bluuebunny/crossref_metadata_2025_split huggingface dataset:
NSMCE2, a novel super-enhancer-regulated gene, is linked to poor prognosis and therapy resistance in breast cancer
Authors: Di Benedetto Carolina , Oh Justin , Choudhery Zainab , Shi Weiquan , Valdes Gilmer , Betancur Paola 
Published: October 2022

Abstract
Background
Despite today’s advances in the treatment of cancer, breast cancer-related mortality remains high, in part due to the lack of effective targeted therapies against breast tumor types that do not respond to standard treatments. Therefore, identifying additional breast cancer molecular targets is urgently needed. Super-enhancers are large regions of open chromatin involved in the overactivation of oncogenes. Thus, inhibition of super-enhancers has become a focus in clinical trials for its therapeutic potential. Here, we aimed to identify novel super-enhancer dysregulated genes highly associated with breast cancer patients’ poor prognosis and negative response to treatment.

Methods
Using existing datasets containing super-enhancer-associated genes identified in breast tumors and public databases comprising genomic and clinical information for breast cancer patients, we investigated whether highly expressed super-enhancer-associated genes correlate to breast cancer patients’ poor prognosis and to patients’ poor response to therapy. Our computational findings were experimentally confirmed in breast cancer cells by pharmacological SE disruption and gene silencing techniques.

Results
We bioinformatically identified two novel super-enhancer-associated genes – NSMCE2 and MAL2 – highly upregulated in breast tumors, for which high RNA levels significantly and specifically correlate with breast cancer patients’ poor prognosis. Through in-vitro pharmacological super-enhancer disruption assays, we confirmed that super-enhancers upregulate NSMCE2 and MAL2 transcriptionally, and, through bioinformatics, we found that high levels of NSMCE2 strongly associate with patients’ poor response to chemotherapy, especially for patients diagnosed with aggressive triple negative and HER2 positive tumor types. Finally, we showed that decreasing NSMCE2 gene expression increases breast cancer cells’ sensitivity to chemotherapy treatment.

Conclusions
Our results indicate that moderating the transcript levels of NSMCE2 could improve patients’ response to standard chemotherapy consequently improving disease outcome. Our approach offers a new avenue to identify a signature of tumor specific genes that are not frequently mutated but dysregulated by super-enhancers. As a result, this strategy can lead to the discovery of potential and novel pharmacological targets for improving targeted therapy and the treatment of breast cancer.
Pilot evaluation to assess the effectiveness of youth peer community support via the Kooth online mental wellbeing website
Authors: Stevens Madeleine , Cartagena Farías Javiera , Mindel Charlotte , D’Amico Francesco , Evans-Lacko Sara 
Published: October 2022

Abstract
Background
Mental health problems among young people are of growing concern globally. UK adolescent mental health services are increasingly restricted to those with the most severe needs. Many young people turn to the internet for advice and support, but little is known about the effectiveness, and potential harms, of online support. Kooth is a widely-used, anonymised and moderated online platform offering access to professional and peer support. This pilot evaluation sought to assess changes in the wellbeing and mental health of Kooth users, and changes in their use of formal services, over one month. We explored how community aspects of the site were used, and we considered the economic implications for commissioners making Kooth available to young people.

Methods
We surveyed young people when they first accessed Kooth and again one month later (n = 302). Respondents completed measures of mental health and wellbeing, including family relationships and pandemic-related anxiety, and reported on their use of services and, at follow-up, their perceptions of whether and how they had benefitted. We carried out qualitative interviews with ten participants, exploring perceptions of the Kooth community and its impact.

Results
We found improvements across nearly all measures, including reductions in psychological distress, suicidal ideation and loneliness. Subsample analyses suggested similar benefits for those who used only the community/peer parts of Kooth as for those who engaged with Kooth’s counsellors. Participants reported learning from peers’ suggestions and experiences, described as different from the advice given by professionals. Helping others gave users a sense of purpose; participants learnt self-help strategies and became more confident in social interactions. Service use and opinion data suggested Kooth experiences may help users make more appropriate and effective use of formal services.

Conclusion
This pilot evaluation suggests that Kooth is likely to be a cost-effective way of providing preventative support to young people with concerns about their mental health, with possible benefits across a range of domains which could be investigated in a future controlled trial.
Pre-pandemic socio-economic status and changes in employment during the first lockdown (2020) on the health of middle-aged people in England: a longitudinal study
Authors: D’Angelo Stefania , Ntani Georgia , Bloom Ilse , Walker-Bone Karen 
Published: October 2022

Abstract
Background
The COVID-19 pandemic markedly disrupted people’s lives. It caused higher mortality and morbidity amongst individuals from poorer socio-economic position (SEP). It is well-recognised that job loss has a negative impact on health. We hypothesised that health effects of the pandemic on middle-aged people might be different depending on SEP and changes in employment.

Methods
Data are from the Health and Employment After Fifty (HEAF), a cohort recruited 2013–2014 when aged 50–64 through 24 English general practices. At baseline and annually since, participants completed a questionnaire reporting about demographics, employment, health, lifestyle, and finances. In 2021 we sent an e-survey to all contactable HEAF participants, asking about effects of the first lockdown (March-July 2020). Outcomes were participants’ perception of worsening of mental, physical health, and self-rated health (SRH) since lockdown. Associations between SEP, COVID-19 related employment changes and health were explored with Poisson regression with robust standard error, with adjustment for age, sex, and pre-pandemic SRH.

Results
In total, 2,469 (53%) returned a usable questionnaire, amongst whom 2,344 provided complete information for these analyses (44% men, mean age 65.7 years). Worsening of mental, physical or SRH since lockdown was reported by 21%, 27% and 17% respectively. Mutually adjusted models showed that reporting struggling financially pre-pandemic (versus living comfortably) was associated with an increased risk of deterioration in: mental (RR = 2.0, 95%CI 1.7–2.5), physical health (RR = 2.0, 95%CI 1.6–2.3), and SRH (RR = 1.6, 95%CI 1.2–2.1). Participants working from home during lockdown and those who lost their job (as opposed to those with unchanged employment) were at increased risk of reporting deterioration in mental health and SRH.

Conclusion
In a cohort of older workers, working from home, job loss and poorer pre-pandemic SEP were all associated with worsening of mental health and SRH since lockdown.
A co-created nurse-driven catheterisation protocol can reduce bladder distension in acute hip fracture patients - results from a longitudinal observational study
Authors: Frödin Maria , Nellgård Bengt , Rogmark Cecilia , Gillespie Brigid M. , Wikström Ewa , Andersson Annette Erichsen 
Published: October 2022

Abstract
Background
Urinary retention is common in elderly patients undergoing acute hip fracture surgery. Avoiding overfilling the urinary bladder is important to avoid detrusor muscle damage and associated motility problems. The aim of this study was to analyse associations between the co-creation of a nurse-driven urinary catheterisation protocol and the incidence of bladder distension in patients undergoing hip fracture surgery.

Methods
This is a single-centre implementation intervention with a retrospective longitudinal observation design, using five measures points, spanning from June 2015 to March 2020. The intervention was theory driven and the participants, together with the facilitators and researcher, co-created a nurse-driven urinary catheterisation protocol. Data were retrieved from the hip fracture register. Uni- and multivariable logistic regressions were used for analyses of changes in bladder distension and urinary volume of ≥500 ml over the years.

Results
A total of 3078 patients were included over a five-year period. The implementation intervention was associated with a reduction in the proportion of patients with bladder distension of 31.5% (95% confidence interval 26.0–37.0), from year 1 to year 5. The multivariable analysis indicated a 39% yearly reduction in bladder distension, OR 0.61 (95% confidence interval 0.57–0.64, p <  0001). There was a reduction in the proportion of patients with a bladder volume of ≥500 ml of 42.8% (95% confidence interval 36.2–49.4), from year 1 to year 5. The multivariable analysis found a 41% yearly reduction in patients with a bladder volume of ≥500 ml, OR 0.59 (95% confidence interval 0.55–0.64, p <  0.0001). The intervention was associated with improved documentation of both catheter indications and removal plans.

Conclusion
The use of predefined catheter indications and a tighter bladder scanning schedule were associated with a reduction in the incidence of both bladder distension and urine volume ≥ 500 ml in hip fracture patients. Registered nurses can play an active role in the facilitation of timely and appropriate catheter treatment in patients with hip fractures.

Trial registration
Clinical Trial Registry ISRCTN 17022695 registered retrospectively on 23 December 2021, in the end of the study, after data collection.
STING pathway contributes to the prognosis of hepatocellular carcinoma and identification of prognostic gene signatures correlated to tumor microenvironment
Authors: Pu Zhangya , Liu Jinghua , Liu Zelong , Peng Fang , Zhu Yuanyuan , Wang Xiaofang , He Jiayan , Yi Panpan , Hu Xingwang , Fan Xuegong , Chen Jiang 
Published: October 2022

Abstract
Background
Hepatocellular carcinoma (HCC) is one of the most malignant solid tumors worldwide. Recent evidence shows that the stimulator of interferon genes (STING) pathway is essential for anti-tumor immunity via inducing the production of downstream inflammatory cytokines. However, its impact on the prognosis and tumor microenvironment of HCC was still limited known.

Methods
We obtained gene expression profiles of HCC from GEO, TCGA, and ICGC databases, and immune-related genes (IRGs) from the ImmPort database. Multivariate Cox regression was performed to identify independent prognostic factors. Nomogram was established to predict survival probability for individual patients. Kaplan–Meier curve was used to evaluate the survival difference. Afterward, ESTIMATE, TISCH, and TIMER databases were combined to assess the immune cell infiltration. Furthermore, the qPCR, western blotting, and immunohistochemistry were done to evaluate gene expression, and in vitro cell models were built to determine cell migratory ability.

Results
We found that gene markers of NLRC3, STING1, TBK1, TRIM21, and XRCC6 within STING pathway were independent prognostic factors in HCC patients. Underlying the finding, a predictive nomogram was constructed in TCGA-training cohort and further validated in TCGA-all and ICGC datasets, showing credible performance. Experimentally, up-regulated TBK1 promotes the ability of HCC cell migration. Next, the survival-related immune-related co-expressed gene signatures (IRCGS) (VAV1, RHOA, and ZC3HAV1) were determined in HCC cohorts and their expression was verified in human HCC cells and clinical samples. Furthermore, survival-related IRCGS was associated with the infiltration of various immune cell subtypes in HCC, the transcriptional expression of prominent immune checkpoints, and immunotherapeutic response.

Conclusion
Collectively, we constructed a novel prognostic nomogram model for predicting the survival probability of individual HCC patients. Moreover, an immune-related prognostic gene signature was determined. Both might function as potential therapeutic targets for HCC treatment in the future.
Midazolam exhibits antitumour and enhances the efficiency of Anti-PD-1 immunotherapy in hepatocellular carcinoma
Authors: Kang Junwei , Zheng Zhiying , Li Xian , Huang Tian , Rong Dawei , Liu Xinyang , Qin Miaomiao , Wang Yuliang , Kong Xiangyi , Song Jinhua , Lv Chengyu , Pan Xiongxiong 
Published: October 2022

Abstract
Background
Midazolam (MDZ) is an anaesthetic that is widely used for anxiolysis and sedation. More recently, MDZ has also been described to be related to the outcome of various types of carcinomas. However, how MDZ influences the progression of hepatocellular carcinoma (HCC) and its effects on the biological function and tumour immune microenvironment of this type of tumour remain unknown.

Methods
The effects of MDZ on the proliferation, invasion, and migration of HCC cell lines were examined in vitro using the Cell Counting Kit 8 (CCK8), 5-ethynyl-2ʹ-deoxyuridine (EdU), Transwell, and wound healing assays. Additionally, western blotting was employed to confirm that PD-L1 was expressed. Chromatin immunoprecipitation-seq (ChIP-seq) analysis was used to pinpoint the transcriptional regulation regions of NF-κB and programmed death-ligand 1 (PD-L1). A C57BL/6 mouse model was used to produce subcutaneous HCC tumors in order to evaluate the in vivo performance of MDZ. Mass spectrometry was also used to assess changes in the tumour immunological microenvironment following MDZ injection.

Results
The HCC-LM3 and Hep-3B cell lines’ proliferation, invasion, and migration were controlled by MDZ, according to the results of the CCK8, EdU, Transwell, and wound healing assays. PD-L1 expression was shown by ChIP-seq analysis to be boosted by NF-κB, and by Western blotting analysis, it was shown that MDZ downregulated the expression of NF-κB. Additionally, in vivo tests revealed that intraperitoneal MDZ injections reduced HCC tumor development and enhanced the effectiveness of anti-PD-1 therapy. The CD45+ immune cell proportions were higher in the MDZ group than in the PBS group, according to the mass spectrometry results. Injection of MDZ resulted in a decrease in the proportions of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, monocytes, Tregs, and M2 macrophages and a rise in the proportion of dendritic cells. Additionally, the concentrations of the cytokines IFN-g and TNF-a were noticeably raised whereas the concentrations of the CD8+ T-cell fatigue markers ICOS, TIGIT, and TIM3 were noticeably lowered.

Conclusion
According to this study, MDZ inhibited the progression of HCC by inhibiting the NF-κB pathway and reducing the exhaustion of CD8+ T cells. In clinical practice, MDZ combined with anti-PD-1 therapy might contribute to synergistically improving the antitumor efficacy of HCC treatment.
Current understanding of epigenetics role in melanoma treatment and resistance
Authors: Karami Fath Mohsen , Azargoonjahromi Ali , Soofi Asma , Almasi Faezeh , Hosseinzadeh Shahnaz , Khalili Saeed , Sheikhi Kamran , Ferdousmakan Saeid , Owrangi Soroor , Fahimi Minoovash , Zalpoor Hamidreza , Nabi Afjadi Mohsen , Payandeh Zahra , Pourzardosht Navid 
Published: October 2022

AbstractMelanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.
Assessing road criticality and loss of healthcare accessibility during floods: the case of Cyclone Idai, Mozambique 2019
Authors: Petricola Sami , Reinmuth Marcel , Lautenbach Sven , Hatfield Charles , Zipf Alexander 
Published: October 2022

Abstract
Background
The ability of disaster response, preparedness, and mitigation efforts to assess the loss of physical accessibility to health facilities and to identify impacted populations is key in reducing the humanitarian consequences of disasters. Recent studies use either network- or raster-based approaches to measure accessibility in respect to travel time. Our analysis compares a raster- and a network- based approach that both build on open data with respect to their ability to assess the loss of accessibility due to a severe flood event. As our analysis uses open access data, the approach should be transferable to other flood-prone sites to support decision-makers in the preparation of disaster mitigation and preparedness plans.

Methods
Our study is based on the flood events following Cyclone Idai in Mozambique in 2019 and uses both raster- and network-based approaches to compare accessibility to health sites under normal conditions to the aftermath of the cyclone to assess the loss of accessibility. Part of the assessment is a modified centrality indicator, which identifies the specific use of the road network for the population to reach health facilities.

Results
Results for the raster- and the network-based approaches differed by about 300,000 inhabitants (~ 800,000 to ~ 500,000) losing accessibility to healthcare sites. The discrepancy was related to the incomplete mapping of road networks and affected the network-based approach to a higher degree. The modified centrality indicator allowed us to identify road segments that were most likely to suffer from flooding and to highlight potential backup roads in disaster settings.

Conclusions
The different results obtained between the raster- and network-based methods indicate the importance of data quality assessments in addition to accessibility assessments as well as the importance of fostering mapping campaigns in large parts of the Global South. Data quality is therefore a key parameter when deciding which method is best suited for local conditions. Another important aspect is the required spatial resolution of the results. Identification of critical segments of the road network provides essential information to prepare for potential disasters.
Medical student medium-term skill retention following cardiac point-of-care ultrasound training based on the American Society of Echocardiography curriculum framework
Authors: Jujo Satoshi , Sakka Brandan I. , Lee-Jayaram Jannet J. , Kataoka Akihisa , Izumo Masaki , Kusunose Kenya , Nakahira Atsushi , Oikawa Sayaka , Kataoka Yuki , Berg Benjamin W. 
Published: October 2022

Abstract
Background
No studies have demonstrated medium- or long-term skill retention of cardiac point-of-care ultrasound (POCUS) curriculum for medical student. Based on the American Society of Echocardiography (ASE) curriculum framework, we developed a blended-learning cardiac POCUS curriculum with competency evaluation. The objective of this study was to investigate the curriculum impact on image acquisition skill retention 8 weeks after initial training.

Methods
This study was a prospective, pre-post education intervention study for first- and second-year medical students, with blinded outcome assessment. The curriculum included a pre-training ASE online module and healthy volunteer hands-on training to obtain 5 views: parasternal long-axis (PLAX), parasternal short-axis (PSAX), apical 4-chamber (A4C), subcostal 4-chamber (S4C), and subcostal inferior vena cava (SIVC) views. Students took 5-view image acquisition skill tests at pre-, immediate post-, and 8-week post-training, using a healthy volunteer. Three blinded assessors rated the image quality using a validated 10-point maximum scoring system. Students used a hand-held ultrasound probe (Butterfly iQ).

Results
Fifty-four students completed hands-on training, and pre- and immediate post-training skill tests. Twenty-seven students completed 8-week post-training skill tests. Skill test score improvement between pre- and 8-week post-training was 2.11 points (95% CI, 1.22–3.00; effect size, 1.13).

Conclusion
The cardiac POCUS curriculum demonstrated medium-term skill retention. The curriculum was sufficient for S4C and SIVC skill retention, but inadequate for PLAX, PSAX, and A4C. Therefore, instructional design modifications or re-training for PLAX, PSAX, and A4C are needed to make the curriculum more effective for clinically relevant skill retention.
Delayed puberty, gonadotropin abnormalities and subfertility in male Padi2/Padi4 double knockout mice
Authors: Sams Kelly L. , Mukai Chinatsu , Marks Brooke A. , Mittal Chitvan , Demeter Elena Alina , Nelissen Sophie , Grenier Jennifer K. , Tate Ann E. , Ahmed Faraz , Coonrod Scott A. 
Published: October 2022

AbstractBackgroundPeptidylarginine deiminase enzymes (PADs) convert arginine residues to citrulline in a process called citrullination or deimination. Recently, two PADs, PAD2 and PAD4, have been linked to hormone signaling in vitro and the goal of this study was to test for links between PAD2/PAD4 and hormone signaling in vivo.MethodsPreliminary analysis ofPadi2andPadi4single knockout (SKO) mice did not find any overt reproductive defects and we predicted that this was likely due to genetic compensation. To test this hypothesis, we created aPadi2/Padi4double knockout (DKO) mouse model and tested these mice along with wild-type FVB/NJ (WT) and both strains of SKO mice for a range of reproductive defects.ResultsControlled breeding trials found that male DKO mice appeared to take longer to have their first litter than WT controls. This tendency was maintained when these mice were mated to either DKO or WT females. Additionally, unsexed 2-day old DKO pups and male DKO weanlings both weighed significantly less than their WT counterparts, took significantly longer than WT males to reach puberty, and had consistently lower serum testosterone levels. Furthermore, 90-day old adult DKO males had smaller testes than WT males with increased rates of germ cell apoptosis.ConclusionsThePadi2/Padi4DKO mouse model provides a new tool for investigating PAD function and outcomes from our studies provide the first in vivo evidence linking PADs with hormone signaling.