bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncogenic KRAS alters splicing factor phosphorylation and alternative splicing in lung cancer
Authors: Lo April , McSharry Maria , Berger Alice H.
Published: December 2022

Background

Alternative RNA splicing is widely dysregulated in cancers including lung adenocarcinoma, where aberrant splicing events are frequently caused by somatic splice site mutations or somatic mutations of splicing factor genes. However, the majority of mis-splicing in cancers is unexplained by these known mechanisms. We hypothesize that the aberrant Ras signaling characteristic of lung cancers plays a role in promoting the alternative splicing observed in tumors.

Methods

We recently performed transcriptome and proteome profiling of human lung epithelial cells ectopically expressing oncogenic KRAS and another cancer-associated Ras GTPase, RIT1. Unbiased analysis of phosphoproteome data identified altered splicing factor phosphorylation in KRAS-mutant cells, so we performed differential alternative splicing analysis using rMATS to identify significantly altered isoforms in lung epithelial cells. To determine whether these isoforms were uniquely regulated by KRAS, we performed a large-scale splicing screen in which we generated over 300 unique RNA sequencing profiles of isogenic A549 lung adenocarcinoma cells ectopically expressing 75 different wild-type or variant alleles across 28 genes implicated in lung cancer.

Results

Mass spectrometry data showed widespread downregulation of splicing factor phosphorylation in lung epithelial cells expressing mutant KRAS compared to cells expressing wild-type KRAS. We observed alternative splicing in the same cells, with 2196 and 2416 skipped exon events in KRASG12V and KRASQ61H cells, respectively, 997 of which were shared (p < 0.001 by hypergeometric test). In the high-throughput splicing screen, mutant KRAS induced the greatest number of differential alternative splicing events, second only to the RNA binding protein RBM45 and its variant RBM45M126I. We identified ten high confidence cassette exon events across multiple KRAS variants and cell lines. These included differential splicing of the Myc Associated Zinc Finger (MAZ). As MAZ regulates expression of KRAS, this splice variant may be a mechanism for the cell to modulate wild-type KRAS levels in the presence of oncogenic KRAS.

Conclusion

Proteomic and transcriptomic profiling of lung epithelial cells uncovered splicing factor phosphorylation and mRNA splicing events regulated by oncogenic KRAS. These data suggest that in addition to widespread transcriptional changes, the Ras signaling pathway can promote post-transcriptional splicing changes that may contribute to oncogenic processes.
Galectin-9 expression clinically associated with mature dendritic cells infiltration and T cell immune response in colorectal cancer
Authors: Wang Yang , Zheng Ruizhi , Zhang Yanhui , Guo Yuhong , Hui Zhenzhen , Wang Peijing , Sun Yan
Published: December 2022

Background

Galectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study.

Methods

The expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases.

Results

The level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p < 0.0001). In the relationship between galectin-9 expression and the infiltration of DCs, there was a negative correlation in CD1a + immature DCs (R = -0.263, p = 0.042). A strong positive correlation was observed in CD208 + mature DCs (R = 0.391, p < 0.01). Patients with high galectin-9 expression also exhibited abundant CD8 + T-cell and CD3 + T-cell infiltration.

Conclusion

Collectively, our findings provide evidence that galectin-9 may increase the antitumor immune response of patients with CRC. DCs play an important role in galectin-9-mediated antitumor immune responses, which provides further insight into the development of immunotherapy.
Evaluating impact of Nd: YAG laser associated defects on optical quality of hydrophilic and hydrophobic intraocular lenses using visualization of light propagation and USAF test targets
Authors: Borkenstein A. F. , Borkenstein E. M. , Omidi P. , Langenbucher A.
Published: December 2022

Background

Neodymium:yttrium aluminum garnet (Nd:YAG) laser capsulotomy is a well-accepted, safe, and effective measure in the treatment of posterior capsule opacification. However, iatrogenic intraocular lens damage is a relatively common side effect that happens due to inappropriate focusing during the procedure. This experimental study analyzes the impact of YAG-pits to obtain qualitative information.

Methods

Acrylic, monofocal hydrophilic and hydrophobic intraocular lenses (IOLs) with 6.0 mm optic and the with the same power (21D) were studied. First, all measurements were done with unmodified IOLs. Damage was intentionally created, performing YAG-pits (n = 5) in the central area of the lens optic (3.0 mm) using a photodisruption laser with the same energy level of 1.8 mJ. To simulate the cruciate pattern, the 5 defects were created in a cross shape within the 3.0 mm optical zone. Afterwards, all laboratory measurements were repeated: These included the United States Air Force (USAF) resolution test chart to study the imaging performance of the IOL, light field measurements to show the course of the rays behind the IOL and the modulation transfer function (MTF) measurements were analyzed.

Results

Evaluating USAF showed that unmodified lenses produced a sharper image. Damaged lenses led to a more blurred image and to the impression of a lower contrast with a kind of halo/glare effect. The light field measurement showed that YAG-pits led to a kind of dispersion and scattering effect, which was higher in hydrophobic IOLs. MTF showed a deterioration in damaged hydrophilic and hydrophobic IOLs, respectively.

Conclusion

Our experimental study confirms that YAG-pits can reduce imaging quality of intraocular lenses. These defects behave as a new Huygens source, distribute a spherical wave that additionally illuminate the background of the USAF target. It can be assumed that material properties of the IOL (water content, refractive index) play an important role and affect results. The impact level is strongly dependent on the number, size and position of YAG-pits within the optic. Limitation: Only monofocal IOLs have been investigated so far, further tests with various IOL optics have to follow. In addition, simulating the circular pattern of YAG capsulotomy is necessary.
Protocol for a multi-site randomized controlled trial of a stepped-care intervention for emergency department patients with panic-related anxiety
Authors: Sung Sharon C. , Lim Leslie , Lim Swee Han , Finkelstein Eric A. , Chin Steven Lim Hoon , Annathurai Annitha , Chakraborty Bibhas , Strauman Timothy J. , Pollack Mark H. , Ong Marcus Eng Hock
Published: December 2022

Background

Approximately 40% of Emergency Department (ED) patients with chest pain meet diagnostic criteria for panic-related anxiety, but only 1–2% are correctly diagnosed and appropriately managed in the ED. A stepped-care model, which focuses on providing evidence-based interventions in a resource-efficient manner, is the state-of-the art for treating panic disorder patients in medical settings such as primary care. Stepped-care has yet to be tested in the ED setting, which is the first point of contact with the healthcare system for most patients with panic symptoms.

Methods

This multi-site randomized controlled trial (RCT) aims to evaluate the clinical, patient-centred, and economic effectiveness of a stepped-care intervention in a sample of 212 patients with panic-related anxiety presenting to the ED of Singapore’s largest public healthcare group. Participants will be randomly assigned to either: 1) an enhanced care arm consisting of a stepped-care intervention for panic-related anxiety; or 2) a control arm consisting of screening for panic attacks and panic disorder. Screening will be followed by baseline assessments and blocked randomization in a 1:1 ratio. Masked follow-up assessments will be conducted at 1, 3, 6, and 12 months. Clinical outcomes will be panic symptom severity and rates of panic disorder. Patient-centred outcomes will be health-related quality of life, daily functioning, psychiatric comorbidity, and health services utilization. Economic effectiveness outcomes will be the incremental cost-effectiveness ratio of the stepped-care intervention relative to screening alone.

Discussion

This trial will examine the impact of early intervention for patients with panic-related anxiety in the ED setting. The results will be used to propose a clinically-meaningful and cost-effective model of care for ED patients with panic-related anxiety.

Trial registration

ClinicalTrials.gov NCT03632356. Retrospectively registered 15 August 2018.
Evaluation of a pilot, community-led mental illness de-stigmatization theater intervention in rural Uganda
Authors: Lee Yang Jae , Rauben Kazungu , Liu Curtis , Kim Rebecca , van der Velde Nina , Taylor Chelsea , Walsh Alyssa , Asasira Mildred , Katongole Ivan , Hatfield-King Jolee , Blackwell Scott , Iheanacho Theddeus , Christ Ryan , Ssekalo Ibrahim
Published: December 2022

Background

In rural areas of low- and middle- income countries, mental health care is often unavailable and inaccessible, and stigma is a major barrier to treatment. Destigmatization can increase treatment-seeking attitudes, community support, and acceptance of individuals suffering from mental illness. This study’s primary objective was to evaluate the impact of a community-led, theater-based destigmatization campaign for mental illness conducted in the Busoga region of Eastern Uganda.

Methods

One hundred residents of the Busoga region were randomly selected via cluster sampling to complete a structured questionnaire assessing mental health stigma. Four focus groups were conducted for qualitative data on mental health stigma. Common misconceptions and specific points of stigma were identified from these responses, and local village health team personnel developed and performed a culturally-adapted theatrical performance addressing these points. Changes in perceptions of mental illness were measured among 57 attendees using two measures, the Broad Acceptance Scale (designed to reflect factors that contribute to structural stigma) and Personal Acceptance Scale (designed to reflect factors that contribute to interpersonal, or public stigma), before and after the performance.

Results

There was a significant increase in acceptance according to the Broad Acceptance Scale (p < .001) and Personal Acceptance Scale (p < .001). Qualitative responses from play attendees also indicated a decrease in stigma and an increased sense of the importance of seeking treatment for mentally ill patients.

Conclusion

This study shows community-led, theater intervention may be an effective tool for the destigmatization of mental illness in rural areas of Uganda. Larger studies are needed to further test the efficacy of this approach and potential for longer-term scalabilityand sustainability.
Correlates of physical activity and sedentary behaviour in children attending before and after school care: a systematic review
Authors: Woods Andrew J. , Probst Yasmine C. , Norman Jennifer , Wardle Karen , Ryan Sarah T. , Patel Linda , Crowe Ruth K. , Okely Anthony D.
Published: December 2022

Background

Out of School Hours Care (OSHC) offers structured care to elementary/primary-aged children before and after school, and during school holidays. The promotion of physical activity in OSHC is important for childhood obesity prevention. The aim of this systematic review was to identify correlates of objectively measured physical activity and sedentary behaviour in before and after school care.

Methods

A systematic search was conducted in Scopus, ERIC, MEDLINE (EBSCO), PsycINFO and Web of Science databases up to December 2021. Study inclusion criteria were: written in English; from a peer-reviewed journal; data from a centre-based before and/or after school care service; children with a mean age < 13 years; an objective measure of physical activity or sedentary behaviour; reported correlations and significance levels; and if an intervention study design these correlates were reported at baseline. Study quality was assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. The PRISMA guidelines informed the reporting, and data were synthesised according to shared correlations and a social ecological framework.

Results

Database searches identified 4559 papers, with 18 cross-sectional studies meeting the inclusion criteria.There were a total of 116 physical activity correlates and 64 sedentary behaviour correlates identified. The most frequently reported correlates of physical activity were child sex (males more active), staff engaging in physical activity, an absence of elimination games, and scheduling physical activity in daily programming (all more positively associated). The most frequently reported correlates of sedentary behaviour were child sex (females more sedentary) and age (older children more sedentary).

Conclusions

Encouraging physical activity engagement of female children, promoting positive staff behaviours, removing elimination elements from games, and scheduling more time for physical activity should be priorities for service providers. Additional research is needed in before school care services.
Application of the Capability, Opportunity, Motivation and Behavior (COM-B) model to identify predictors of two self-reported hand hygiene behaviors (handwashing and hand sanitizer use) to prevent COVID-19 infection among U.S. adults, Fall 2020
Authors: Brown Laura G. , Hoover E. Rickamer , Besrat Bethlehem N. , Burns-Lynch Claire , Frankson Rebekah , Jones Shantrice L. , Garcia-Williams Amanda G.
Published: December 2022

Background

Handwashing with soap and water is an important way to prevent transmission of viruses and bacteria and worldwide it is estimated handwashing can prevent 1 in 5 viral respiratory infections. Frequent handwashing is associated with a decreased risk for infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). Using a hand sanitizer with at least 60% alcohol when handwashing is not feasible can also help prevent the transmission of viruses and bacteria.

Objective

Since early 2020, the public has been encouraged to handwash frequently with soap and water and use alcohol-based hand sanitizer when soap and water are not available to reduce COVID-19 transmission. This study’s objectives were to assess U.S. adults’ perceptions of components of the Capability, Opportunity, Motivation and Behavior (COM-B) Model in relation to these two hand hygiene behaviors and to identify relationships between these components and hand hygiene behaviors.

Methods

Items assessing capability, opportunity, motivation, and hand hygiene behaviors were included in FallStyles, a survey completed by 3,625 adults in the fall of 2020 through an online panel representative of the U.S. population. We calculated composite capability, opportunity, and motivation measures and descriptive statistics for all measures. Finally, we conducted multiple logistic regressions to identify predictors of handwashing and hand sanitizer use.

Results

Most respondents reported frequently washing hands with soap and water (89%) and using alcohol-based hand sanitizer (72%) to prevent coronavirus. For capability, over 90% of respondents said that neither behavior takes a lot of effort, but fewer agreed that they knew when, or how, they should engage in handwashing (67%; 74%) and hand sanitizer use (62%; 64%). For opportunity, over 95% of respondents said lack of time didn’t make it hard to engage in either behavior; fewer said visual cues reminded them to engage in the behaviors (handwashing: 30%; sanitizer use: 48%). For motivation, the majority believed the two behaviors were good ways to prevent coronavirus illness (handwashing: 76%; sanitizer use: 59%). Regressions indicated that capability, opportunity, and particularly motivation were positively associated with both hand hygiene behaviors.

Conclusions

The COM-B model was a helpful framework for increasing understanding of hand hygiene behavior; it identified capability, opportunity, and motivation as predictors of both handwashing and hand sanitizer use.
Overcome the Fear (Vencer el Miedo): using entertainment education to impact adolescent sexual and reproductive health and parent-child communication in Mexico
Authors: Montoya Jorge A. , Plant Aaron , Neffa-Creech Deborah , Orvañanos Cecilia , Barker Kriss
Published: December 2022

Background

Adolescents in Mexico experience high pregnancy and birth rates. A collaboration with Grupo Televisa led to the development of an entertainment-education telenovela intervention, Overcome the Fear (OTF), which aired in 2020 to a national audience and addressed adolescent sexual and reproductive health (SRH) topics. This study details the development and evaluation of OTF’s impact on adolescent contraceptive practices and parent-adolescent SRH communication in Mexico.

Methods

We conducted cross-sectional survey interviews (street-intercept and telephone) with 12–19-year-olds (n = 1640) and parents of adolescent children (n = 820) post-broadcast across Mexico’s five most-populated metropolitan zones. Quotas were implemented for gender, zone, and OTF viewership (viewer vs. non-viewer). Bivariate statistics and multivariable binary logistic regression models assessed the relationship between OTF viewership (including parent-adolescent co-viewing) and adolescent contraceptive practices and parent-adolescent SRH communication. Adolescent and parent data are not dyadic and were analyzed separately.

Results

Nearly half of adolescents (47.9%) and parents (47.7%) were viewers. Among adolescents, bivariate analyses suggest that viewers had less negative attitudes towards contraception (p < .001). Logistic regression models suggest that adolescent viewers were more likely to seek out information about contraception (p < .001) and unhealthy romantic relationships (p = .019), and to use contraception other than condoms (p = .027) and dual contraception (p = .042) in the last 3 months. Among parents, bivariate analyses suggest that non-viewers had more positive attitudes towards abstinence (p = .045) and more negative attitudes towards contraception and communication with adolescents about sex (p = .001). Logistic regression models suggest that parent viewers were more likely to have talked with adolescent children about sexual relations (p < .001), contraceptive methods (p = .01), condoms (p = .002), and abstinence (p = .002) in the last 3 months. Parent-adolescent co-viewing of OTF was also significantly related to certain outcomes in bivariate analyses.

Conclusions

This study suggests that viewership of a high-quality entertainment-education telenovela informed by extensive formative research is related to adolescent health outcomes and to parent-adolescent SRH communication on a country-wide scale in Mexico. Entertainment-education remains an underutilized public health strategy, despite its promise to engage viewers and motivate healthful behaviors.
“Data makes the story come to life:” understanding the ethical and legal implications of Big Data research involving ethnic minority healthcare workers in the United Kingdom—a qualitative study
Authors: Dove Edward S. , Reed-Berendt Ruby , Pareek Manish ,   UK-REACH Study Collaborative Group, Gray Laura , Nellums Laura B. , Guyatt Anna L. , Johns Catherine , McManus I. Chris , Woolf Katherine , Abubakar Ibrahim , Gupta Amit , Abrams Keith R. , Tobin Martin D. , Wain Louise , Carr Sue , Khunti Kamlesh , Ford David , Free Robert
Published: December 2022

The aim of UK-REACH (“The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers”) is to understand if, how, and why healthcare workers (HCWs) in the United Kingdom (UK) from ethnic minority groups are at increased risk of poor outcomes from COVID-19. In this article, we present findings from the ethical and legal stream of the study, which undertook qualitative research seeking to understand and address legal, ethical, and social acceptability issues around data protection, privacy, and information governance associated with the linkage of HCWs’ registration data and healthcare data. We interviewed 22 key opinion leaders in healthcare and health research from across the UK in two-to-one semi-structured interviews. Transcripts were coded using qualitative thematic analysis. Participants told us that a significant aspect of Big Data research in public health is varying drivers of mistrust—of the research itself, research staff and funders, and broader concerns of mistrust within participant communities, particularly in the context of COVID-19 and those situated in more marginalised community settings. However, despite the challenges, participants also identified ways in which legally compliant and ethically informed approaches to research can be crafted to mitigate or overcome mistrust and establish greater confidence in Big Data public health research. Overall, our research indicates that a “Big Data Ethics by Design” approach to research in this area can help assure (1) that meaningful community and participant engagement is taking place and that extant challenges are addressed, and (2) that any new challenges or hitherto unknown unknowns can be rapidly and properly considered to ensure potential (but material) harms are identified and minimised where necessary. Our findings indicate such an approach, in turn, will help drive better scientific breakthroughs that translate into medical innovations and effective public health interventions, which benefit the publics studied, including those who are often marginalised in research.
The novel and powerful ICD-11 classification system for neoplasm coding: a comparative study with the ICD-O
Authors: Xu Yicong , Zhou Jingya , Wang Yi
Published: December 2022

Background

The International Classification of Diseases (ICD) and the International Classification of Diseases for Oncology (ICD-O) are both widely used global classification systems. In 2018, the initial release of the ICD-11 was published by the World Health Organization (WHO), integrating the morphology section of the ICD-O.

Methods

This paper aims to provide potential ICD-11 users with a profound understanding of the neoplasm classifications of the ICD-11 by analysing the differences and relationships between the ICD-11 and ICD-O in terms of the coding framework, compatibility and intelligence level.

Results

The ICD-11 and ICD-O have remarkable differences in coding structure. Compared to the ICD-O, the ICD-11 has the following advantages: adding histopathology to the stem codes, obtaining a meaningful minimum amount of information through stem codes for statistics, supporting the usage of ICD-O morphology categories and capturing clinical details via extension codes for multiaxial coding. In addition, the rich Foundation Component, linearization derived from the Foundation Component and updating mechanism all support the compatibility of the ICD-11 with other classification systems. Notably, the WHO provides terminology coding with a smart coding tool, and coding in the ICD-11 can draw on statistical codes and uniform resource identifiers (URIs) simultaneously.

Conclusions

The ICD-11 represents a novel classification system with distinguishing features that include facilitating statistics, multiaxial coding, coding granularity, compatibility and intelligence. These features enable the ICD-11 to be more powerful for neoplasm coding than the ICD-O and basically meet the needs of stakeholders.
Working as a nurse in community health services during Covid-19: a qualitative study
Authors: Moi Ellen Benestad , Skisland Anne Valen , Johannessen Berit , Haraldstad Kristin , Rohde Gudrun , Flateland Sylvi Monika
Published: December 2022

Background

During the Covid-19 pandemic, new roles, increased workload, lack of staffing and infection control equipment, unclear infection control guidelines and conflicting information have led to uncertainty and unpredictability for health workers. Although community home-care nurses have been exposed to a range of personal and professional stressors during the pandemic, few studies have focused on their experiences. The aim of this study was to explore how Norwegian home-care nurses experienced the first wave of the Covid-19 pandemic. This knowledge may contribute to preparations for meetings with patients in future pandemics, how management can support its employees and how to structure a successful organization.

Methods

This study was a qualitative descriptive design comprising 12 semi-structured individual interviews with home-care nurses. A thematic analysis was carried out.

Results

Four main themes and 11 subthemes were constructed. The results revealed challenges related both to the organization and to management, experiences of unclear information, lack of available equipment, redeployment of staff and increased workload. Furthermore, it was challenging to provide high qualitative care. The nurses missed collegial togetherness and had feelings of uncertainty with a great fear of infecting others. Positive consequences were feelings of being valued and a greater awareness of infection control.

Conclusion

This study highlighted the importance of unambiguous information and clear delegation of responsibility, and that enough infection control equipment will likely minimize the fear of infecting each other. Being visible and admired for their work was important for the nurses’ psychological well-being. Nurses, nursing managers and policymakers in community health care can use these results to develop strategies for future pandemic planning.
A signature of six-hypoxia-related genes to evaluate the tumor immune microenvironment and predict prognosis in gastric cancer
Authors: Zhou Kena , Cai Congbo , Ding Guanjun , He Yi , Hu Di
Published: December 2022

Background

Hypoxia will trigger a series of immunosuppressive process in tumor microenvironment, leading to the progression in gastric cancer (GC). This research aims to establish a prognostic model made up of hypoxia-risk-related genes in GC.

Methods

Hypoxic genes were outlined via the protein–protein interaction network. And a prognostic model was developed using univariate cox analysis and lasso regression from data in TCGA. Two independent queues of GEO were used for validation.

Results

We set up a hypoxic model presented as an independent prognostic factor for GC. And a nomogram combined this model with clinical features can predict OS with great performance. Furthermore, DNA methylation, IHC and cell line analyses validated the expression of hypoxic genes in GC.

Conclusions

In summary, we proposed and verified a hypoxia-risk-related model, which could reflect the immune microenvironment and predict prognosis in GC.
The effects of ischaemic conditioning on lung ischaemia–reperfusion injury
Authors: Vlastos Dimitrios , Zeinah Mohamed , Ninkovic-Hall George , Vlachos Stefanos , Salem Agni , Asonitis Athanasios , Chavan Hemangi , Kalampalikis Lazaros , Al Shammari Abdullah , Alvarez Gallesio José María , Pons Aina , Andreadou Ioanna , Ikonomidis Ignatios
Published: December 2022

Ischaemia–reperfusion injury (IRI) encompasses the deleterious effects on cellular function and survival that result from the restoration of organ perfusion. Despite their unique tolerance to ischaemia and hypoxia, afforded by their dual (pulmonary and bronchial) circulation as well as direct oxygen diffusion from the airways, lungs are particularly susceptible to IRI (LIRI). LIRI may be observed in a variety of clinical settings, including lung transplantation, lung resections, cardiopulmonary bypass during cardiac surgery, aortic cross-clamping for abdominal aortic aneurysm repair, as well as tourniquet application for orthopaedic operations. It is a diagnosis of exclusion, manifesting clinically as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Ischaemic conditioning (IC) signifies the original paradigm of treating IRI. It entails the application of short, non-lethal ischemia and reperfusion manoeuvres to an organ, tissue, or arterial territory, which activates mechanisms that reduce IRI. Interestingly, there is accumulating experimental and preliminary clinical evidence that IC may ameliorate LIRI in various pathophysiological contexts. Considering the detrimental effects of LIRI, ranging from ALI following lung resections to primary graft dysfunction (PGD) after lung transplantation, the association of these entities with adverse outcomes, as well as the paucity of protective or therapeutic interventions, IC holds promise as a safe and effective strategy to protect the lung. This article aims to provide a narrative review of the existing experimental and clinical evidence regarding the effects of IC on LIRI and prompt further investigation to refine its clinical application.
Temperature and particulate matter as environmental factors associated with seasonality of influenza incidence – an approach using Earth observation-based modeling in a health insurance cohort study from Baden-Württemberg (Germany)
Authors: Rittweger Jörn , Gilardi Lorenza , Baltruweit Maxana , Dally Simon , Erbertseder Thilo , Mittag Uwe , Naeem Muhammad , Schmid Matthias , Schmitz Marie-Therese , Wüst Sabine , Dech Stefan , Jordan Jens , Antoni Tobias , Bittner Michael
Published: December 2022

Background

Influenza seasonality has been frequently studied, but its mechanisms are not clear. Urban in-situ studies have linked influenza to meteorological or pollutant stressors. Few studies have investigated rural and less polluted areas in temperate climate zones.

Objectives

We examined influences of medium-term residential exposure to fine particulate matter (PM2.5), NO2, SO2, air temperature and precipitation on influenza incidence.

Methods

To obtain complete spatial coverage of Baden-Württemberg, we modeled environmental exposure from data of the Copernicus Atmosphere Monitoring Service and of the Copernicus Climate Change Service. We computed spatiotemporal aggregates to reflect quarterly mean values at post-code level. Moreover, we prepared health insurance data to yield influenza incidence between January 2010 and December 2018. We used generalized additive models, with Gaussian Markov random field smoothers for spatial input, whilst using or not using quarter as temporal input.

Results

In the 3.85 million cohort, 513,404 influenza cases occurred over the 9-year period, with 53.6% occurring in quarter 1 (January to March), and 10.2%, 9.4% and 26.8% in quarters 2, 3 and 4, respectively. Statistical modeling yielded highly significant effects of air temperature, precipitation, PM2.5 and NO2. Computation of stressor-specific gains revealed up to 3499 infections per 100,000 AOK clients per year that are attributable to lowering ambient mean air temperature from 18.71 °C to 2.01 °C. Stressor specific gains were also substantial for fine particulate matter, yielding up to 502 attributable infections per 100,000 clients per year for an increase from 7.49 μg/m3 to 15.98 μg/m3.

Conclusions

Whilst strong statistical association of temperature with other stressors makes it difficult to distinguish between direct and mediated temperature effects, results confirm genuine effects by fine particulate matter on influenza infections for both rural and urban areas in a temperate climate. Future studies should attempt to further establish the mediating mechanisms to inform public health policies.
PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells
Authors: Päth Günter , Perakakis Nikolaos , Mantzoros Christos S. , Seufert Jochen
Published: December 2022

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathology of atherosclerotic cardiovascular disease. For decades, the gold standard for LDL-C lowering have been statins, although these drugs carry a moderate risk for the development of new-onset diabetes. The inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged in the last years as potential alternatives to statins due to their high efficiency and safety without indications for a diabetes risk so far. Both approaches finally eliminate LDL-C from bloodstream by upregulation of LDL receptor surface expression. Due to their low antioxidant capacity, insulin producing pancreatic β-cells are sensitive to increased lipid oxidation and related generation of reactive oxygen species. Thus, PCSK9 inhibition has been argued to promote diabetes like statins. Potentially, the remaining patients at risk will be identified in the future. Otherwise, there is increasing evidence that loss of circulating PCSK9 does not worsen glycaemia since it is compensated by local PCSK9 expression in β-cells and other islet cells. This review explores the situation in β-cells. We evaluated the relevant biology of PCSK9 and the effects of its functional loss in rodent knockout models, carriers of LDL-lowering gene variants and PCSK9 inhibitor-treated patients.
The upregulation of NLRP3 inflammasome in dorsal root ganglion by ten-eleven translocation methylcytosine dioxygenase 2 (TET2) contributed to diabetic neuropathic pain in mice
Authors: Chen Wen , Wang Xiaotong , Sun Qingyu , Zhang Yurui , Liu Jing , Hu Tingting , Wu Weihua , Wei Chao , Liu Meng , Ding Yumeng , Liu Dianxin , Chong Yingzi , Wang Peipei , Zhu Hongwei , Cui Weihua , Zhang Jiannan , Li Qian , Yang Fei
Published: December 2022

Background

The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology.

Methods

DNP was induced in mice via the intraperitoneal injection of streptozotocin (STZ) for five consecutive days and the mechanical threshold was evaluated in STZ-diabetic mice by using von Frey hairs. The expression level of the NLRP3 pathway and TET2 in DRG were determined through molecular biology experiments. The regulation of the NLRP3 pathway by TET2 was examined in in vitro and in vivo conditions.

Results

In the present research, we first established the DNP model and found that NLRP3 pathway was activated in DRG. The treatment of NLRP3 inhibitor MCC950 alleviated the mechanical allodynia of DNP mice. Then we revealed that in STZ-diabetic mice DRG, the genomic DNA was demethylated, and the expression of DNA demethylase TET2 was increased evidently. Using RNA-sequencing analysis, we found that the expression of Txnip, a gene that encodes a thioredoxin-interacting protein (TXNIP) which mediates NLRP3 activation, was elevated in the DRG after STZ treatment. In addition, knocking down of TET2 expression in DRG using TET2-siRNA suppressed the mRNA expression of Txnip and subsequently inhibited the expression/activation of NLRP3 inflammasome in vitro and in vivo as well as relieved the pain sensitivity of DNP animals.

Conclusion

The results suggested that the upregulation of the TXNIP/NLRP3 pathway by TET2 in DRG was involved in the pain hypersensitivity of the DNP model.
A detailed analysis of F-MuLV- and SFFV-infected cells in Friend virus-infected mice reveals the contribution of both F-MuLV- and SFFV-infected cells to the interleukin-10 host response
Authors: Podschwadt Philip , Malyshkina Anna , Windmann Sonja , Werner Tanja , Hansen Wiebke , Bayer Wibke
Published: December 2022

Background

Friend virus (FV) is a complex of the Friend murine leukemia virus (F-MuLV) and the replication-defective, pathogenic spleen focus forming virus (SFFV). In the past, we used a fluorescently labeled F-MuLV to analyze FV target cells. To build on these findings, we have now created a double-labeled FV that contains a Katushka-labeled F-MuLV and an mTagBFP-labeled SFFV, which we have used to study the infection by the two individual viruses in the FV infection of highly susceptible BALB/c mice.

Results

Our data show that the target cells of SFFV largely mirror those of F-MuLV, with the highest virus loads in erythroblasts, B cells and myeloid cells. The early phase of infection was dominated by cells infected by either SFFV or F-MuLV, whereas double-infected cells became dominant later in the course of infection with increasing viral loads. In the late phase of infection, the frequency of double-infected cells was similarly high as the frequencies of SFFV or F-MuLV single-infected cells, and single- and double-infected cells outnumbered the uninfected cells in the most highly infected cell populations such as erythroblasts. FV and retroviruses in general have been shown to induce interleukin 10 (IL-10) as a means of suppressing immune responses. Interestingly, we found in infected IL-10-eGFP reporter mice that SFFV-infected cells contributed to the IL-10-producing cell pool much more significantly than F-MuLV-infected cells, suggesting that the truncated SFFV envelope protein gp55 might play a role in IL-10 induction. Even though BALB/c mice mount notoriously weak immune responses against FV, infection of mice with an ablation of IL-10 expression in T cells showed transiently lower viral loads and stronger T cell activation, suggesting that IL-10 induction by FV and by SFFV in particular may contribute to a suppressed immune response in BALB/c mice.

Conclusion

Our data provide detailed information about both F-MuLV- and SFFV-infected cells during the course of FV infection in highly susceptible mice and imply that the pathogenic SFFV contributes to immune suppression.
Astragaloside IV attenuates IL-1β-induced intervertebral disc degeneration through inhibition of the NF-κB pathway
Authors: Tian Yueyang , Chu Xu , Huang Qia , Guo Xing , Xue Yuan , Deng Weimin
Published: December 2022

Background

Intervertebral disc degeneration (IDD) is the main cause of low back pain. Patients with low back pain may experience significant socio-economic burdens and decreased productivity. Previous studies have shown that inflammation is one of the main causes of IDD. Astragaloside IV (AS IV), a traditional Chinese medicine, has been reported to have therapeutic effects on many inflammation-related diseases; however, the effectiveness of AS IV as the treatment for IDD has not been studied.

Methods

Nucleus pulposus (NP) cells from patients with IDD were used for the experiments. Cell counting kit 8 (CCK8) was used to evaluate the effect of AS IV on the viability of NP cells (NPCs). To mimic IDD in vitro, NPCs were divided into the following groups: control group, interleukin 1β (IL-1β) group, and AS IV + IL-1β group. To analyse the effect of AS IV on IL-1β-induced IDD, Western blotting, RT-qPCR, flow cytometry, and immunofluorescence assays were performed. To evaluate the effect of AS IV in vivo, a rat model of puncture-induced IDD was established.

Results

AS IV effectively alleviated IL-1β-induced inflammation, apoptosis, and extracellular matrix degeneration in NPCs. We also observed that AS IV decreased the IL-1β-induced phosphorylation of inhibitor of kappa B-alpha (p-IκBα) in the cytosol, and reduced nuclear translocation of NF-κB p65, indicating that AS IV inhibited the NF-κB pathway. Using the puncture-induced rat IDD model, our results showed that AS IV had a protective effect against the progression of IDD, suggesting that AS IV could alleviate IDD in vivo.

Conclusions

Our results demonstrated that AS IV effectively alleviated IDD in vivo and in vitro, indicating that it could be used as a therapeutic to treat IDD.
Correlative studies of the Breast Cancer Index (HOXB13/IL17BR) and ER, PR, AR, AR/ER ratio and Ki67 for prediction of extended endocrine therapy benefit: a Trans-aTTom study
Authors: Sgroi Dennis C. , Treuner Kai , Zhang Yi , Piper Tammy , Salunga Ranelle , Ahmed Ikhlaaq , Doos Lucy , Thornber Sarah , Taylor Karen J. , Brachtel Elena , Pirrie Sarah , Schnabel Catherine A. , Rea Daniel , Bartlett John M. S.
Published: December 2022

Background

Multiple clinical trials demonstrate consistent but modest benefit of adjuvant extended endocrine therapy (EET) in HR + breast cancer patients. Predictive biomarkers to identify patients that benefit from EET are critical to balance modest reductions in risk against potential side effects of EET. This study compares the performance of the Breast Cancer Index, BCI (HOXB13/IL17BR, H/I), with expression of estrogen (ER), progesterone (PR), and androgen receptors (AR), and Ki67, for prediction of EET benefit.

Methods

Node-positive (N+) patients from the Trans-aTTom study with available tissue specimen and BCI results (N = 789) were included. Expression of ER, PR, AR, and Ki67 was assessed by quantitative immunohistochemistry. BCI (H/I) gene expression analysis was conducted by quantitative RT-PCR. Statistical significance of the treatment by biomarker interaction was evaluated by likelihood ratio tests based on multivariate Cox proportional models, adjusting for age, tumor size, grade, and HER2 status. Pearson’s correlation coefficients were calculated to evaluate correlations between BCI (H/I) versus ER, PR, AR, Ki67 and AR/ER ratio.

Results

EET benefit, measured by the difference in risk of recurrence between patients treated with tamoxifen for 10 versus 5 years, is significantly associated with increasing values of BCI (H/I) (interaction P = 0.01). In contrast, expression of ER (P = 0.83), PR (P = 0.66), AR (P = 0.78), Ki67 (P = 0.87) and AR/ER ratio (P = 0.84) exhibited no significant relationship with EET benefit. BCI (H/I) showed a very weak negative correlation with ER (r = − 0.18), PR (r = − 0.25), and AR (r = − 0.14) expression, but no correlation with either Ki67 (r = 0.04) or AR/ER ratio (r = 0.02).

Conclusion

These findings are consistent with the growing body of evidence that BCI (H/I) is significantly predictive of response to EET and outcome. Results from this direct comparison demonstrate that expression of ER, PR, AR, Ki67 or AR/ER ratio are not predictive of benefit from EET. BCI (H/I) is the only clinically validated biomarker that predicts EET benefit.
Internet delivered, non-inferiority, two-arm, assessor-blinded intervention comparing mindfulness-based stress reduction and cognitive-behavioral treatment for insomnia: a protocol study for a randomized controlled trial for nursing staff with insomnia
Authors: Li Yaling , Nazari Nabi , Sadeghi Masoud
Published: December 2022

Background

Insomnia and poor sleep quality are highly prevalent conditions related to coronavirus disease 2019 (COVID-19) complications among clinical nurses. Although cognitive behavioral therapy for insomnia (CBT-I) is a first-line treatment, CBT-I suffers from several major drawbacks. This study investigates whether the application of the internet-delivered mindfulness-based stress reduction (iMBSR) intervention will produce effects that are non-inferior to the internet-delivered CBT-I (iCBT-I) intervention in reducing the severity of insomnia in clinical nurses with insomnia at the end of the study.

Methods

This study protocol presents an internet-delivered, parallel-groups, assessor-blinded, two-arm, non-inferiority randomized controlled trial. The primary outcome is sleep quality, assessed by the Insomnia Severity Index. Secondary outcomes include depression, dysfunctional beliefs, five facets of mindfulness, and client satisfaction.

Conclusion

It is expected that this study may address several gaps in the literature. The non-inferiority study design is a novel approach to evaluating whether a standardized, complementary treatment (i.e., MBSR) is as practical as a gold standard treatment rather than its potential benefits. This approach may lead to expanded evidence-based practice and improve patient access to effective treatments.

Trial registration

Trial registration number: ISRCTN36198096. Registered on 24th May 2022.
Spatial–temporal regulation of fatty alcohol biosynthesis in yeast
Authors: Gao Ning , Gao Jiaoqi , Yu Wei , Kong Sijia , Zhou Yongjin J.
Published: December 2022

Background

Construction of efficient microbial cell factories is one of the core steps for establishing green bio-manufacturing processes. However, the complex metabolic regulation makes it challenging in driving the metabolic flux toward the product biosynthesis. Dynamically coupling the biosynthetic pathways with the cellular metabolism at spatial–temporal manner should be helpful for improving the production with alleviating the cellular stresses.

Results

In this study, we observed the mismatch between fatty alcohol biosynthesis and cellular metabolism, which compromised the fatty alcohol production in Saccharomyces cerevisiae. To enhance the fatty alcohol production, we spatial-temporally regulated fatty alcohol biosynthetic pathway by peroxisomal compartmentalization (spatial) and dynamic regulation of gene expression (temporal). In particular, fatty acid/acyl-CoA responsive promoters were identified by comparative transcriptional analysis, which helped to dynamically regulate the expression of acyl-CoA reductase gene MaFAR1 and improved fatty alcohol biosynthesis by 1.62-fold. Furthermore, enhancing the peroxisomal supply of acyl-CoA and NADPH further improved fatty alcohol production to 282 mg/L, 2.52 times higher than the starting strain.

Conclusions

This spatial–temporal regulation strategy partially coordinated fatty alcohol biosynthesis with cellular metabolism including peroxisome biogenesis and precursor supply, which should be applied for production of other products in microbes.