bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of PD-L1 through evolution phase from pre-invasive to invasive lung adenocarcinoma
Authors: Zhou Jiebai , Lin Huo , Ni Zheng , Luo Rongkui , Yang Dawei , Feng Mingxiang , Zhang Yong
Published: January 2023

Background

This study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution.

Methods

We evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1–IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score:  < 1% (negative),  ≥ 1% (positive) and  ≥ 50% (strongly positive). Correlations between PD-L1 expression and T stage, pathological subtype, adenocarcinoma grade, spread through air space (STAS), vascular invasion, lymphatic invasion and driven genes were analyzed.

Results

There was almost no PD-L1 expression in AIS or MIA. However, PD-L1 expression was correlated with invasiveness of lung adenocarcinoma. The percentages of PD-L1 positive in IA1–IA3 were 7.22%, 11.29%, and 14.20%, respectively. The strongly positive rates of PD-L1 were 0.38%, 1.64%, and 3.70% in IA1–IA3, respectively. PD-L1 expression and positive rate were also associated with poor pathological subtype and poor biological behavior, such as adenocarcinoma Grade 3, micropapillary or solid dominant subtype, STAS and vascular invasion. Finally, PD-L1 positive rate seems also corrected with driven gene ALK, ROS-1 and KRAS.

Conclusions

PD-L1 expression was positively correlated with the emergence of invasiveness and poor pathological subtype or biological behavior of early-stage lung adenocarcinoma. PD-L1 pathway may be involved in the early evolution of lung adenocarcinoma from AIS to IAC.
Efficacy and safety of long-term use of a positive expiratory pressure device in chronic obstructive pulmonary disease patients, a randomized controlled trial
Authors: Xu Zhaoning , Han Zhuo , Ma Dedong
Published: January 2023

Background

Exercise intolerance is among the most common symptoms experienced by patients with chronic obstructive pulmonary disease (COPD), which is associated with lung dynamic hyperinflation (DH). There was evidence that positive expiratory pressure (PEP), which could be offered by less costly devices, could reduce DH. The purpose of this study was to evaluate the efficacy and safety of long-term domiciliary use of PEP device in subjects with COPD.

Methods

A randomized controlled trial was conducted and 25 Pre-COPD or mild-to-very severe subjects with COPD were randomized to intervention group (PEP device, PEP = 5 cmH2O, n = 13) and control group (Sham-PEP device, PEP = 0 cmH2O, n = 12). PEP device was a spring-loaded resistor face mask. Subjects were treated 4 h per day for a total of 2 months. Six-minute walk test (6MWT), pulmonary function, the Modified British Medical Research Council score, and partial pressure of end-tidal carbon dioxide were evaluated at baseline and after two months.

Results

The 6MWD (− 71.67 ± 8.70 m, P < 0.001), end-dyspnea (P = 0.002), and end-fatigue (P = 0.022) improved significantly in the intervention group when compared with the control group. All subjects in the intervention group reported that 4 h of daily use of the PEP device was well tolerated and accepted and there were no adverse events.

Conclusion

Regular daily use of PEP device is safe and may improve exercise capacity in subjects with COPD or pre-COPD. PEP device could be used as an add-on to pulmonary rehabilitation programs due to its efficacy, safety, and low cost.

Trial registration: The study was prospectively registered on ClinicalTrials.gov (NCT04742114).
Lifestyle management in polycystic ovary syndrome – beyond diet and physical activity
Authors: Cowan Stephanie , Lim Siew , Alycia Chelsea , Pirotta Stephanie , Thomson Rebecca , Gibson-Helm Melanie , Blackmore Rebecca , Naderpoor Negar , Bennett Christie , Ee Carolyn , Rao Vibhuti , Mousa Aya , Alesi Simon , Moran Lisa
Published: January 2023

Polycystic ovary syndrome (PCOS) is a common condition affecting reproductive-aged women with reproductive, metabolic and psychological consequences. Weight and lifestyle (diet, physical activity and behavioural) management are first-line therapy in international evidence-based guidelines for PCOS. While these recommend following population-level diet and physical activity guidelines, there is ongoing interest and research in the potential benefit of including psychological and sleep interventions, as well as a range of traditional, complimentary and integrative medicine (TCIM) approaches, for optimal management of PCOS. There is limited evidence to recommend a specific diet composition for PCOS with approaches including modifying protein, carbohydrate or fat quality or quantity generally having similar effects on the presentations of PCOS. With regards to physical activity, promising evidence supports the provision of vigorous aerobic exercise, which has been shown to improve body composition, cardiorespiratory fitness and insulin resistance. Psychological and sleep interventions are also important considerations, with women displaying poor emotional wellbeing and higher rates of clinical and subclinical sleep disturbance, potentially limiting their ability to make positive lifestyle change. While optimising sleep and emotional wellbeing may aid symptom management in PCOS, research exploring the efficacy of clinical interventions is lacking. Uptake of TCIM approaches, in particular supplement and herbal medicine use, by women with PCOS is growing. However, there is currently insufficient evidence to support integration into routine clinical practice. Research investigating inositol supplementation have produced the most promising findings, showing improved metabolic profiles and reduced hyperandrogenism. Findings for other supplements, herbal medicines, acupuncture and yoga is so far inconsistent, and to reduce heterogeneity more research in specific PCOS populations, (e.g. defined age and BMI ranges) and consistent approaches to intervention delivery, duration and comparators are needed. While there are a range of lifestyle components in addition to population-recommendations for diet and physical activity of potential benefit in PCOS, robust clinical trials are warranted to expand the relatively limited evidence-base regarding holistic lifestyle management. With consumer interest in holistic healthcare rising, healthcare providers will be required to broaden their knowledge pertaining to how these therapies can be safely and appropriately utilised as adjuncts to conventional medical management.
Common hierarchies, varied rules - the problem of governing community first responders in prehospital care for quality standards: documentary discourse analysis
Authors: Patel Gupteswar , Phung Viet-Hai , Trueman Ian , Orner Roderick , Siriwardena Aloysius Niroshan
Published: January 2023

A key focus is placed on engaging communities to become involved in making decisions to support health and care services in healthcare policies in England, UK. An example is the deployment of volunteers such as community first responders (CFRs), who are members of the public with basic life support skills, trained to intervene in emergency situations prior to the arrival of ambulance services. CFR policies have been devised by National Health Service (NHS) Trusts as a way of governing these and related activities. This paper critically examines the discourse around CFR policies to understand how CFR roles are organised and monitoring governance mechanisms are delineated in ensuring quality care delivery. We collected ten CFR policies from six ambulance services. Inductive analysis, guided by Foucault’s theory, enabled the identification of themes and subthemes. We found that Trusts have a common goal to make care quality assurances to regulatory bodies on CFR roles, and this is depicted in common hierarchies of individual responsibilities across Trusts. However, policies that govern approaches to CFRs activity vary. Firstly, the paper highlights institutional approaches to ensuring public safety through the application of organised surveillance systems to monitor CFR activities, and draws parallels between such surveillance and Foucault’s docile bodies. Secondly, the paper discusses how varying rules in the surveillance system compromises safety by decentralising knowledge to regulatory bodies to whom NHS Trusts must make safety assurances. We suggest that stronger interrelationships between Trusts in considering the CFR role has potential to increase public safety and outline a clearer direction for CFRs.
How to scale-up: a comparative case study of scaling up a district health management strengthening intervention in Ghana, Malawi and Uganda
Authors: Bulthuis Susan , Kok Maryse , Onvlee Olivier , O’Byrne Thomasena , Amon Samuel , Namakula Justine , Chikaphupha Kingsley , Gerold Jana , Mansour Wesam , Raven Joanna , Broerse Jacqueline E. W. , Dieleman Marjolein
Published: January 2023

Background

The need to scale up public health interventions in low- and middle-income countries to ensure equitable and sustainable impact is widely acknowledged. However, there has been little understanding of how projects have sought to address the importance of scale-up in the design and implementation of their initiatives. This paper aims to gain insight into the facilitators of the scale-up of a district-level health management strengthening intervention in Ghana, Malawi and Uganda.

Methods

The study took a comparative case study approach with two rounds of data collection (2019 and 2021) in which a combination of different qualitative methods was applied. Interviews and group discussions took place with district, regional and national stakeholders who were involved in the implementation and scale-up of the intervention.

Results

A shared vision among the different stakeholders about how to institutionalize the intervention into the existing system facilitated scale-up. The importance of champions was also identified, as they influence buy-in from key decision makers, and when decision makers are convinced, political and financial support for scale-up can increase. In two countries, a specific window of opportunity facilitated scale-up. Taking a flexible approach towards scale-up, allowing adaptations of the intervention and the scale-up strategy to the context, was also identified as a facilitator. The context of decentralization and the politics and power relations between stakeholders involved also influenced scale-up.

Conclusions

Despite the identification of the facilitators of the scale-up, full integration of the intervention into the health system has proven challenging in all countries. Approaching scale-up from a systems change perspective could be useful in future scale-up efforts, as it focuses on sustainable systems change at scale (e.g. improving district health management) by testing a combination of interventions that could contribute to the envisaged change, rather than horizontally scaling up and trying to embed one particular intervention in the system.
Predictors of delayed Anti-Retroviral Therapy initiation among adults referred for HIV treatment in Uganda: a cross-sectional study
Authors: Kiyingi Micheal , Nankabirwa Joaniter I. , Sekaggya-Wiltshire Christine , Nangendo Joan , Kiweewa John M. , Katahoire Anne R. , Semitala Fred C.
Published: January 2023

Background

Uganda’s current guidelines recommend immediate initiation of Anti-Retroviral Therapy (ART) for persons living with HIV in order to reduce HIV/AIDS related morbidity and mortality. However, not all eligible PLHIV initiate ART within the recommended time following HIV diagnosis. We assessed the prevalence and factors associated with delayed ART initiation among PLHIV referred for ART initiation, five years since rolling out the test and treat guidelines.

Methods

In this cross-sectional study, we enrolled adult patients referred to Mulago Immune Suppressive Syndrome (Mulago ISS) clinic for ART initiation from January 2017 to May 2021. We collected data on socio-demographics, HIV diagnosis and referral circumstances, and time to ART initiation using a questionnaire. The outcome of interest was proportion of patients that delayed ART, defined as spending more than 30 days from HIV diagnosis to ART initiation. We performed multivariable logistic regression and identified significant factors.

Results

A total of 312 patients were enrolled of which 62.2% were female. The median (inter-quartile range [IQR]) age and baseline CD4 count of the patients were 35 (28–42) years and 315 (118.8–580.5) cells/μL respectively. Forty-eight (15.4%) patients delayed ART initiation and had a median (IQR) time to ART of 92 (49.0–273.5) days. The factors associated with delayed ART initiation were; 1) having had the HIV diagnosis made from a private health facility versus public, (adjusted odds ratio [aOR] = 2.4 (95% confidence interval [CI] 1.1–5.5); 2) initial denial of positive HIV test results, aOR = 5.4 (95% CI: 2.0–15.0); and, 3) having not received a follow up phone call from the place of HIV diagnosis, aOR = 2.8 (95% CI: 1.2–6.8).

Conclusion

There was significant delay of ART initiation among referred PLHIV within 5 years after the rollout of test and treat guidelines in Uganda. Health system challenges in the continuity of HIV care services negatively affects timely ART initiation among referred PLHIV in Uganda.
Real-time forecasting the trajectory of monkeypox outbreaks at the national and global levels, July–October 2022
Authors: Bleichrodt Amanda , Dahal Sushma , Maloney Kevin , Casanova Lisa , Luo Ruiyan , Chowell Gerardo
Published: January 2023

Background

Beginning May 7, 2022, multiple nations reported an unprecedented surge in monkeypox cases. Unlike past outbreaks, differences in affected populations, transmission mode, and clinical characteristics have been noted. With the existing uncertainties of the outbreak, real-time short-term forecasting can guide and evaluate the effectiveness of public health measures.

Methods

We obtained publicly available data on confirmed weekly cases of monkeypox at the global level and for seven countries (with the highest burden of disease at the time this study was initiated) from the Our World in Data (OWID) GitHub repository and CDC website. We generated short-term forecasts of new cases of monkeypox across the study areas using an ensemble n-sub-epidemic modeling framework based on weekly cases using 10-week calibration periods. We report and assess the weekly forecasts with quantified uncertainty from the top-ranked, second-ranked, and ensemble sub-epidemic models. Overall, we conducted 324 weekly sequential 4-week ahead forecasts across the models from the week of July 28th, 2022, to the week of October 13th, 2022.

Results

The last 10 of 12 forecasting periods (starting the week of August 11th, 2022) show either a plateauing or declining trend of monkeypox cases for all models and areas of study. According to our latest 4-week ahead forecast from the top-ranked model, a total of 6232 (95% PI 487.8, 12,468.0) cases could be added globally from the week of 10/20/2022 to the week of 11/10/2022. At the country level, the top-ranked model predicts that the USA will report the highest cumulative number of new cases for the 4-week forecasts (median based on OWID data: 1806 (95% PI 0.0, 5544.5)). The top-ranked and weighted ensemble models outperformed all other models in short-term forecasts.

Conclusions

Our top-ranked model consistently predicted a decreasing trend in monkeypox cases on the global and country-specific scale during the last ten sequential forecasting periods. Our findings reflect the potential impact of increased immunity, and behavioral modification among high-risk populations.
Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characteristics in pancreatic adenocarcinoma
Authors: Li Jian , Yin Jingyang , Li Wenhua , Wang Huaizhi , Ni Bing
Published: January 2023

Background

Multiple molecular subtypes with distinct clinical outcomes in pancreatic adenocarcinoma (PAAD) have been identified in recent years. Cuproptosis is a new form of cell death that likely involved in tumor progression. However, the cuproptosis-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics largely remain unclear.

Methods

Expression profiles of 10 cuproptosis-related genes (CRGs) and their association with patient survival, TME, cancer stemness and drug resistance were studied in 33 cancer types using the TCGA pan-cancer data. Using 437 PAAD samples from five cohorts (TCGA-PAAD cohort and four GEO cohorts), we explored the molecular subtypes mediated by CRGs, along with the associated TME cell infiltration. Unsupervised methods were utilized to perform cuproptosis subtype clustering. The cuproptosis score was constructed using the COX regression model with least absolute shrinkage and selection operator regression (LASSO) algorithm to quantify the cuproptosis characteristics of a single tumor.

Results

The expression of 10 CRGs varies in different cancer types with striking inter- and intra- cancer heterogeneity. We integrated the genomic profiling of the CRGs and identified three distinct cuproptosis subtypes, and found that multi-layer CRG alterations were correlated with patient prognosis and TME cell infiltration characteristics. In addition, a cuproptosis score signature was constructed to predict prognosis, and its clinical impacts were characterized in the TCGA-PAAD cohort. The cuproptosis signature was significantly associated with prognosis, tumor subtypes, CD8 T-cell infiltration, response to immune checkpoint inhibitors (ICIs) and chemotherapeutic drug sensitivity. Furthermore, the expression patterns of CRGs in pancreatic cancer cells and normal controls were validated, which was almost consistent with the results from the public database. The expression level and prognostic predictive capability of DLAT were verified in 97 PAAD patients from our patient cohort.

Conclusions

These findings may help understand the roles of CRGs in PAAD and the molecular characterization of cuproptosis subtypes. In addition, the cuproptosis score could serve as a promising biomarker for predicting prognosis and response to immunotherapy in PAAD patients.
Retraction Note: CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p
Authors: Rong Dawei , Lu Chen , Zhang Betty , Fu Kai , Zhao Shuli , Tang Weiwei , Cao Hongyong
Published: January 2023

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-019-0958-6.
Intestinal epithelium penetration of liraglutide via cholic acid pre-complexation and zein/rhamnolipids nanocomposite delivery
Authors: Bao Xiaoyan , Qian Kang , Xu Mengjiao , Chen Yi , Wang Hao , Pan Ting , Wang Zhengyi , Yao Ping , Lin Li
Published: January 2023

Background

Oral administration offered a painless way and improved compliance for diabetics. However, the emerging GLP-1 analog peptide drugs for diabetes primarily rely on the injection route, and the development of oral dosage forms was hampered by the low oral bioavailability due to the structural vulnerability to digestive enzymes and molecule impermeability in the gastrointestinal tract.

Results

In this study, the non-covalent interaction between cholic acid (CA) and liraglutide (LIRA) was found and theoretically explained by molecular docking simulation. Formation of this physical complex of liraglutide and cholic acid (LIRA/CA Complex) reduced the self-aggregation of LIRA and accelerated intestinal epithelium penetration. By the anti-solvent method, LIRA/CA Complex was loaded into zein/rhamnolipids nanoparticles (LIRA/CA@Zein/RLs) with a loading efficiency of 76.8%. LIRA was protected from fast enzymatic degradation by the hydrophobic zein component. Meanwhile, Rhamnolipids, a glycolipid with surface activity, promoted endocytosis while also stabilizing the nanoparticles. The two components worked synergistically to ensure the delivery of LIRA/CA Complex to intestinal villi and improved oral absorption without disrupting tight junctions. LIRA/CA@Zein/RLs demonstrated a considerable intestinal epithelium absorption in mouse gastrointestinal section and a retentionin vivo over 24 h, resulting in a significant and long-lasting hypoglycemic effect in Type 2 diabetes mice.

Conclusion

This study provided a promising oral delivery approach for LIRA and exhibited the potential for further translation into clinical application.
Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon–bone healing
Authors: Zou Jiaxuan , Yang Weinan , Cui Wushi , Li Congsun , Ma Chiyuan , Ji Xiaoxiao , Hong Jianqiao , Qu Zihao , Chen Jing , Liu An , Wu Haobo
Published: January 2023

Tendon–bone insertion (TBI) injuries, such as anterior cruciate ligament injury and rotator cuff injury, are the most common soft tissue injuries. In most situations, surgical tendon/ligament reconstruction is necessary for treating such injuries. However, a significant number of cases failed because healing of the enthesis occurs through scar tissue formation rather than the regeneration of transitional tissue. In recent years, the therapeutic potential of mesenchymal stem cells (MSCs) has been well documented in animal and clinical studies, such as chronic paraplegia, non-ischemic heart failure, and osteoarthritis of the knee. MSCs are multipotent stem cells, which have self-renewability and the ability to differentiate into a wide variety of cells such as chondrocytes, osteoblasts, and adipocytes. Numerous studies have suggested that MSCs could promote angiogenesis and cell proliferation, reduce inflammation, and produce a large number of bioactive molecules involved in the repair. These effects are likely mediated by the paracrine mechanisms of MSCs, particularly through the release of exosomes. Exosomes, nano-sized extracellular vesicles (EVs) with a lipid bilayer and a membrane structure, are naturally released by various cell types. They play an essential role in intercellular communication by transferring bioactive lipids, proteins, and nucleic acids, such as mRNAs and miRNAs, between cells to influence the physiological and pathological processes of recipient cells. Exosomes have been shown to facilitate tissue repair and regeneration. Herein, we discuss the prospective applications of MSC-derived exosomes in TBI injuries. We also review the roles of MSC–EVs and the underlying mechanisms of their effects on promoting tendon–bone healing. At last, we discuss the present challenges and future research directions.

Graphical Abstract
Output-orientated policy engagement: a model for advancing the use of epidemiological evidence in health policy
Authors: Banks Emily , Haynes Abby , Lovett Ray , Yadav Uday Narayan , Agostino Jason
Published: January 2023

Background

Use of epidemiological research in policy and practice is suboptimal, contributing to significant preventable morbidity and mortality. Barriers to the use of research evidence in policy include lack of research–policy engagement, lack of policy-relevant research, differences in policymaker and researcher practice norms, time constraints, difficulties in coordination, and divergent languages and reward systems.

Approach and outcomes

In order to increase policy-relevant research and research uptake, we developed the output-orientated policy engagement (OOPE) model, in Australia. It integrates a foundational approach to engagement with cycles of specific activity focused around selected research outputs. Foundational elements include measures to increase recognition and valuing of policymaker expertise, emphasis on policy uptake, policy awareness of the research group’s work, regular policy engagement and policy-relevant capacity-building. Specific activities include (i) identification of an “output”—usually at draft stage—and program of work which are likely to be of interest to policymakers; (ii) initial engagement focusing on sharing “preview” evidence from this output, with an invitation to provide input into this and to advise on the broader program of work; and (iii) if there is sufficient interest, formation of a researcher–policy-maker partnership to shape and release the output, as well as inform the program of work. This cycle is repeated as the relationship continues and is deepened. As well as supporting policy-informed evidence generation and research-aware policymakers, the output-orientated model has been found to be beneficial in fostering the following: a pragmatic starting place for researchers, in often large and complex policy environments; purposeful and specific engagement, encouraging shared expectations; non-transactional engagement around common evidence needs, whereby researchers are not meeting with policymakers with the expectation of receiving funding; built-in translation; time and resource efficiency; relationship-building; mutual learning; policy-invested researchers and research-invested policy-makers; and tangible policy impacts. A case study outlines how the output-orientated approach supported researcher–policymaker collaboration to generate new evidence regarding Aboriginal and Torres Strait Islander cardiovascular disease risk and to apply this to national guidelines.

Conclusion

Output-orientated policy engagement provides a potentially useful pragmatic model to catalyse and support partnerships between researchers and policymakers, to increase the policy-relevance and application of epidemiological evidence.
EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma
Authors: Zhou Yujie , Xiao Dongdong , Jiang Xiaobing , Nie Chuansheng
Published: January 2023

Background

Glioma is the most prevalent primary tumor of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant form of glioma with an extremely poor prognosis. A novel, regulated cell death form of copper-induced cell death called “cuproptosis” provides a new prospect for cancer treatment by regulating cuproptosis.

Methods

Data from bulk RNA sequencing (RNA-seq) analysis (The Cancer Genome Atlas cohort and Chinese Glioma Genome Atlas cohort) and single cell RNA-seq (scRNA-seq) analysis were integrated to reveal their relationships. A scoring system was constructed according to the cuproptosis-related gene expression, and core genes were experimentally verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Moreover, cell counting kit-8 (CCK8), colony formation, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, transwell, and flow cytometry cell cycle were performed to evaluate cell proliferation, invasion, and migration.

Results

The Cuproptosis Activation Scoring (CuAS) Model has stable and independent prognostic efficacy, as verified by two CGGA datasets. Epiregulin (EREG), the gene of the model has the most contributions in the principal component analysis (PCA), is an onco-immunological gene that can affect immunity by influencing the expression of programmed death-ligand 1 (PD-L1) and mediate the process of cuproptosis by influencing the expression of ferredoxin 1 (FDX1). Single cell transcriptome analysis revealed that high CuAS GBM cells are found in vascular endothelial growth factor A (VEGFA) + malignant cells. Oligodendrocyte transcription factor 1 (OLIG1) + malignant is the original clone, and VEGF and CD99 are the differential pathways of specific cell communication between the high and low CuAS groups. This was also demonstrated by immunofluorescence in the tissue sections. Furthermore, CuAS has therapeutic potential for immunotherapy, and we predict that many drugs (methotrexate, NU7441, KU -0063794, GDC-0941, cabozantinib, and NVP-BEZ235) may be used in patients with high CuAS.

Conclusion

EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.
Ethanol extract from Artemisia argyi leaves inhibits HSV-1 infection by destroying the viral envelope
Authors: Liu Ping , Zhong Lishan , Xiao Ji , Hu Yuze , Liu Tao , Ren Zhe , Wang Yifei , Zheng Kai
Published: January 2023

Herpes simplex virus type 1 (HSV-1) is a widely disseminated virus that establishes latency in the brain and causes occasional but fatal herpes simplex encephalitis. Currently, acyclovir (ACV) is the main clinical drug used in the treatment of HSV-1 infection, and the failure of therapy in immunocompromised patients caused by ACV-resistant HSV-1 strains necessitates the requirement to develop novel anti-HSV-1 drugs. Artemisia argyi, a Traditional Chinese Medicine, has been historically used to treat inflammation, bacterial infection, and cancer. In this study, we demonstrated the antiviral effect and mechanism of ethanol extract of A. argyi leaves (hereafter referred to as ‘AEE’). We showed that AEE at 10 μg/ml exhibits potent antiviral effects on both normal and ACV-resistant HSV-1 strains. AEE also inhibited the infection of HSV-2, rotavirus, and influenza virus. Transmission electron microscopy revealed that AEE destroys the membrane integrity of HSV-1 viral particles, resulting in impaired viral attachment and penetration. Furthermore, mass spectrometry assay identified 12 major components of AEE, among which two new flavones, deoxysappanone B 7,3ʹ-dimethyl ether, and 3,7-dihydroxy-3′,4ʹ-dimethoxyflavone, exhibited the highest binding affinity to HSV-1 glycoprotein gB at the surface site critical for gB–gH–gL interaction and gB-mediated membrane fusion, suggesting their involvement in inactivating virions. Therefore, A. argyi is an important source of antiviral drugs, and the AEE may be a potential novel antiviral agent against HSV-1 infection.
Short- and long-term polystyrene nano- and microplastic exposure promotes oxidative stress and divergently affects skin cell architecture and Wnt/beta-catenin signaling
Authors: Schmidt Anke , da Silva Brito Walison Augusto , Singer Debora , Mühl Melissa , Berner Julia , Saadati Fariba , Wolff Christina , Miebach Lea , Wende Kristian , Bekeschus Sander
Published: January 2023

Nano- and microplastic particles (NMP) are strong environmental contaminants affecting marine ecosystems and human health. The negligible use of biodegradable plastics and the lack of knowledge about plastic uptake, accumulation, and functional consequences led us to investigate the short- and long-term effects in freshly isolated skin cells from mice. Using fluorescent NMP of several sizes (200 nm to 6 µm), efficient cellular uptake was observed, causing, however, only minor acute toxicity as metabolic activity and apoptosis data suggested, albeit changes in intracellular reactive species and thiol levels were observed. The internalized NMP induced an altered expression of various targets of the nuclear factor-2-related transcription factor 2 pathway and were accompanied by changed antioxidant and oxidative stress signaling responses, as suggested by altered heme oxygenase 1 and glutathione peroxide 2 levels. A highly increased beta-catenin expression under acute but not chronic NMP exposure was concomitant with a strong translocation from membrane to the nucleus and subsequent transcription activation of Wnt signaling target genes after both single-dose and chronic long-term NMP exposure. Moreover, fibroblast-to-myofibroblast transdifferentiation accompanied by an increase of α smooth muscle actin and collagen expression was observed. Together with several NMP-induced changes in junctional and adherence protein expression, our study for the first time elucidates the acute and chronic effects of NMP of different sizes in primary skin cells' signaling and functional biology, contributing to a better understanding of nano- and microplastic to health risks in higher vertebrates.
Five-year follow-up of mitral valve repair versus replacement: a propensity score analysis
Authors: Makarious Laham Majd , Easo Jerry , Szczechowicz Marcin , Roosta-Azad Mehdy , Weymann Alexander , Ruhparwar Arjang , Kamler Markus
Published: January 2023

Background

Mitral valve repair (MVRe) is considered to have a superior outcome compared to replacement (MVRp) in patients with mitral valve regurgitation (MVR). It was the aim of the study to analyse the clinical results and identify risk factors for short and long-term mortality.

Methods

In a retrospective single-center analysis, patients undergoing an isolated mitral valve procedure from June 2010 to December 2016 were identified. These were subsequently homogenized using 10 baseline characteristics for propensity-score matching. Comparative analyses were performed for early and long-term results, using adequate statistical tools, and identifying risk factors for the investigated endpoints, primary end-point: all-cause mortality within 5 years and secondary end-points: recurrent MVR, reoperation, endocarditis and/or mortality with 30 days, 1, 3 and 5 years.

Results

241 patients were identified in the entire patient cohort. After matching, patients were divided into 2 groups of 64 each respectively. The median age was similar in the two groups. There was a significant interaction between early mortality risk of MV in patients with coronary artery disease (CAD) (OR 11.94, 95% CI 1.49–285.92, p = 0.04) and late mortality in patients with higher EuroSCORE II (HR 1.14, 95% CI 1.06–1.23, p < 0.001). The primary end-point showed 5-year survival rate was significantly higher in MVRe versus MVRp (90.06% vs. 79.54% respectively, p = 0.04). The secondary end-point demonstrated recurrent MVR not to be statistically significant between the 2 groups (p = 0.09) as well as reoperation (p = 0.28). Endocarditis was observed in one patient after MVRp.

Conclusions

We concluded MVRe to be associated with lower operative and 5-year mortality and good postoperative outcomes compared to patients undergoing MVRp. Concomitant CAD was identified as one of the risk factors for increasing the in-hospital mortality rate. There was no significant difference in rehospitalisation over the follow-up period. MVRe should be the treatment of choice for severe MVR and should remain a central aspect in valve centers' treatment algorithms and quality measures.
A life cycle and product type based estimator for quantifying the carbon stored in wood products
Authors: Wei Xinyuan , Zhao Jianheng , Hayes Daniel J. , Daigneault Adam , Zhu He
Published: January 2023

Background

Timber harvesting and industrial wood processing laterally transfer the carbon stored in forest sectors to wood products creating a wood products carbon pool. The carbon stored in wood products is allocated to end-use wood products (e.g., paper, furniture), landfill, and charcoal. Wood products can store substantial amounts of carbon and contribute to the mitigation of greenhouse effects. Therefore, accurate accounts for the size of wood products carbon pools for different regions are essential to estimating the land-atmosphere carbon exchange by using the bottom-up approach of carbon stock change.

Results

To quantify the carbon stored in wood products, we developed a state-of-the-art estimator (Wood Products Carbon Storage Estimator, WPsCS Estimator) that includes the wood products disposal, recycling, and waste wood decomposition processes. The wood products carbon pool in this estimator has three subpools: (1) end-use wood products, (2) landfill, and (3) charcoal carbon. In addition, it has a user-friendly interface, which can be used to easily parameterize and calibrate an estimation. To evaluate its performance, we applied this estimator to account for the carbon stored in wood products made from the timber harvested in Maine, USA, and the carbon storage of wood products consumed in the United States.

Conclusion

The WPsCS Estimator can efficiently and easily quantify the carbon stored in harvested wood products for a given region over a specific period, which was demonstrated with two illustrative examples. In addition, WPsCS Estimator has a user-friendly interface, and all parameters can be easily modified.
Perioperative changes in fluid distribution and haemodynamics in acute high-risk abdominal surgery
Authors: Cihoric Mirjana , Kehlet Henrik , Højlund Jakob , Lauritsen Morten Laksáfoss , Kanstrup Katrine , Foss Nicolai Bang
Published: January 2023

Background

Understanding the pathophysiology of fluid distribution in acute high-risk abdominal (AHA) surgery is essential in optimizing fluid management. There is currently no data on the time course and haemodynamic implications of fluid distribution in the perioperative period and the differences between the surgical pathologies.

Methods

Seventy-three patients undergoing surgery for intestinal obstruction, perforated viscus, and anastomotic leakage within a well-defined perioperative regime, including intraoperative goal-directed therapy, were included in this prospective, observational study. From 0 to 120 h, we measured body fluid volumes and hydration status by bioimpedance spectroscopy (BIA), fluid balance (input vs. output), preload dependency defined as a > 10% increase in stroke volume after preoperative fluid challenge, and post-operatively evaluated by passive leg raise.

Results

We observed a progressive increase in fluid balance and extracellular volume throughout the study, irrespective of surgical diagnosis. BIA measured variables indicated post-operative overhydration in 36% of the patients, increasing to 50% on the 5th post-operative day, coinciding with a progressive increase of preload dependency, from 12% immediately post-operatively to 58% on the 5th post-operative day and irrespective of surgical diagnosis. Patients with overhydration were less haemodynamically stable than those with normo- or dehydration.

Conclusion

Despite increased fluid balance and extracellular volumes, preload dependency increased progressively during the post-operative period. Our observations indicate a post-operative physiological incoherence between changes in the extracellular volume compartment and inadequate physiological preload control in patients undergoing AHA surgery. Considering the increasing overhydration during the observational period, our findings show that an indiscriminate correction of preload dependency with intravenous fluid bolus could lead to overhydration.

Trial registration clinicaltrials.gov. (NCT03997721), Registered 23 May 2019, first participant enrolled 01 June 2019.
Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART)
Authors: Parker Richard A. , Weir Christopher J. , Pham Tra My , White Ian R. , Stallard Nigel , Parmar Mahesh K. B. , Swingler Robert J. , Dakin Rachel S. , Pal Suvankar , Chandran Siddharthan
Published: January 2023

Background

MND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival.

Methods

Initially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022.

Discussion

In developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects.

Trial registration

EudraCT Number, 2019–000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smart

ClinicalTrials.gov, NCT04302870. Registered 10 March 2020.
Gastric volvulus associated with shrinkage of a gastrointestinal stromal tumor by neoadjuvant imatinib: a case report
Authors: Sugiyama Yoichi , Komo Toshiaki , Tazaki Tatsuya , Kohyama Mohei , Takahashi Shinya , Sasaki Masaru
Published: January 2023

Background

During neoadjuvant chemotherapy for giant gastrointestinal stromal tumors, changes in gastrointestinal stromal tumor size are rarely associated with events such as perforation and bleeding that require emergency surgery. Moreover, it is very rare for gastrointestinal stromal tumors to shrink and become mobile, resulting in gastric volvulus. Herein, we report a case of gastrointestinal stromal tumor shrinkage during neoadjuvant imatinib treatment, resulting in gastric volvulus that required surgery. To the best of our knowledge, this is the first reported occurrence of gastric volvulus during neoadjuvant imatinib treatment for a giant gastrointestinal stromal tumor.

Case presentation

A 58-year-old Japanese woman who was diagnosed with a giant gastric gastrointestinal stromal tumor and administered neoadjuvant imatinib presented to our hospital with complaints of abdominal pain and retching. Enhanced computed tomography revealed that the gastrointestinal stromal tumor had shrunk and shifted in position, and the stomach had organoaxially twisted. Accordingly, the patient was diagnosed with gastric volvulus caused by a gastric gastrointestinal stromal tumor. Conservative treatment did not improve the volvulus; hence, laparotomy was performed. The tumor developed from the lesser curvature of the stomach and caused rotation of the gastric body. The local gastric wall was resected. Histopathological examination confirmed the diagnosis of gastrointestinal stromal tumor. The patient received adjuvant imatinib for 3 years and has been alive for 5 years without recurrence.

Conclusions

Gastric volvulus can be caused by the laxity of the ligaments that hold the stomach and gastric ptosis or esophageal hernia and diaphragmatic hernia; therefore, gastric gastrointestinal stromal tumors rarely cause gastric volvulus. However, a risk of torsion exists if the gastrointestinal stromal tumor develops extramural to lesser curvature and attains a certain size.
Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration
Authors: Jiang Dongfang , Li Tingting , Guo Caixia , Tang Tie-Shan , Liu Hongmei
Published: January 2023

The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.
Comparison of DNA targeting CRISPR editors in human cells
Authors: Huang Hongxin , Lv Weiqi , Li Jinhe , Huang Guanjie , Tan Zhihong , Hu Yongfei , Ma Shufeng , Zhang Xin , Huang Linxuan , Lin Ying
Published: January 2023

Background

Profiling and comparing the performance of current widely used DNA targeting CRISPR systems provide the basic information for the gene-editing toolkit and can be a useful resource for this field. In the current study, we made a parallel comparison between the recently reported miniature Cas12f1 (Un1Cas12f1 and AsCas12f1) and the widely used Cas12a and Cas9 nucleases in mammalian cells.

Results

We found that as a CRISPRa activator, Un1Cas12f1 could induce gene expression with a comparable level to that of Cas12a and Cas9, while as a DNA cleavage editor, Cas12f1 exhibited similar properties to Cas12a, like high specificity and dominantly induced deletions over insertions, but with less activity. In contrast, wild-type SpCas9 showed the highest activity, lowest specificity, and induced balanced deletions and insertions. Thus, Cas12f1 is recommended for gene-activation-based applications, Cas12a is for therapy applications, and wild-type Cas9 is for in vitro and animal investigations.

Conclusion

The comparison provided the editing properties of the widely used DNA-targeting CRISPR systems in the gene-editing field.