bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgically resectable nonsmall cell lung cancer: a contemporary approach
Authors: D'Amours Marie-Frédérique , Wu Florence T.H. , Theisen-Lauk Olivia , Chan Elisa K. , McGuire Anna , Ho Cheryl
Published: June 2024

New treatment paradigms for resectable nonsmall cell lung cancer (NSCLC), with an emphasis on personalised care and a multidisciplinary approach, have significantly improved patient outcomes. The incorporation of immune checkpoint inhibitors into neoadjuvant, perioperative and adjuvant treatment algorithms is reshaping the standard of care for resectable NSCLC. Adjuvant targeted therapy trials have also paved the way for a much-needed personalised approach for patients with actionable genomic alterations. Innovative surgical techniques and judicious use of postoperative radiotherapy may mitigate the toxicity associated with a multimodality approach. Amid the many new treatment options, questions remain about the best approach to consider for each patient. Measurement of minimal residual disease and achievement of pathological complete response are emerging biomarkers of interest to help further refine treatment selection. This review summarises the current management of resectable NSCLC, focusing on ongoing and recent advances in surgical approaches, the role of postoperative radiotherapy and the rapidly changing field of systemic therapies.
European Respiratory Society statement on preschool wheezing disorders: updated definitions, knowledge gaps and proposed future research directions
Authors: Makrinioti Heidi , Fainardi Valentina , Bonnelykke Klaus , Custovic Adnan , Cicutto Lisa , Coleman Courtney , Eiwegger Thomas , Kuehni Claudia , Moeller Alexander , Pedersen Eva , Pijnenburg Marielle , Pinnock Hilary , Ranganathan Sarath , Tonia Thomy , Subbarao Padmaja , Saglani Sejal
Published: June 2024

Since the publication of the European Respiratory Society (ERS) task force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting that the clinical phenotypes that were proposed (episodic (viral) wheezing and multiple-trigger wheezing) do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS task force reviewed the literature published after 2008 related to preschool wheezing and has suggested that the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to <6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever. Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the task force identified an absence of caregiver-reported outcomes, caregiver/self-management options and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying 1) mechanisms driving preschool wheezing; 2) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia; 3) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials; 4) the need for a suitable action plan for children with preschool wheezing; and 5) a definition of severe/difficult-to-treat preschool wheezing.
Wogonin upregulates SOCS3 to alleviate the injury in Diabetic Nephropathy by inhibiting TLR4-mediated JAK/STAT/AIM2 signaling pathway
Authors: Liu Yufeng , Zhang Mengbi , Zeng Lu , Lai Yanhong , Wu Songzhao , Su Xiaoyan
Published: June 2024

Background

Diabetic nephropathy (DN) is a life-threatening renal disease and needs urgent therapies. Wogonin is renoprotective in DN. This study aimed to explore the mechanism of how wogonin regulated high glucose (HG)-induced renal cell injury.

Methods

Diabetic mice (db/db), control db/m mice, and normal glucose (NG)- or HG-treated human tubule epithelial cells (HK-2) were used to evaluate the levels of suppressor of cytokine signaling 3 (SOCS3), Toll-like receptor 4 (TLR4), inflammation and fibrosis. Lentivirus was used to regulate SOCS3 and TLR4 expressions. After oral gavage of wogonin (10 mg/kg) or vehicle in db/db mice, histological morphologies, blood glucose, urinary protein, serum creatinine values (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH), and reactive oxygen species (ROS) were assessed. RT-qPCR and Western blot evaluated inflammation and fibrosis-related molecules.

Results

HG exposure induced high blood glucose, severe renal injuries, high serumal Src and BUN, low SOD and GSH, and increased ROS. HG downregulated SOCS3 but upregulated TLR4 and JAK/STAT, fibrosis, and inflammasome-related proteins. Wogonin alleviated HG-induced renal injuries by decreasing cytokines, ROS, Src, and MDA and increasing SOD and GSH. Meanwhile, wogonin upregulated SOCS3 and downregulated TLR4 under HG conditions. Wogonin-induced SOCS3 overexpression directly decreased TLR4 levels and attenuated JAK/STAT signaling pathway-related inflammation and fibrosis, but SOCS3 knockdown significantly antagonized the protective effects of wogonin. However, TLR4 knockdown diminished SOCS3 knockdown-induced renal injuries.

Conclusion

Wogonin attenuates renal inflammation and fibrosis by upregulating SOCS3 to inhibit TLR4 and JAK/STAT pathway.
Using expression data to fine map QTL associated with fertility in dairy cattle
Authors: van den Berg Irene , Chamberlain Amanda J. , MacLeod Iona M. , Nguyen Tuan V. , Goddard Mike E. , Xiang Ruidong , Mason Brett , Meier Susanne , Phyn Claire V. C. , Burke Chris R. , Pryce Jennie E.
Published: June 2024

Background

Female fertility is an important trait in dairy cattle. Identifying putative causal variants associated with fertility may help to improve the accuracy of genomic prediction of fertility. Combining expression data (eQTL) of genes, exons, gene splicing and allele specific expression is a promising approach to fine map QTL to get closer to the causal mutations. Another approach is to identify genomic differences between cows selected for high and low fertility and a selection experiment in New Zealand has created exactly this resource. Our objective was to combine multiple types of expression data, fertility traits and allele frequency in high- (POS) and low-fertility (NEG) cows with a genome-wide association study (GWAS) on calving interval in Australian cows to fine-map QTL associated with fertility in both Australia and New Zealand dairy cattle populations.

Results

Variants that were significantly associated with calving interval (CI) were strongly enriched for variants associated with gene, exon, gene splicing and allele-specific expression, indicating that there is substantial overlap between QTL associated with CI and eQTL. We identified 671 genes with significant differential expression between POS and NEG cows, with the largest fold change detected for the CCDC196 gene on chromosome 10. Our results provide numerous candidate genes associated with female fertility in dairy cattle, including GYS2 and TIGAR on chromosome 5 and SYT3 and HSD17B14 on chromosome 18. Multiple QTL regions were located in regions with large numbers of copy number variants (CNV). To identify the causal mutations for these variants, long read sequencing may be useful.

Conclusions

Variants that were significantly associated with CI were highly enriched for eQTL. We detected 671 genes that were differentially expressed between POS and NEG cows. Several QTL detected for CI overlapped with eQTL, providing candidate genes for fertility in dairy cattle.
Definition of metafounders based on population structure analysis
Authors: Anglhuber Christine , Edel Christian , Pimentel Eduardo C. G. , Emmerling Reiner , Götz Kay-Uwe , Thaller Georg
Published: June 2024

Background

Limitations of the concept of identity by descent in the presence of stratification within a breeding population may lead to an incomplete formulation of the conventional numerator relationship matrix ($$\mathbf{A}$$
A
). Combining $$\mathbf{A}$$
A
with the genomic relationship matrix ($$\mathbf{G}$$
G
) in a single-step approach for genetic evaluation may cause inconsistencies that can be a source of bias in the resulting predictions. The objective of this study was to identify stratification using genomic data and to transfer this information to matrix $$\mathbf{A}$$
A
, to improve the compatibility of $$\mathbf{A}$$
A
and $$\mathbf{G}$$
G
.

Methods

Using software to detect population stratification (ADMIXTURE), we developed an iterative approach. First, we identified 2 to 40 strata ($$k$$
k
) with ADMIXTURE, which we then introduced in a stepwise manner into matrix $$\mathbf{A}$$
A
, to generate matrix $${\mathbf{A}}^{{\varvec{\Gamma}}}$$

A

Γ

using the metafounder methodology. Improvements in consistency between matrix $$\mathbf{G}$$
G
and $${\mathbf{A}}^{{\varvec{\Gamma}}}$$

A

Γ

were evaluated by regression analysis and through the comparison of the overall mean and mean diagonal values of both matrices. The approach was tested on genotype and pedigree information of European and North American Brown Swiss animals (85,249). Analyses with ADMIXTURE were initially performed on the full set of genotypes (S1). In addition, we used an alternative dataset where we avoided sampling of closely related animals (S2).

Results

Results of the regression analyses of standard $$\mathbf{A}$$
A
on $$\mathbf{G}$$
G
were – 0.489, 0.780 and 0.647 for intercept, slope and fit of the regression. When analysing S1 data results of the regression for $${\mathbf{A}}^{{\varvec{\Gamma}}}$$

A

Γ

on $$\mathbf{G}$$
G
corresponding values were – 0.028, 1.087 and 0.807 for $$k$$
k
=7, while there was no clear optimum $$k$$
k
. Analyses of S2 gave a clear optimal $$k$$
k
=24, with − 0.020, 0.998 and 0.817 as results of the regression. For this $$k$$
k
differences in mean and mean diagonal values between both matrices were negligible.

Conclusions

The derivation of hidden stratification information based on genotyped animals and its integration into $$\mathbf{A}$$
A
improved compatibility of the resulting $${\mathbf{A}}^{{\varvec{\Gamma}}}$$

A

Γ

and $$\mathbf{G}$$
G
considerably compared to the initial situation. In dairy breeding populations with large half-sib families as sub-structures it is necessary to balance the data when applying population structure analysis to obtain meaningful results.
Serum beta2-microglobulin acts as a biomarker for severity and prognosis in glioma patients: a preliminary clinical study
Authors: Liu Zhen-Yuan , Tang Feng , Wang Jing , Yang Jin-Zhou , Chen Xi , Wang Ze-Fen , Li Zhi-Qiang
Published: June 2024

Background

Gliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas.

Methods

Medical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM).

Results

Patients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05–3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients.

Conclusions

High preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response.
Preparation of the pre-service teacher to deliver comprehensive sexuality education: teaching content and evaluation of provision
Authors: Hendriks Jacqueline , Mayberry Lorel , Burns Sharyn
Published: June 2024

Background

Despite the extensive benefits associated with the provision of comprehensive sexuality education (CSE) within a school context, many initial teacher training programs inadequately prepare pre-service teachers to deliver this content. Programs that do provide such instruction do not routinely share details of their curriculum, syllabi, or evaluation data.

Methods

This paper outlines the structure of an Australian undergraduate course for pre-service teachers that focuses on instruction in CSE. This course spans twelve teaching weeks, aligns with evidence-based principles for sexuality education, prioritises experiential learning and requires students to complete authentic, practical assessment tasks. Formative, process, and short-term impact evaluation data, based upon five years of delivery, are described.

Results

Students completing this course reported statistically significant improvements in attitudes associated with CSE and comfort in facilitating all domains of learning (knowledge, attitudes, skills).

Conclusions

Positive process and short-term impact data provide strong evidence for the provision of CSE to pre-service teachers, regardless of future teaching speciality. Proposed amendments include the creation of a fully online tuition pattern and an expansion of content to incorporate other audiences, such as community-based educators.
In vivo non-contact regions of proximal scaphoid in six extreme wrist positions
Authors: Xie Ren-Guo
Published: June 2024

Introduction

Fractures of the scaphoid are the most common carpal injuries, account for 80-90% of all carpal fractures. 5-15% nonunion of scaphoid fractures were reported even with adequate primary treatment, which probably progresses to osteoarthritic changes several decades later. Researches regarding to scaphoid physiological characteristic in vitro and in vivo and kinds of trials in clinical practice are being kept on going, which contribute much to our clinical practice. With the advancing wrist arthroscopy, 3D-print patient-specific drill guide, and intraoperative fluoroscopic guidance, dorsal approach (mini-invasive and percutaneous technique) is being popular, through which we can implant the screw in good coincidence with biomechanics and with less disturbing tenuous blood supply of the scaphoid. Investigating the noncontact area of the dorsal proximal scaphoid in different wrist positions can facilitate preoperatively estimating insert point of the screw.

Materials and methods

Eight volunteers were recruited to accept CT scans in six extreme wrist positions. The images of DICOM mode were imput into the Mimics analytical system, the segmented scaphoid, lunate and radius were exported in mode of ASCII STL and were opened in the software of Geomagic studio. We created four planes based on anatomic markers on the surface of the radius and scaphoid to confine the proximal scaphoid to form the so-called non-contact regions. We measured and compared the areas in six targeted positions.

Results

Amidst six extreme wrist positions, area of the non-contact region in extreme dorsal extension (59.81 ± 26.46 mm2) was significantly the smallest, and it in extreme palmar flexion significantly was largest (170.51 ± 30.44 mm2). The non-contact regions increased in order of dorsal extension, supination, ulnar deviation, radial deviation, pronation and palmar flexion. As for two-group comparison, the non-contact region showed significantly larger (p < 0.05) in palmar flexion than the others except for in pronation individually, and in radial deviation (p < 0.05) than in dorsal extension.

Conclusions

Sufficient space was available for the screw started from the dorsal approach despite the wrist positions.
Stress and exhaustion among medical students: a prospective longitudinal study on the impact of the assessment period on medical education
Authors: Santiago Isabela Silva , de Castro e Castro Safira , de Brito Ana Paula Amaral , Sanches Daniel , Quintanilha Luiz Fernando , Avena Katia de Miranda , Andrade Bruno Bezerril
Published: June 2024

Background

Stress significantly affects both the physical and emotional health of individuals, particularly students in health-related fields. Medical students in Brazil face unique challenges due to the demanding nature of their studies, especially during assessment periods, which heighten academic pressure. These pressures often lead to poor coping strategies and mental health concerns. It is crucial to understand the complex dynamics of stress within medical education to develop strategies that improve student well-being and promote a healthier academic environment. This study aims to investigate the intricate relationship between assessment periods and stress levels among medical students. It seeks to understand how academic demands and sociodemographic factors contribute to stress dynamics during these periods.

Methods

An online observational, longitudinal, and prospective study was conducted from February to October 2022. Medical students were recruited through snowball sampling and participated in surveys administered via Google Forms at two timepoints: before (T1) and during (T2) assessment periods. The surveys collected sociodemographic data and stress symptoms using Lipp’s Inventory of Stress Symptoms for Adults (LSSI).

Results

The transition from T1 to T2 was defined by a rise in the prevalence of stress from 59.6 to 84.2% (p = 0.001) and a decline in symptom-free students from 40.4 to 15.8% (p = 0.001). There was a significant increase in exhaustion, from 12.3 to 31.6% (p = 0.0001). Higher stress levels were notably more prevalent among younger students (≤ 24 years), females, those from wealthier families, students without scholarships, those without prior degrees, and those in the clinical phase of their studies. However, non significant correlations were found between these sociodemographic and academic factors and the increase in stress.

Conclusion

The findings highlight significant concerns regarding the mental health of medical students during assessment periods, marked by increased stress and exhaustion levels. These results emphasize the need for proactive interventions to manage stress effectively in medical education, considering its profound impact on students’ well-being.
The relationship between nurses’ moral competency and missed nursing care: a descriptive-correlational study
Authors: Nazari Amir Mohamad , Borhani Fariba , Zare-Kaseb Akbar , Zafarnia Niloofar
Published: June 2024

Background

When any aspect of patient care is overlooked or delayed, it is known as Missed Nursing Care (MNC), leading to adverse events such as medication errors, infections, increased mortality rates, and poor prognosis. Moral competence is crucial for clinical nurses as it guarantees high-quality patient care in nursing practice. Thus, this study aimed to investigate the correlation between moral competencies and MNC among nurses.

Methods

This study was conducted with a descriptive-correlational design. The participants in the study were nurses who were currently enrolled at Shahid Beheshti University of Medical Sciences. In order to recruit nurses for the study, a convenience sampling method was implemented. The study tools were completed by a total of two hundred nurses. Research tools included a demographic questionnaire, the Moral Competence of Clinical Nurses Questionnaire, and the Kalisch and Williams Missed Nursing Care (MISSCARE) survey.

Ethical consideration

This study was approved by the Medical Ethics and Law Research Center of Shahid Beheshti University of Medical Sciences.

Results

The mean scores of moral competencies and MNC were 151.83 ± 12.60 and 42.71 ± 9.38, respectively. In other words, descriptive statistics showed that the moral competence score was more than 75%, and the MNC score was less than 50%. Also, there was a significant negative correlation between the total scores of moral competencies and MNC (r = -0.38, p < 0.001), indicating that more moral competence was correlated with lower levels of MNC.

Conclusion

The study revealed a negative correlation between nurses’ moral competence and MNC, suggesting that enhancing moral competence could reduce MNC. To reduce MNC occurrences, hospitals, and organizations should prioritize moral competency, according to our research.
Changes in the combination of the triglyceride-glucose index and obesity indicators estimate the risk of cardiovascular disease
Authors: Zhu Xiaoqing , Xu Weihao , Song Tingting , Wang Xinyan , Wang Qingsong , Li Jun , Liu Xixi , Hao Benchuan , Chen Tao , Guo Jun
Published: June 2024

Background

Cardiovascular disease (CVD) is closely associated with the triglyceride glucose (TyG) index and its related indicators, particularly its combination with obesity indices. However, there is limited research on the relationship between changes in TyG-related indices and CVD, as most studies have focused on baseline TyG-related indices.

Methods

The data for this prospective cohort study were obtained from the China Health and Retirement Longitudinal Study. The exposures were changes in TyG-related indices and cumulative TyG-related indices from 2012 to 2015. The K-means algorithm was used to classify changes in each TyG-related index into four classes (Class 1 to Class 4). Multivariate logistic regressions were used to evaluate the associations between the changes in TyG-related indices and the incidence of CVD.

Results

In total, 3243 participants were included in this study, of whom 1761 (54.4%) were female, with a mean age of 57.62 years at baseline. Over a 5-year follow-up, 637 (19.6%) participants developed CVD. Fully adjusted logistic regression analyses revealed significant positive associations between changes in TyG-related indices, cumulative TyG-related indices and the incidence of CVD. Among these changes in TyG-related indices, changes in TyG-waist circumference (WC) showed the strongest association with incident CVD. Compared to the participants in Class 1 of changes in TyG-WC, the odds ratio (OR) for participants in Class 2 was 1.41 (95% confidence interval (CI) 1.08–1.84), the OR for participants in Class 3 was 1.54 (95% CI 1.15–2.07), and the OR for participants in Class 4 was 1.94 (95% CI 1.34–2.80). Moreover, cumulative TyG-WC exhibited the strongest association with incident CVD among cumulative TyG-related indices. Compared to the participants in Quartile 1 of cumulative TyG-WC, the OR for participants in Quartile 2 was 1.33 (95% CI 1.00–1.76), the OR for participants in Quartile 3 was 1.46 (95% CI 1.09–1.96), and the OR for participants in Quartile 4 was 1.79 (95% CI 1.30–2.47).

Conclusions

Changes in TyG-related indices are independently associated with the risk of CVD. Changes in TyG-WC are expected to become more effective indicators for identifying individuals at a heightened risk of CVD.
Elevated SLC1A5 associated with poor prognosis and therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma
Authors: Zhang Guixiong , Xiao Yitai , Tan Jizhou , Liu Hang , Fan Wenzhe , Li Jiaping
Published: June 2024

Background

Hepatocellular carcinoma (HCC) is a common malignant tumor, and glutamine is vital for tumor cells. The role of glutamine transporter SLC1A5 in tumor progression and transarterial chemoembolization (TACE) efficacy is under study. This research seeks to determine the impact of SLC1A5 expression on the prognosis and TACE efficacy of HCC and elucidate its mechanisms.

Methods

SLC1A5 expression in HCC, correlation with patient outcomes, and response to TACE were studied in an open access liver cancer dataset and confirmed in our cohort. Additionally, the correlation between SLC1A5 expression and hypoxia, angiogenesis and immune infiltration was analyzed and verified by immunohistochemistry, immunofluorescence and transcriptome sequencing. Liver cancer cell lines with SLC1A5 expression knockdown or overexpression were constructed, and cell proliferation, colony formation, apoptosis, migration and drug sensitivity as well as in vivo xenograft tumor were measured. A gene set enrichment analysis was conducted to determine the signaling pathway influenced by SLC1A5, and a western blot analysis was performed to detect protein expression alterations.

Results

SLC1A5 expression was higher in HCC tissue and associated with poor survival and TACE resistance. Hypoxia could stimulate the upregulation of glutamine transport, angiogenesis and SLC1A5 expression. The SLC1A5 expression was positively correlated with hypoxia and angiogenesis-related genes, immune checkpoint pathways, macrophage, Tregs, and other immunosuppressive cells infiltration. Knockdown of SLC1A5 decreased proliferation, colony formation, and migration, but increased apoptosis and increased sensitivity to chemotherapy drugs. Downregulation of SLC1A5 resulted in a decrease in Vimentin and N-cadherin expression, yet an increase in E-cadherin expression. Upregulation of SLC1A5 increased Vimentin and N-cadherin expression, while decreasing E-cadherin. Overexpression of β-catenin in SLC1A5-knockdown HCC cell lines could augment Vimentin and N-cadherin expression, suppress E-cadherin expression, and increase the migration and drug resistance.

Conclusions

Elevated SLC1A5 was linked to TACE resistance and survival shortening in HCC patients. SLC1A5 was positively correlated with hypoxia, angiogenesis, and immunosuppression. SLC1A5 may mediate HCC cell migration and drug resistance via Epithelial-mesenchymal transition (EMT) pathway.
The tumour microenvironment, treatment resistance and recurrence in glioblastoma
Authors: White Jasmine , White Madeleine P. J. , Wickremesekera Agadha , Peng Lifeng , Gray Clint
Published: June 2024

The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.
CAPN2 promotes apalutamide resistance in metastatic hormone-sensitive prostate cancer by activating protective autophagy
Authors: Qi Zihao , Bai Xiaojie , Wu Linjie , Zhang Peng , Guo Zhongqiang , Yu Ying
Published: June 2024

Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca2+) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.
Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer
Authors: Ding Zhuoyu , Wei Yiyi , Dai Jingping , Pan Chaomin , Yang Li , Li Qingyuan , Zhang Yue , Yan Qun , Wu Changjie , Li Aimin , Lan Zhixian , Liu Side , Wang Xinke
Published: June 2024

Background

Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation.

Methods

Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot.

Results

Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A).

Conclusions

SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.
Factor of time in dendritic cell (DC) maturation: short-term activation of DCs significantly improves type 1 cytokine production and T cell responses
Authors: Poženel Primož , Zajc Kaja , Švajger Urban
Published: June 2024

Dendritic cells (DCs) have been intensively studied in correlation to tumor immunology and for the development DC-based cancer vaccines. Here, we present the significance of the temporal aspect of DC maturation for the most essential subsequent timepoint, namely at interaction with responding T cells or after CD40-Ligand restimulation. Mostly, DC maturation is still being achieved by activation processes which lasts 24 h to 48 h. We hypothesized this amount of time is excessive from a biological standpoint and could be the underlying cause for functional exhaustion. Indeed, shorter maturation periods resulted in extensive capacity of monocyte-derived DCs to produce inflammatory cytokines after re-stimulation with CD40-Ligand. This effect was most evident for the primary type 1 polarizing cytokine, IL-12p70. This capacity reached peak at 6 h and dropped sharply with longer exposure to initial maturation stimuli (up to 48 h). The 6 h maturation protocol reflected superiority in subsequent functionality tests. Namely, DCs displayed twice the allostimulatory capacity of 24 h- and 48 h-matured DCs. Similarly, type 1 T cell response measured by IFN-γ production was 3-fold higher when CD4+ T cells had been stimulated with shortly matured DC and over 8-fold greater in case of CD8+ T cells, compared to longer matured DCs. The extent of melanoma-specific CD8+ cytotoxic T cell induction was also greater in case of 6 h DC maturation. The major limitation of the study is that it lacks in vivo evidence, which we aim to examine in the future. Our findings show an unexpectedly significant impact of temporal exposure to activation signals for subsequent DC functionality, which we believe can be readily integrated into existing knowledge on in vitro/ex vivo DC manipulation for various uses. We also believe this has important implications for DC vaccine design for future clinical trials.
Low clinical impact of HIV drug resistance mutations in oral pre-exposure prophylaxis: a systematic review and meta-analysis
Authors: Rachman Brian Eka , Khairunisa Siti Qamariyah , Wungu Citrawati Dyah Kencono , Asmarawati Tri Pudy , Rusli Musofa , Bramantono  , Arfijanto M. Vitanata , Hadi Usman , Kameoka Masanori , Nasronudin
Published: June 2024

Introduction

Despite the widespread use of pre-exposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) transmission, scant information on HIV drug resistance mutations (DRMs) has been gathered over the past decade. This review aimed to estimate the pooled prevalence of pre-exposure prophylaxis and its two-way impact on DRM.

Methods

We systematically reviewed studies on DRM in pre-exposure prophylaxis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines. PubMed, Cochrane, and SAGE databases were searched for English-language primary studies published between January 2001 and December 2023. The initial search was conducted on 9 August 2021 and was updated through 31 December 2023 to ensure the inclusion of the most recent findings. The registration number for this protocol review was CRD42022356061.

Results

A total of 26,367 participants and 562 seroconversion cases across 12 studies were included in this review. The pooled prevalence estimate for all mutations was 6.47% (95% Confidence Interval-CI 3.65–9.93), while Tenofovir Disoproxil Fumarate/Emtricitabine-associated drug resistance mutation prevalence was 1.52% (95% CI 0.23–3.60) in the pre-exposure prophylaxis arm after enrolment. A subgroup analysis, based on the study population, showed the prevalence in the heterosexual and men who have sex with men (MSM) groups was 5.53% (95% CI 2.55–9.40) and 7.47% (95% CI 3.80–12.11), respectively. Notably, there was no significant difference in the incidence of DRM between the pre-exposure prophylaxis and placebo groups (log-OR = 0.99, 95% CI −0.20 to 2.18, I2 = 0%; p = 0.10).

Discussion

Given the constrained prevalence of DRM, the World Health Organization (WHO) advocates the extensive adoption of pre-exposure prophylaxis. Our study demonstrated no increased risk of DRM with pre-exposure prophylaxis (p > 0.05), which is consistent with these settings. These findings align with the previous meta-analysis, which reported a 3.14-fold higher risk in the pre-exposure prophylaxis group than the placebo group, although the observed difference did not reach statistical significance (p = 0.21).

Conclusions

Despite the low prevalence of DRM, pre-exposure prophylaxis did not significantly increase the risk of DRM compared to placebo. However, long-term observation is required to determine further disadvantages of extensive pre-exposure prophylaxis use.

PROSPERO Number: CRD42022356061.
Automated, IMU-based spine angle estimation and IMU location identification for telerehabilitation
Authors: Pan Huiming , Wang Hong , Li Dongxuan , Zhu Kezhe , Gao Yuxiang , Yin Ruiqing , Shull Peter B.
Published: June 2024

Background

Telerehabilitation is a promising avenue for improving patient outcomes and expanding accessibility. However, there is currently no spine-related assessment for telerehabilitation that covers multiple exercises.

Methods

We propose a wearable system with two inertial measurement units (IMUs) to identify IMU locations and estimate spine angles for ten commonly prescribed spinal degeneration rehabilitation exercises (supine chin tuck head lift rotation, dead bug unilateral isometric hold, pilates saw, catcow full spine, wall angel, quadruped neck flexion/extension, adductor open book, side plank hip dip, bird dog hip spinal flexion, and windmill single leg). Twelve healthy subjects performed these spine-related exercises, and wearable IMU data were collected for spine angle estimation and IMU location identification.

Results

Results demonstrated average mean absolute spinal angle estimation errors of 2.59$$^\circ$$

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and average classification accuracy of 92.97%. The proposed system effectively identified IMU locations and assessed spine-related rehabilitation exercises while demonstrating robustness to individual differences and exercise variations.

Conclusion

This inexpensive, convenient, and user-friendly approach to spine degeneration rehabilitation could potentially be implemented at home or provide remote assessment, offering a promising avenue to enhance patient outcomes and improve accessibility for spine-related rehabilitation.

Trial registration: No. E2021013P in Shanghai Jiao Tong University.
Health information management systems and practices in conflict-affected settings: the case of northwest Syria
Authors: Ladadwa Reem , Hariri Mahmoud , Alatras Muhammed Mansur , Elferruh Yasir , Ramadan Abdulhakim , Dowah Mahmoud , Bawaneh Yahya Mohammad , Aljerk Wassel , Patel Preeti , Ekzayez Abdulkarim , El Achi Nassim
Published: June 2024

Background

In conflict settings, as it is the case in Syria, it is crucial to enhance health information management to facilitate an effective and sustainable approach to strengthening health systems in such contexts. In this study, we aim to provide a baseline understanding of the present state of health information management in Northwest Syria (NWS) to better plan for strengthening the health information system of the area that is transitioning to an early-recovery stage.

Methods

A combination of questionnaires and subsequent interviews was used for data collection. Purposive sampling was used to select twenty-one respondents directly involved in managing and directing different domains of health information in the NWS who worked with local NGOs, INGOs, UN-agencies, or part of the Health Working Group. A scoring system for each public health domain was constructed based on the number and quality of the available datasets for these domains, which were established by Checci and others.

Results & conclusions

Reliable and aggregate health information in the NWS is limited, despite some improvements made over the past decade. The conflict restricted and challenged efforts to establish a concentrated and harmonized HIS in the NWS, which led to a lack of leadership, poor coordination, and duplication of key activities. Although the UN established the EWARN and HeRAMS as common data collection systems in the NWS, they are directed toward advocacy and managed by external experts with little participation or access from local stakeholders to these datasets.

Recommendations

There is a need for participatory approaches and the empowerment of local actors and local NGOs, cooperation between local and international stakeholders to increase access to data, and a central domain for planning, organization, and harmonizing the process. To enhance the humanitarian health response in Syria and other crisis areas, it is imperative to invest in data collection and utilisation, mHealth and eHealth technologies, capacity building, and robust technical and autonomous leadership.
Revisiting superiority and stability metrics of cultivar performances using genomic data: derivations of new estimators
Authors: Carvalho Humberto Fanelli , Rio Simon , García-Abadillo Julian , Isidro y Sánchez Julio
Published: June 2024

The selection of highly productive genotypes with stable performance across environments is a major challenge of plant breeding programs due to genotype-by-environment (GE) interactions. Over the years, different metrics have been proposed that aim at characterizing the superiority and/or stability of genotype performance across environments. However, these metrics are traditionally estimated using phenotypic values only and are not well suited to an unbalanced design in which genotypes are not observed in all environments. The objective of this research was to propose and evaluate new estimators of the following GE metrics: Ecovalence, Environmental Variance, Finlay–Wilkinson regression coefficient, and Lin–Binns superiority measure. Drawing from a multi-environment genomic prediction model, we derived the best linear unbiased prediction for each GE metric. These derivations included both a squared expectation and a variance term. To assess the effectiveness of our new estimators, we conducted simulations that varied in traits and environment parameters. In our results, new estimators consistently outperformed traditional phenotype-based estimators in terms of accuracy. By incorporating a variance term into our new estimators, in addition to the squared expectation term, we were able to improve the precision of our estimates, particularly for Ecovalence in situations where heritability was low and/or sparseness was high. All methods are implemented in a new R-package: GEmetrics. These genomic-based estimators enable estimating GE metrics in unbalanced designs and predicting GE metrics for new genotypes, which should help improve the selection efficiency of high-performance and stable genotypes across environments.
POLR1D silencing suppresses lung cancer cells proliferation and migration via inhibition of PI3K-Akt pathway
Authors: Yuan Zhize , Wang Yichao , Yang Yong , Qin Xiong
Published: June 2024

Aim

The most common type of cancer that leads to death worldwide is lung cancer. Despite significant surgery and chemotherapy improvements, lung cancer patient’s survival rate is still poor. The RNA polymerase I subunit D (POLR1D) gene can induce various cancers. A current study reported that POLR1D plays a vital role in cancer prognosis. However, its biological function in the development of lung cancer remains unclear.

Methods

Reverse transcription PCR (RT-PCR) measured the relative POLR1D protein expression level in lung cancer cell lines. Lung cancer cell proliferation, migration, and invasion were analyzed by performing cell counting kit-8 (CCK-8), and transwell. The phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/AKT) signaling pathway-related protein expressions were examined by Western blotting assay.

Results

POLR1D protein expression was elevated in lung cancer. Lung cancer cell loss-of-function tests showed that POLR1D silencing could attenuate cell viability both in SK-MES-1 and in H2170 cells. Furthermore, silencing POLR1D inhibited SK-MES-1 and H2170 cells proliferation, migration, and invasion. Moreover, SK-MES-1 and H2170 cells’ migration and invasion capacity were potentially suppressed by the knockdown of POLR1D. The progression of multiple cancers has been implicated in the PI3K/AKT pathway. Here, we observed that POLR1D silencing suppressed lung cancer progression by inhibition of the PI3K-Akt pathway.

Conclusions

The study speculated that POLR1D might provide a new potential therapeutic possibility for treating lung cancer patients via targeting PI3K/AKT.
Deciphering potential causative factors for undiagnosed Waardenburg syndrome through multi-data integration
Authors: Sun Fengying , Xiao Minmin , Ji Dong , Zheng Feng , Shi Tieliu
Published: June 2024

Background

Waardenburg syndrome (WS) is a rare genetic disorder mainly characterized by hearing loss and pigmentary abnormalities. Currently, seven causative genes have been identified for WS, but clinical genetic testing results show that 38.9% of WS patients remain molecularly unexplained. In this study, we performed multi-data integration analysis through protein-protein interaction and phenotype-similarity to comprehensively decipher the potential causative factors of undiagnosed WS. In addition, we explored the association between genotypes and phenotypes in WS with the manually collected 443 cases from published literature.

Results

We predicted two possible WS pathogenic genes (KIT, CHD7) through multi-data integration analysis, which were further supported by gene expression profiles in single cells and phenotypes in gene knockout mouse. We also predicted twenty, seven, and five potential WS pathogenic variations in gene PAX3, MITF, and SOX10, respectively. Genotype-phenotype association analysis showed that white forelock and telecanthus were dominantly present in patients with PAX3 variants; skin freckles and premature graying of hair were more frequently observed in cases with MITF variants; while aganglionic megacolon and constipation occurred more often in those with SOX10 variants. Patients with variations of PAX3 and MITF were more likely to have synophrys and broad nasal root. Iris pigmentary abnormality was more common in patients with variations of PAX3 and SOX10. Moreover, we found that patients with variants of SOX10 had a higher risk of suffering from auditory system diseases and nervous system diseases, which were closely associated with the high expression abundance of SOX10 in ear tissues and brain tissues.

Conclusions

Our study provides new insights into the potential causative factors of WS and an alternative way to explore clinically undiagnosed cases, which will promote clinical diagnosis and genetic counseling. However, the two potential disease-causing genes (KIT, CHD7) and 32 potential pathogenic variants (PAX3: 20, MITF: 7, SOX10: 5) predicted by multi-data integration in this study are all computational predictions and need to be further verified through experiments in follow-up research.