bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of the CRISPR-cas system and its association with antibiotic resistance in clinical Klebsiella pneumoniae isolates
Authors: Kadkhoda Hiva , Gholizadeh Pourya , Ghotaslou Reza , Pirzadeh Tahereh , Ahangarzadeh Rezaee Mohammad , Nabizadeh Edris , Feizi Hadi , Samadi Kafil Hossein , Aghazadeh Mohammad
Published: June 2024

Background and objective(s)

CRISPR-Cas is a prokaryotic adaptive immune system that protects bacteria and archaea against mobile genetic elements (MGEs) such as bacteriophages plasmids, and transposons. In this study, we aimed to assess the prevalence of the CRISPR-Cas systems and their association with antibiotic resistance in one of the most challenging bacterial pathogens, Klebsiella pneumoniae.

Materials and methods

A total of 105 K. pneumoniae isolates were collected from various clinical infections. Extended-spectrum β-lactamases (ESBLs) phenotypically were detected and the presence of ESBL, aminoglycoside-modifying enzymes (AME), and CRISPR-Cas system subtype genes were identified using PCR. Moreover, the diversity of the isolates was determined by enterobacterial repetitive intergenic consensus (ERIC)-PCR.

Results

Phenotypically, 41.9% (44/105) of the isolates were found to be ESBL producers. A significant inverse correlation existed between the subtype I-E CRISPR-Cas system’s presence and ESBL production in K. pneumoniae isolates. Additionally, the frequency of the ESBL genes blaCTX−M1 (3%), blaCTX−M9 (12.1%), blaSHV (51.5%), and blaTEM (33.3%), as well as some AME genes such as aac(3)-Iva (21.2%) and ant(2’’)-Ia (3%) was significantly lower in the isolates with the subtype I-E CRISPR-Cas system in comparison to CRISPR-negative isolates. There was a significant inverse correlation between the presence of ESBL and some AME genes with subtype I-E CRISPR-Cas system.

Conclusion

The presence of the subtype I-E CRISPR-Cas system was correlated with the antibiotic-resistant gene (ARGs). The isolates with subtype I-E CRISPR-Cas system had a lower frequency of ESBL genes and some AME genes than CRISPR-negative isolates.
The effect of cumulative energy in repeated subliminal transscleral cyclophotocoagulation: a retrospective study
Authors: Szabó Áron , Árpádffy-Lovas Tamás , Hagyó Krisztina , Cseke István , Vámosi Péter , Tóth-Molnár Edit
Published: June 2024

Background

The long-term safety and efficacy of repeated applications of subliminal transscleral cyclophotocoagulation (SL-TSCPC) with a focus on cumulative energy was evaluated in glaucoma patients.

Methods

In this retrospective, multicentric study the data of a total of 82 eyes with various causes of glaucoma that were treated with a single or multiple applications of SL-TSCPC were collected. Treatments were performed under general or local anesthesia with an 810 nm diode laser. Power was 2000 mW; duty cycle, 31.3%; total treatment duration, 80–320 s; equaling a total energy of 50–200 J per treatment session. Fifty-five eyes (55 patients) presented for all follow-ups, and these eyes were selected for further statistical analysis. The mean age was 60.0 ± 17.1 years, and 22 (40%) of the patients were female. Intraocular pressure (IOP) and dependence on further glaucoma medication were evaluated at 12 months following the initial treatment.

Results

Eyes underwent 1 or 2 consecutive SL-TSCPC treatments. Median (min–max) baseline IOP of 34 (13–69) decreased to 21.5 (7–61), 22 (8–68), 20 (9–68), and 19.5 (3–60) mmHg at the 1, 3, 6, and 12-month postoperative timepoints respectively. The mean (± SD) IOP decrease at 12 months was 26 ± 27%, 39 ± 32%, and 49 ± 33% in the low (below 120 J, n = 18), medium (120–200 J, n = 24), and high (above 200 J, n = 13) cumulative energy groups respectively. At the 12-month timepoint, oral carbonic anhydrase use was discontinued in ¾ of the cases.

Conclusions

It was found that the repeated application of SL-TSCPC safely and efficiently decreases IOP in a Caucasian population with heterogenous causes of glaucoma, eyes with silicone oil responded to a greater extent. Inclusion of cumulative energy scales may contribute to better addressing repeated procedures in a standardized fashion.
Interventions to increase vaccination in vulnerable groups: rapid overview of reviews
Authors: Norman Gill , Kletter Maartje , Dumville Jo
Published: June 2024

Objective

Groups which are marginalised, disadvantaged or otherwise vulnerable have lower uptake of vaccinations. This differential has been amplified in COVID-19 vaccination compared to (e.g.) influenza vaccination. This overview assessed the effectiveness of interventions to increase vaccination in underserved, minority or vulnerable groups.

Methods

In November 2022 we searched four databases for systematic reviews that included RCTs evaluating any intervention to increase vaccination in underserved, minority or vulnerable groups; our primary outcome was vaccination. We used rapid review methods to screen, extract data and assess risk of bias in identified reviews. We undertook narrative synthesis using an approach modified from SWiM guidance. We categorised interventions as being high, medium or low intensity, and as targeting vaccine demand, access, or providers.

Results

We included 23 systematic reviews, including studies in high and low or middle income countries, focused on children, adolescents and adults. Groups were vulnerable based on socioeconomic status, minority ethnicity, migrant/refugee status, age, location or LGBTQ identity. Pregnancy/maternity sometimes intersected with vulnerabilities. Evidence supported interventions including: home visits to communicate/educate and to vaccinate, and facilitator visits to practices (high intensity); telephone calls to communicate/educate, remind/book appointments (medium intensity); letters, postcards or text messages to communicate/educate, remind/book appointments and reminder/recall interventions for practices (low intensity). Many studies used multiple interventions or components.

Conclusion

There was considerable evidence supporting the effectiveness of communication in person, by phone or in writing to increase vaccination. Both high and low intensity interventions targeting providers showed effectiveness. Limited evidence assessed additional clinics or targeted services for increasing access; only home visits had higher confidence evidence showing effectiveness. There was no evidence for interventions for some communities, such as religious minorities which may intersect with gaps in evidence for additional services. None of the evidence related to COVID-19 vaccination where inequalities of outcome are exacerbated.

Prospero registration

CRD42021293355
Association of Medicaid expansion with birth outcomes: evidence from a natural experiment in Texas
Authors: Saygili Meryem , Bayindir Esra Eren
Published: June 2024

Background

Empirical evidence on the effects of Medicaid expansion is mixed and highly state-dependent. The objective of this study is to examine the association of Medicaid expansion with preterm birth and low birth weight, which are linked to a higher risk of infant mortality and chronic health conditions throughout life, providing evidence from a non-expansion state, overall and by race/ethnicity.

Methods

We used the newborn patient records obtained from Texas Public Use Data Files from 2010 to 2019 for hospitals in Texarkana, which is located on the border of Texas and Arkansas, with all of the hospitals serving pregnancy and childbirth patients on the Texas side of the border. We employed difference-in-differences models to estimate the effect of Medicaid expansion on birth outcomes (preterm birth and low birth weight) overall and by race/ethnicity. Newborns from Arkansas (expanded Medicaid in 2014) constituted the treatment group, while those from Texas (did not adopt the expansion) were the control group. We utilized a difference-in-differences event study framework to examine the gradual impact of the Medicaid expansion on birth outcomes.

Results

Medicaid expansion was associated with a 1.38-percentage-point decrease (95% confidence interval (CI), 0.09–2.67) in preterm birth overall. Event study results suggest that preterm births decreased gradually over time. Medicaid expansion was associated with a 2.04-percentage-point decrease (95% CI, 0.24–3.85) in preterm birth and a 1.75-percentage-point decrease (95% CI, 0.42–3.08) in low birth weight for White infants. However, Medicaid expansion was not associated with significant changes in birth outcomes for other race/ethnicity groups. 

Conclusions

Our findings suggest that Medicaid expansion in Texas can potentially improve birth outcomes. However, bridging racial disparities in birth outcomes might require further efforts such as promoting preconception and prenatal care, especially among the Black population.
Polishing methods for composites restoration: the influence on human gingival fibroblasts behaviour
Authors: Ghezzi Benedetta , Meglioli Matteo , Salvaterra Toffoli Andrea , Mergoni Giovanni , Rossi Francesca , Manfredi Maddalena , Lumetti Simone , Manfredi Edoardo
Published: June 2024

Background

Carious/Non-carious cervical lesions with gingival recessions may require both dental and periodontal reconstructive therapy, where flaps/grafts may be placed in contact with a dental filling material. Human Gingival Fibroblasts (HGF-1) response during the early phase of healing could vary according to the procedures employed to cure the dental composite. Moreover, oxygen diffusion into dental composite inhibits the polymerization reaction, creating an oxygen-inhibited layer (OIL) that presents residual unreacted monomers. The aim of this study was to assess the effect of different polishing techniques and OIL on HGF-1.

Methods

Composite discs polished with different techniques (diamond rubber, abrasive discs and tungsten carbide burr) were used. An additional not polished smooth group obtained with and without OIL was used as control. Samples were physically characterized through the analysis of their hydrophilicity and surface topography through contact angle measurement and SEM, respectively; afterwards the biologic response of HGF-1 when cultured on the different substrates was analyzed in terms of cytotoxicity and gene expression.

Results

The finishing systems caused alterations to the wettability, even if without a proportional relation towards the results of the proliferation essay, from which emerges a greater proliferation on surfaces polished with one-step diamond rubber and with abrasive discs as well as a direct effect of the glycerin layer, confirming that surface roughness can heavily influence the biological response of HGF-1.

Conclusions

Surfaces wettability as well as cellular behavior seem to be affected by the selection of the finishing system used to lastly shape the restoration. Especially, the presence of OIL act as a negative factor in the regards of human gingival fibroblasts. The present study may provide the first clinical instruction regarding the best polishing system of composite material when the restoration is placed directly in contact with soft tissue cells. Understanding HGF-1 behavior can help identifying the polishing treatment for direct restoration of carious/non-carious cervical lesions associated with gingival recessions.
Stress reduction through taiji: a systematic review and meta-analysis
Authors: Kraft Jana , Waibl Paula J. , Meissner Karin
Published: June 2024

Purpose

In light of the mounting prevalence of stress in contemporary society and the growing interest in stress reduction methods, this review investigates the potential of taiji as a viable strategy for alleviating stress.

Methods

MEDLINE, EMBASE, the Cochrane Controlled Trials Register (CENTRAL), PsycINFO, and Web of Science were searched up to April 2023 to identify randomized controlled trials of taiji. Studies in both patients and healthy populations were considered. They had to provide a measure of perceived stress and include a no treatment or placebo control group. Data were extracted by two reviewers. Pooled standardized mean differences (SMD) were calculated for perceived stress, biological stress markers, anxiety, depression, and quality of life (QoL). Meta-regression analyses were performed to identify sources of heterogeneity.

Results

Eleven trials with a total of 1323 patients comparing taiji to no intervention met the inclusion criteria. The included studies varied strongly with regard to patient characteristics, taiji intervention, and methodological quality. The overall SMD for perceived stress was significant at -0.41 (95% confidence interval, CI, -0.63 to -0.19; I2 = 63%). Exclusion of studies with less than 100 participants yielded a diminished SMD at -0.26 (95% CI, -0.45 to -0.06). The SMD for perceived stress at follow-up was significant (-0.25, 95% CI -0.46 to -0.05). Secondary outcomes highlighted improvements in anxiety and physical QoL, while depression, mental QoL, and biological stress markers remained unchanged.

Conclusions

Results underscore taiji's potential in mitigating perceived stress in both patients and healthy populations, paralleled by enhancements in depressive symptoms, anxiety levels, and physical QoL.
Extracting patient lifestyle characteristics from Dutch clinical text with BERT models
Authors: Muizelaar Hielke , Haas Marcel , van Dortmont Koert , van der Putten Peter , Spruit Marco
Published: June 2024

Background

BERT models have seen widespread use on unstructured text within the clinical domain. However, little to no research has been conducted into classifying unstructured clinical notes on the basis of patient lifestyle indicators, especially in Dutch. This article aims to test the feasibility of deep BERT models on the task of patient lifestyle classification, as well as introducing an experimental framework that is easily reproducible in future research.

Methods

This study makes use of unstructured general patient text data from HagaZiekenhuis, a large hospital in The Netherlands. Over 148 000 notes were provided to us, which were each automatically labelled on the basis of the respective patients’ smoking, alcohol usage and drug usage statuses. In this paper we test feasibility of automatically assigning labels, and justify it using hand-labelled input. Ultimately, we compare macro F1-scores of string matching, SGD and several BERT models on the task of classifying smoking, alcohol and drug usage. We test Dutch BERT models and English models with translated input.

Results

We find that our further pre-trained MedRoBERTa.nl-HAGA model outperformed every other model on smoking (0.93) and drug usage (0.77). Interestingly, our ClinicalBERT model that was merely fine-tuned on translated text performed best on the alcohol task (0.80). In t-SNE visualisations, we show our MedRoBERTa.nl-HAGA model is the best model to differentiate between classes in the embedding space, explaining its superior classification performance.

Conclusions

We suggest MedRoBERTa.nl-HAGA to be used as a baseline in future research on Dutch free text patient lifestyle classification. We furthermore strongly suggest further exploring the application of translation to input text in non-English clinical BERT research, as we only translated a subset of the full set and yet achieved very promising results.
The factors of job crafting in emergency nurses: regression models versus qualitative comparative analysis
Authors: Wang Yu , Yang Qiaofang , Wang Luwen , Zhang Qingwei , Li Yingli
Published: June 2024

Background

Job crafting is defined as a series of proactive behaviors exhibited by employees in order to balance work resources and needs, which has a significant positive impact on the nurses. It is necessary to find the core factors that influence the job crafting, as emergency nurses deal with the most complex tasks, so as to improve their job satisfaction.

Objectives

To investigate the core factors of job crafting among emergency nurses.

Methods

A cross-sectional design was used in the study. A total of 255 nurses were recruited from two hospitals in Zhengzhou and Shenzhen, China in December 2021. 255 nurses completed an online questionnaire. Hierarchical regression models and fsQCA models were used to explore the factors influencing job crafting among emergency nurses and helped us to identify core factors.

Results

The hierarchical regression model and the fsQCA model found that the occupational benefit, psychological empowerment, and research experience were the core factors affecting their job crafting. Job involvement was not significant in the regression model, but the QCA model indicated that it needs to be combined with other factors to impact on job crafting. The QCA model uncovered seven key conditional configurations that led to high and low job crafting among emergency nurses, explaining 80.0% of the results for high job crafting and 82.6% of the results for the low job crafting, respectively.

Conclusions

The results of this study provide valuable insights into the job crafting experienced by emergency nurses. Junior emergency nurses should be granted a high level of psychological empowerment without assigning them overly complex tasks, such as research tasks, as these challenges can stop their job crafting. Intermediate and senior emergency nurses, on the other hand, can be assigned research tasks coupled with high psychological empowerment to enhance their job crafting.
The introduction of video-enabled directly observed therapy (video-DOT) for patients with drug-resistant TB disease in Eswatini amid the COVID-19 pandemic – a retrospective cohort study
Authors: Kerschberger Bernhard , Daka Michelle , Shongwe Bhekiwe , Dlamini Themba , Ngwenya Siphiwe , Danbakli Clara , Mamba Bheki , Nxumalo Bongekile , Sibanda Joyce , Dube Sisi , Dlamini Lindiwe Mdluli , Mabhena Edwin , Mukooza Esther , Crumley Iona , Ciglenecki Iza , Vambe Debrah
Published: June 2024

Background

Video-enabled directly observed therapy (video-DOT) has been proposed as an additional option for treatment provision besides in-person DOT for patients with drug-resistant TB (DRTB) disease. However, evidence and implementation experience mainly originate from well-resourced contexts. This study describes the operationalization of video-DOT in a low-resourced setting in Eswatini facing a high burden of HIV and TB amid the emergence of the COVID-19 pandemic.

Methods

This is a retrospectively established cohort of patients receiving DRTB treatment during the implementation of video-DOT in Shiselweni from May 2020 to March 2022. We described intervention uptake (vs. in-person DOT) and assessed unfavorable DRTB treatment outcome (death, loss to care) using Kaplan-Meier statistics and multivariable Cox-regression models. Video-related statistics were described with frequencies and medians. We calculated the fraction of expected doses observed (FEDO) under video-DOT and assessed associations with missed video uploads using multivariable Poisson regression analysis.

Results

Of 71 DRTB patients eligible for video-DOT, the median age was 39 (IQR 30–54) years, 31.0% (n = 22) were women, 67.1% (n = 47/70) were HIV-positive, and 42.3% (n = 30) were already receiving DRTB treatment when video-DOT became available. About half of the patients (n = 37; 52.1%) chose video-DOT, mostly during the time when COVID-19 appeared in Eswatini. Video-DOT initiations were lower in new DRTB patients (aHR 0.24, 95% CI 0.12–0.48) and those aged ≥ 60 years (aHR 0.27, 95% CI 0.08–0.89). Overall, 20,634 videos were uploaded with a median number of 553 (IQR 309–748) videos per patient and a median FEDO of 92% (IQR 84–97%). Patients aged ≥ 60 years were less likely to miss video uploads (aIRR 0.07, 95% CI 0.01–0.51). The cumulative Kaplan-Meier estimate of an unfavorable treatment outcome among all patients was 0.08 (95% CI 0.03–0.19), with no differences detected by DOT approach and other baseline factors in multivariable analysis.

Conclusions

Implementing video-DOT for monitoring of DRTB care provision amid the intersection of the HIV and COVID-19 pandemics seemed feasible. Digital health technologies provide additional options for patients to choose their preferred way to support treatment taking, thus possibly increasing patient-centered health care while sustaining favorable treatment outcomes.
Virtual reality as an engaging and enjoyable method for delivering emergency clinical simulation training: a prospective, interventional study of medical undergraduates
Authors: Walls Risheka , Nageswaran Priyanka , Cowell Adrian , Sehgal Tunav , White Thomas , McVeigh James , Staykov Stefan , Basett Paul , Mitelpunkt Daniel , Sam Amir H.
Published: June 2024

Background

It is a requirement that medical students are educated in emergencies and feel well prepared for practice as a doctor, yet national surveys show that many students feel underprepared. Virtual reality (VR), combined with 360-degree filming, provides an immersive, realistic, and interactive simulation experience. Unlike conventional in-person simulation, it is scalable with reduced workforce demands. We sought to compare students’ engagement and enjoyment of VR simulation to desktop computer-based simulation.

Methods

We conducted a prospective, interventional, evaluation study. The study was carried out on final year medical students undertaking their Pre-Foundation Assistantship (n = 116) at Imperial College School of Medicine (ICSM) in London. We compared objective engagement, subjective engagement, and subjective enjoyment of VR simulation to desktop computer-based simulation using cardiac arrest and life-threatening asthma scenarios. Engagement was measured objectively using students’ physiological parameters, including heart rate and eye tracking, and facilitator observations using the validated ‘Behavioural Engagement Related to Instruction’ (BERI) protocol. Students’ subjective engagement and enjoyment levels were measured using a post-session survey.

Results

Students’ maximum heart rates were significantly higher during VR simulation with a mean difference of 4.2 beats per minute (3.2 to 5.2, p < 0.001), and eye tracking showed they spent a significantly greater mean percentage of time of 6.4% (5.1 to 7.7, p < 0.001) focusing on the scenarios in VR compared to standard desktop. Qualitative data showed students enjoyed and felt engaged with the sessions, which provided a safe space for learning.

Conclusions

Our study shows that students found VR simulations enjoyable and were more engaged compared to standard desktop simulation. This suggests that 360-degree VR simulation experiences provide students with immersive, realistic training, which is scalable, giving them the unique opportunity to manage emergencies and work within emergency teams, which would not typically occur during traditional training.
Adherence to a Mediterranean diet is associated with a lower risk of diabetic kidney disease among individuals with hyperglycemia: a prospective cohort study
Authors: Qu Changbo , Zhao Jinyu , Lai Jicai , Wu Xinxiang , Huang Peng , Zhu Ting , Li Yan , Liu Taoli , Yuan Jinqiu , Wang Ning , Peppelenbosch Maikel P , Chen Hongda , Xia Bin , Qin Jian
Published: June 2024

Background

Type 2 diabetes is associated with a variety of complications, including micro- and macrovascular complications, neurological manifestations and poor wound healing. Adhering to a Mediterranean Diet (MED) is generally considered an effective intervention in individuals at risk for type 2 diabetes mellitus (T2DM). However, little is known about its effect with respect to the different specific manifestations of T2DM. This prompted us to explore the effect of MED on the three most significant microvascular complications of T2DM: diabetic retinopathy (DR), diabetic kidney disease (DKD), and vascular diabetic neuropathies (DN).

Methods

We examined the association between the MED and the incidence of these microvascular complications in a prospective cohort of 33,441 participants with hyperglycemia free of microvascular complications at baseline, identified in the UK Biobank. For each individual, we calculated the Alternate Mediterranean Diet (AMED) score, which yields a semi-continuous measure of the extent to which an individual’s diet can be considered as MED. We used Cox proportional hazard models to analyze hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographics, lifestyle factors, medical histories and cardiovascular risk factors.

Results

Over a median of 12.3 years of follow-up, 3,392 cases of microvascular complications occurred, including 1,084 cases of diabetic retinopathy (DR), 2,184 cases of diabetic kidney disease (DKD), and 632 cases of diabetic neuropathies (DN), with some patients having 2 or 3 microvascular complications simultaneously. After adjusting for confounders, we observed that higher AMED scores offer protection against DKD among participants with hyperglycemia (comparing the highest AMED scores to the lowest yielded an HR of 0.79 [95% CIs: 0.67, 0.94]). Additionally, the protective effect of AMED against DKD was more evident in the hyperglycemic participants with T2DM (HR, 0.64; 95% CI: 0.50, 0.83). No such effect, however, was seen for DR or DN.

Conclusions

In this prospective cohort study, we have demonstrated that higher adherence to a MED is associated with a reduced risk of DKD among individuals with hyperglycemia. Our study emphasizes the necessity for continued research focusing on the benefits of the MED. Such efforts including the ongoing clinical trial will offer further insights into the role of MED in the clinical management of DKD.
Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease
Authors: Pan Binhui , Teng Yangyang , Wang Renban , Chen Dan , Chen Hui
Published: June 2024

Objective

To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism.

Methods

Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively.

Results

Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2’s relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (α-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3.

Conclusion

Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.
NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression
Authors: Shi Yijun , Fang Na , Wu Yutong , Xu Huiwen , Ning Anhui , Zhang Wendi , Liu Yiran , Tao Xiaobo , Chen Qiong , Tian Tian , Zhang Lei , Chu Minjie , Cui Jiahua
Published: June 2024

The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-β domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.
Activation of AMPK inhibits cervical cancer growth by hyperacetylation of H3K9 through PCAF
Authors: Pan Botao , Liu Can , Su Jiyan , Xia Chenglai
Published: June 2024

Background

Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown.

Methods

The impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated.

Results

In this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation.

Conclusions

In conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation.
Local delivery of accutox® synergises with immune-checkpoint inhibitors at disrupting tumor growth
Authors: Bikorimana Jean Pierre , El-Hachem Nehme , Abusarah Jamilah , Gonçalves Marina Pereira , Farah Roudy , Mandl Gabrielle A. , Talbot Sebastien , Beaudoin Simon , Stanga Daniela , Plouffe Sebastien , Rafei Moutih
Published: June 2024

Background

The Accum®platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum®was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum®variants, which led to the identification of the AccuTOX®molecule.

Methods

A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX®along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX®treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX®was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI).

Results

In total, 7 Accum®variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX®enhances H2-Kbcell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model.

Conclusions

AccuTOX®exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum®molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.

Graphical Abstract
A data-driven approach to implementing the HPTN 094 complex intervention INTEGRA in local communities
Authors: Smith Laramie R. , Perez-Brumer Amaya , Nicholls Melanie , Harris Jayla , Allen Qiana , Padilla Alan , Yates Autumn , Samore Eliza , Kennedy Rebecca , Kuo Irene , Lake Jordan E. , Denis Cecile , Goodman-Meza David , Davidson Peter , Shoptaw Steve , El-Bassel Nabila ,   for the HPTN 094 study protocol team
Published: June 2024

Background

HIV burden in the US among people who inject drugs (PWID) is driven by overlapping syndemic factors such as co-occurring health needs and environmental factors that synergize to produce worse health outcomes among PWID. This includes stigma, poverty, and limited healthcare access (e.g. medication to treat/prevent HIV and for opioid use disorder [MOUD]). Health services to address these complex needs, when they exist, are rarely located in proximity to each other or to the PWID who need them. Given the shifting drug use landscapes and geographic heterogeneity in the US, we evaluate a data-driven approach to guide the delivery of such services to PWID in local communities.

Methods

We used a hybrid, type I, embedded, mixed method, data-driven approach to identify and characterize viable implementation neighborhoods for the HPTN 094 complex intervention, delivering integrated MOUD and HIV treatment/prevention through a mobile unit to PWID across five US cities. Applying the PRISM framework, we triangulated geographic and observational pre-implementation phase data (epidemiological overdose and HIV surveillance data) with two years of implementation phase data (weekly ecological assessments, study protocol meetings) to characterize environmental factors that affected the viability of implementation neighborhoods over time and across diverse settings.

Results

Neighborhood-level drug use and geographic diversity alongside shifting socio-political factors (policing, surveillance, gentrification) differentially affected the utility of epidemiological data in identifying viable implementation neighborhoods across sites. In sites where PWID are more geographically dispersed, proximity to structural factors such as public transportation and spaces where PWID reside played a role in determining suitable implementation sites. The utility of leveraging additional data from local overdose and housing response systems to identify viable implementation neighborhoods was mixed.

Conclusions

Our findings suggest that data-driven approaches provide a contextually relevant pragmatic strategy to guide the real-time implementation of integrated care models to better meet the needs of PWID and help inform the scale-up of such complex interventions. This work highlights the utility of implementation science methods that attend to the impact of local community environmental factors on the implementation of complex interventions to PWID across diverse drug use, sociopolitical, and geographic landscapes in the US.

Trial registration

ClincalTrials.gov, Registration Number: NCT04804072. Registered 18 February 2021.
Association between the procedure of tibiotalocalcaneal arthrodesis by hindfoot nailing and quality of life in Charcot’s joint
Authors: Rastegar Shirvan , Teymouri Mehdi , Sabaghi Jamal
Published: June 2024

Introduction

Charcot arthropathy is a progressive disorder of the ankle and foot joints that can lead to foot deformity and instability. Surgical intervention is often necessary for deformity and ulcer management during the chronic phase. The device used for arthrodesis remains a challenge.

Methods

This clinical trial study included diabetic patients aged 40 years or older with Charcot foot. Lateral approach with lateral malleolar osteotomy was used to access the ankle joints and remove the cartilage. A small incision was made on the plantar aspect of the foot to pass an appropriately sized intramedullary nail. Demographic information, medical history, surgical details and Clinical data were collected at 2-week and 1-year follow-ups using the Ankle-Hindfoot Scale (AOFAS) score and the EuroQol 5-Dimensional 5-Level (EQ-5D-5L) health utility score.

Results

Twenty-six patients with a mean age of 63 ± 0.23 years were included in the study. The findings showed significant improvements in AOFAS questionnaire items related to pain score, length of the walk, walking surfaces, walking disorders, sagittal alignment, back leg alignment, sustainability, alignment and the total score (P value < 0.001). The EQ-5D-5L questionnaire also showed a significant improvement in the total score (P value = 0.002).

Conclusion

This study provides evidence supporting the effectiveness of tibiotalocalcaneal arthrodesis by hindfoot nailing in diabetic patients with Charcot foot joints and demonstrated comparable and superior outcomes in terms of patient satisfaction and complication rate when compared to previous studies.
Saiga antelope horn suppresses febrile seizures in rats by regulating neurotransmitters and the arachidonic acid pathway
Authors: Wu Wenxing , Song Wencong , Zhao Jingjing , Guo Sheng , Hong Min , Zheng Jie , Hua Yongqing , Cao Peng , Liu Rui , Duan Jin-ao
Published: June 2024

Background

Saiga antelope horn (SAH) is a traditional Chinese medicine for treating febrile seizure (FS) with precise efficacy, but its mechanism of action and functional substances are still unclear. Given the need for further research on SAH, our group conducted studies to elucidate its mechanisms and active substances.

Methods

An FS rat pup model was constructed through intraperitoneal injection of LPS and hyperthermia induction. Behavioural indicators of seizures, hippocampal histopathological alterations, serum levels of inflammatory cytokines and hippocampal levels of neurotransmitters were observed and measured to investigate the effects of SAH on FS model rats. Hippocampal metabolomics and network pharmacology analyses were conducted to reveal the differential metabolites, key peptides and pathways involved in the suppression of FS by SAH.

Results

SAH suppressed FS, decreased the inflammatory response and regulated the Glu-GABA balance. Metabolomic analysis revealed 13 biomarkers of FS, of which SAH improved the levels of 8 differential metabolites. Combined with network pharmacology, a “biomarker-core target-key peptide” network was constructed. The peptides of SAH, such as YGQL and LTGGF, could exert therapeutic effects via the arachidonic acid pathway. Molecular docking and ELISA results indicated that functional peptides of SAH could bind to PTGS2 target, inhibiting the generation of AA and its metabolites in hippocampal samples.

Conclusion

In summary, the functional peptides contained in SAH are the main material basis for the treatment of FS, potentially acting through neurotransmitter regulation and the arachidonic acid pathway.

Graphical abstract
Chronic unpredictable stress induces autophagic death of adult hippocampal neural stem cells
Authors: Choe Seongwon , Jeong Hyeonjeong , Choi Jieun , Yu Seong-Woon
Published: June 2024

Chronic psychological stress is a critical factor for neurological complications like anxiety disorders, dementia, and depression. Our previous results show that chronic restraint stress causes cognitive deficits and mood dysregulation by inducing autophagic death of adult hippocampal neural stem cells (NSCs). However, it is unknown whether other models of psychological stress also induce autophagic death of adult hippocampal NSCs. Here, we show that chronic unpredictable stress (CUS) for 10 days impaired memory function and increased anxiety in mice. Immunohistochemical staining with SOX2 and KI67 revealed a significant reduction in the number of NSCs in the hippocampus following exposure to CUS. However, these deficits were prevented by NSC-specific, inducible conditional deletion of Atg7. These findings suggest that autophagic death of adult hippocampal NSCs is a critical pathogenic mechanism underlying stress-induced brain disorders.
Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer
Authors: Zhou Zhuan , Qu Chunhui , Zhou Peijun , Zhou Qin , Li Dan , Wu Xia , Yang Lifang
Published: June 2024

Background

Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, and mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage is an important molecular event in oxidative stress. In lung cancer, the normal fibroblasts (NFs) are activated as cancer-associated fibroblasts (CAFs), and act in the realms of the tumor microenvironment (TME) with consequences for tumor growth and metastasis. However, its activation mechanism and whether it participates in tumor metastasis through antioxidative stress remain unclear.

Methods

The role and signaling pathways of tumor cell derived extracellular vesicles (EVs) activating NFs and the characteristic of induced CAFs (iCAFs) were measured by the transmission electron microscopy, nanoparticle tracking analysis, immunofluorescence, collagen contraction assay, quantitative PCR, immunoblotting, luciferase reporter assay and mitochondrial membrane potential detection. Mitochondrial genome and single nucleotide polymorphism sequencing were used to investigate the transport of mtDNA from iCAFs to ρ0 cells, which were tumor cells with mitochondrial dysfunction caused by depletion of mtDNA. Further, the effects of iCAFs on mitochondrial function, growth and metastasis of tumor cells were analysed in co-culture models both in vitro and in vivo, using succinate dehydrogenase, glutathione and oxygen consumption rate measurements, CCK-8 assay, transwell assay, xenotransplantation and metastasis experiments as well as in situ hybridization and immunohistochemistry.

Results

Our findings revealed that EVs derived from high-metastatic lung cancer cells packaged miR-1290 that directly targets MT1G, leading to activation of AKT signaling in NFs and inducing NFs conversion to CAFs. The iCAFs exhibit higher levels of autophagy and mitophagy and more mtDNA release, and reactive oxygen species (ROS) could further promote this process. After cocultured with the conditioned medium (CM) of iCAFs, the ρ0 cells may restore its mitochondrial function by acquisition of mtDNA from CAFs, and further promotes tumor metastasis.

Conclusions

These results elucidate a novel mechanism that CAFs activated by tumor-derived EVs can promote metastasis by transferring mtDNA and restoring mitochondrial function of tumor cells which result in resistance of oxidative stress, and provide a new therapeutic target for lung cancer metastasis.
Whole lung lavage and GM-CSF use for pulmonary alveolar proteinosis in an infant with lysinuric protein intolerance: a case report
Authors: Vojcek Eszter , Krikovszky Dóra , Lódi Csaba , Kovács Lajos , Schnur János , Szabó Attila J.
Published: June 2024

Background

Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine, ornithine and arginine. Infants with LPI typically present with recurrent vomiting, poor growth, interstitial lung disease or renal impairment. The early onset of pulmonary alveolar proteinosis (PAP) has been reported to be associated with a severe form of LPI. Treatment of PAP most commonly consists of whole-lung lavage (WLL) and in autoimmune PAP, granulocyte-macrophage colony stimulating factor (GM-CSF) administration. Nevertheless, GM-CSF therapy in LPI-associated PAP has not been scientifically justified.

Case presentation

We describe the case of an 8-month-old infant presenting with respiratory failure due to LPI associated with PAP, who was twice treated with WLL; firstly, while on veno-venous ECMO assistance and then by the use of a selective bronchial blocker. After the two treatments with WLL, she was weaned from daytime respiratory support while on initially subcutaneous, then on inhaled GM-CSF therapy.

Conclusions

This case supports the notion that GM-CSF therapy might be of benefit in patients with LPI-associated PAP. Further studies are needed to clarify the exact mechanism of GM-CSF in patients with LPI-associated PAP.
A case of variant of GBS with positive serum ganglioside GD3 IgG antibody
Authors: Xue Jiao , Song Zhenfeng , Zhao Hongshan , Yi Zhi , Li Fei , Yang Chengqing , Liu Kaixuan , Zhang Ying
Published: June 2024

Background

Acute bulbar palsy-plus (ABPp) syndrome is an unusual variant of Guillain-Barré syndrome (GBS). Anti-GT1a and anti-GQ1b antibodies have been reported in patients with ABPp, but without reports related to GD3 antibodies.

Methods

Clinical data of a patient diagnosed as ABPp syndrome were reviewed clinically. And we summarized the GBS patients with ABP and facial paralysis reported in the literature.

Results

We reported a 13-year-old girl presented with asymmetric bifacial weakness, bulbar palsy and transient limb numbness, and had positive serum IgG anti-GD3 antibody. Through reviewing the GBS patients with ABP and facial paralysis reported previously, we found that facial palsy could be unilateral or bilateral. The bilateral facial palsy could present successively or simultaneously, and could be symmetrical or asymmetrical. Other common symptoms included ophthalmoplegia, sensory abnormality and ataxia. IgG anti-GT1a and IgG anti-GQ1b antibodies were the most frequent. Most of the patients had full recovery within two weeks to one year of follow-up.

Conclusions

We reported a patient with asymmetric bifacial palsy and bulbar palsy, which seemed to fit the diagnosis of ABPp syndrome. This was the first report of ABPp variant of GBS with positive serum ganglioside GD3 IgG antibody.