools to promote multidisciplinary cooperation. The feasibility and efficacy of targeted delivery of ICIs using NPs overcome the primary barrier, improve therapeutic efficacy, and provide a rationale for more clinical investigations. Likewise, NPs can conjugate or encapsulate ICIs, including antibodies, RNAs, and small molecule inhibitors. Therefore, combining the drug delivery system (DDS) with ICP therapy could provide a profitable immunotherapeutic strategy for cancer treatment. This article reviews the significant NPs with controlled DDS using current data from clinical and pre-clinical trials on mono- and combination IMT to overcome ICP therapeutic limitations.

Graphical Abstract
Hypoxic mesenchymal stem cell-derived exosomes promote the survival of skin flaps after ischaemia–reperfusion injury via mTOR/ULK1/FUNDC1 pathways
Authors: Deng Chao , Dong Kangkang , Liu Yongjun , Chen Ken , Min Chuwei , Cao Zheming , Wu Panfeng , Luo Gaojie , Cheng Gechang , Qing Liming , Tang Juyu
Published: September 2023

Flap necrosis, the most prevalent postoperative complication of reconstructive surgery, is significantly associated with ischaemia–reperfusion injury. Recent research indicates that exosomes derived from bone marrow mesenchymal stem cells (BMSCs) hold potential therapeutic applications in several diseases. Traditionally, BMSCs are cultured under normoxic conditions, a setting that diverges from their physiological hypoxic environment in vivo. Consequently, we propose a method involving the hypoxic preconditioning of BMSCs, aimed at exploring the function and the specific mechanisms of their exosomes in ischaemia–reperfusion skin flaps. This study constructed a 3 × 6 cm2 caudal superficial epigastric skin flap model and subjected it to ischaemic conditions for 6 h. Our findings reveal that exosomes from hypoxia-pretreated BMSCs significantly promoted flap survival, decrease MCP-1, IL-1β, and IL-6 levels in ischaemia–reperfusion injured flap, and reduce oxidative stress injury and apoptosis. Moreover, results indicated that Hypo-Exo provides protection to vascular endothelial cells from ischaemia–reperfusion injury both in vivo and in vitro. Through high-throughput sequencing and bioinformatics analysis, we further compared the differential miRNA expression profiles between Hypo-Exo and normoxic exosomes. Results display the enrichment of several pathways, including autophagy and mTOR. We have also elucidated a mechanism wherein Hypo-Exo promotes the survival of ischaemia–reperfusion injured flaps. This mechanism involves carrying large amounts of miR-421-3p, which target and regulate mTOR, thereby upregulating the expression of phosphorylated ULK1 and FUNDC1, and subsequently further activating autophagy. In summary, hypoxic preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of BMSC-derived exosomes in the treatment of flap ischaemia–reperfusion injury.
The health and economic impact and cost effectiveness of interventions for the prevention and control of overweight and obesity in Kenya: a stakeholder engaged modelling study
Authors: Wanjau Mary Njeri , Kivuti-Bitok Lucy W. , Aminde Leopold N. , Veerman J. Lennert
Published: September 2023

Background

The global increase in mean body mass index has resulted in a substantial increase of non-communicable diseases (NCDs), including in many low- and middle-income countries such as Kenya. This paper assesses four interventions for the prevention and control of overweight and obesity in Kenya to determine their potential health and economic impact and cost effectiveness.

Methods

We reviewed the literature to identify evidence of effect, determine the intervention costs, disease costs and total healthcare costs. We used a proportional multistate life table model to quantify the potential impacts on health conditions and healthcare costs, modelling the 2019 Kenya population over their remaining lifetime. Considering a health system perspective, two interventions were assessed for cost-effectiveness. In addition, we used the Human Capital Approach to estimate productivity gains.

Results

Over the lifetime of the 2019 population, impacts were estimated at 203,266 health-adjusted life years (HALYs) (95% uncertainty interval [UI] 163,752 − 249,621) for a 20% tax on sugar-sweetened beverages, 151,718 HALYs (95% UI 55,257 − 250,412) for mandatory kilojoule menu labelling, 3.7 million HALYs (95% UI 2,661,365–4,789,915) for a change in consumption levels related to supermarket food purchase patterns and 13.1 million HALYs (95% UI 11,404,317 − 15,152,341) for a change in national consumption back to the 1975 average levels of energy intake. This translates to 4, 3, 73 and 261 HALYs per 1,000 persons. Lifetime healthcare cost savings were approximately United States Dollar (USD) 0.14 billion (USD 3 per capita), USD 0.08 billion (USD 2 per capita), USD 1.9 billion (USD 38 per capita) and USD 6.2 billion (USD 124 per capita), respectively. Lifetime productivity gains were approximately USD 1.8 billion, USD 1.2 billion, USD 28 billion and USD 92 billion. Both the 20% tax on sugar sweetened beverages and the mandatory kilojoule menu labelling were assessed for cost effectiveness and found dominant (health promoting and cost-saving).

Conclusion

All interventions evaluated yielded substantive health gains and economic benefits and should be considered for implementation in Kenya.
Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications
Authors: Lin Weikai , Fang Jianjun , Wei Shibo , He Guangpeng , Liu Jiaxing , Li Xian , Peng Xueqiang , Li Dai , Yang Shuo , Li Xinyu , Yang Liang , Li Hangyu
Published: September 2023

Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs.
Epigenetic meets metabolism: novel vulnerabilities to fight cancer
Authors: Scumaci Domenica , Zheng Qingfei
Published: September 2023

Histones undergo a plethora of post-translational modifications (PTMs) that regulate nucleosome and chromatin dynamics and thus dictate cell fate. Several evidences suggest that the accumulation of epigenetic alterations is one of the key driving forces triggering aberrant cellular proliferation, invasion, metastasis and chemoresistance pathways. Recently a novel class of histone “non-enzymatic covalent modifications” (NECMs), correlating epigenome landscape and metabolic rewiring, have been described. These modifications are tightly related to cell metabolic fitness and are able to impair chromatin architecture. During metabolic reprogramming, the high metabolic flux induces the accumulation of metabolic intermediate and/or by-products able to react with histone tails altering epigenome homeostasis. The accumulation of histone NECMs is a damaging condition that cancer cells counteracts by overexpressing peculiar “eraser” enzymes capable of removing these modifications preserving histones architecture. In this review we explored the well-established NECMs, emphasizing the role of their corresponding eraser enzymes. Additionally, we provide a parterre of drugs aiming to target those eraser enzymes with the intent to propose novel routes of personalized medicine based on the identification of epi-biomarkers which might be selectively targeted for therapy.
Elucidating the molecular mechanisms underlying the induction of autophagy by antidepressant-like substances in C57BL/6J mouse testis model upon LPS challenge
Authors: Sołek Przemysław , Czechowska Ewelina , Sowa-Kućma Magdalena , Stachowicz Katarzyna , Kaczka Piotr , Tabęcka-Łonczyńska Anna
Published: September 2023

The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis.

Graphical Abstract
Exosomal lncRNA Mir100hg derived from cancer stem cells enhance glycolysis and promote metastasis of lung adenocarcinoma through mircroRNA-15a-5p/31-5p
Authors: Shi Lei , Li Bowen , Zhang Yuhan , Chen Yuting , Tan Jiyu , Chen Yan , Li Jie , Xiang Meng , Xing H. Rosie , Wang Jianyu
Published: September 2023

Background

Exosomes are a new class of molecular entities in the metastatic microenvironment, which can mediate bidirectional communication between cells. While exosomes-mediated interactions between tumor cells and other cell populations in the tumor microenvironment have attracted most attention, little is known about the significance of exosomes in mediating the interaction between non-stemness cancer cells and cancer stem cells during cancer progression.

Methods

The structure, sequence and downstream target miRNAs of lncRNA Mir100hg were predicted by online web resources. The bioinformatics prediction results were validated with experimental verification: exosome tracing, electron microscopy, Luciferase assay, metabolomics sequencing and mouse tail vein model of pulmonary metastasis. A complex regulatory network of "cancer stem cells-exosomal lncRNA-non-stem cancer cells" was constructed.

Results

This study demonstrates firstly that lncRNA Mir100hg is upregulated in lung cancer stem cell LLC-SD (Lung cancer stem cells) and can be delivered to non-stemness cancer cells LLC (Lewis lung cancer cells) via exosomes. In LLC, Mir100hg targets miR-15a-5p and miR-31-5p which leads to the increase of the global glycolytic activity of lung cancer cells and consequently, the enhancement of their metastatic capability.

Conclusion

We delineated a complex regulatory network that utilized by cancer stem cells to transfer their high metastatic activity to the low-metastatic non-stemness cancer cells through exosomal Mir100hg, thereby providing new mechanistic insights into the communication between two heterogeneous tumor cells.
Identification of memory B-cell-associated miRNA signature to establish a prognostic model in gastric adenocarcinoma
Authors: Liu Ruquan , Huang Biaojie , Shao Yongzhao , Cai Yongming , Liu Xi , Ren Zhonglu
Published: September 2023

Background

Memory B cells and microRNAs (miRNAs) play important roles in the progression of gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD). However, few studies have investigated the use of memory B-cell-associated miRNAs in predicting the prognosis of STAD.

Methods

We identified the marker genes of memory B cells by single-cell RNA sequencing (scRNA-seq) and identified the miRNAs associated with memory B cells by constructing an mRNA‒miRNA coexpression network. Then, univariate Cox, random survival forest (RSF), and stepwise multiple Cox regression (StepCox) algorithms were used to identify memory B-cell-associated miRNAs that were significantly related to overall survival (OS). A prognostic risk model was constructed and validated using these miRNAs, and patients were divided into a low-risk group and a high-risk group. In addition, the differences in clinicopathological features, tumour microenvironment, immune blocking therapy, and sensitivity to anticancer drugs in the two groups were analysed.

Results

Four memory B-cell-associated miRNAs (hsa-mir-145, hsa-mir-125b-2, hsa-mir-100, hsa-mir-221) with significant correlations to OS were identified and used to construct a prognostic model. Time-dependent receiver operating characteristic (ROC) curve analysis confirmed the feasibility of the model. Kaplan‒Meier (K‒M) survival curve analysis showed that the prognosis was poor in the high-risk group. Comprehensive analysis showed that patients in the high-risk group had higher immune scores, matrix scores, and immune cell infiltration and a poor immune response. In terms of drug screening, we predicted eight drugs with higher sensitivity in the high-risk group, of which CGP-60474 was associated with the greatest sensitivity.

Conclusions

In summary, we identified memory B-cell-associated miRNA prognostic features and constructed a novel risk model for STAD based on scRNA-seq data and bulk RNA-seq data. Among patients in the high-risk group, STAD showed the highest sensitivity to CGP-60474. This study provides prognostic insights into individualized and precise treatment for STAD patients.
Characterization of tumor microenvironment and tumor immunology based on the double-stranded RNA-binding protein related genes in cervical cancer
Authors: Li Jin , Wan Chong , Li Xiaoqi , Quan Chenlian , Li Xiaoqiu , Wu Xiaohua
Published: September 2023

Background

Cervical cancer is one of the most common gynecological cancers threatening women’s health worldwide. Double-stranded RNA-binding proteins (dsRBPs) regulate innate immunity and are therefore believed to be involved in virus-related malignancies, however, their role in cervical cancer is not well known.

Methods

We performed RNA-seq of tumor samples from cervical cancer patients in local cohort and also assessed the RNA-seq and clinical data derived from public datasets. By using single sample Gene Set Enrichment Analysis (ssGSEA) and univariate Cox analysis, patients were stratified into distinct dsRBP clusters. Stepwise Cox and CoxBoost were performed to construct a risk model based on optimal dsRBPs clusters-related differentially expressed genes (DEGs), and GSE44001 and CGCI-HTMCP-CC were employed as two external validation cohorts. Single cell RNA sequencing data from GSE168652 and Scissor algorithm were applied to evaluated the signature-related cell population.

Results

The expression of dsRBP features was found to be associated with HPV infection and carcinogenesis in CESC. However, only Adenosine deaminases acting on RNA (ADAR) and Dicer, Drosha, and Argonautes (DDR) exhibited significant correlations with the overall survival (OS) of CESC patients. Based on these findings, CESC patients were divided into three dsRBP clusters. Cluster 3 showed superior OS but lower levels of ADAR and DDR. Additionally, Cluster 3 demonstrated enhanced innate immunity, with significantly higher activity in cancer immunity cycles, immune scores, and levels of tumor-infiltrating immune cells, particularly CD8+ T cells. Furthermore, a risk model based on nine dsRBP cluster-related DEGs was established. The accuracy of survival prediction for 1 to 5 years was consistently above 0.78, and this model’s robust predictive capacity was confirmed by two external validation sets. The low-risk group exhibited significantly higher levels of immune checkpoints, such as PDCD1 and CTLA4, as well as a higher abundance of CD8+ T cells. Analysis of single-cell sequencing data revealed a significant association between the dsRBP signature and glycolysis. Importantly, low-risk patients showed improved OS and a higher response rate to immunotherapy, along with enduring clinical benefits from concurrent chemoradiotherapy.

Conclusions

dsRBP played a crucial role in the regulation of prognosis and tumor immunology in cervical cancer, and its prognostic signature provides a strategy for risk stratification and immunotherapy evaluation.