bluuebunny/crossref_metadata_2025 huggingface dataset:
LRP1
Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases
Authors: Liu Lu , Henry Joséphine , Liu Yingwei , Jouve Charlène , Hulot Jean-Sébastien , Georges Adrien , Bouatia-Naji Nabila
Published: October 2024

BACKGROUND:

Genome-wide association studies implicate common genetic variations in the
LRP1
(low-density lipoprotein receptor-related protein 1 gene) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown.

METHODS:

Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9) to delete or modify candidate enhancer regions and generate
LRP1
knockout cell lines. Cells were differentiated into smooth muscle cells through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown, and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA sequencing, and mass spectrometry.

RESULTS:

Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in
LRP1
for fibromuscular dysplasia, migraine, pulse pressure, and spontaneous coronary artery dissection. We found the rs11172113-T allele to associate with higher
LRP1
expression. Genomic deletion in induced pluripotent stem cell–derived smooth muscle cells supported rs11172113 to locate in an enhancer region regulating
LRP1
expression. We found transcription factors MECP2 (methyl CpG binding protein 2) and SNAIL (Zinc Finger Protein SNAI1) to repress
LRP1
expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele.
LRP1
knockout decreased induced pluripotent stem cell–derived smooth muscle cell proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix and connective tissue development.
LRP1
knockout and deletion of rs11172113 enhancer showed potentiated canonical TGF-β (transforming growth factor beta) signaling through enhanced phosphorylation of SMAD2/3 (Mothers against decapentaplegic homolog 2/3). Analyses of the protein content of decellularized extracts indicated partial extracellular matrix remodeling involving enhanced secretion of CYR61 (cystein rich angiogenic protein 61), a known LRP1 ligand involved in vascular integrity and TIMP3 (Metalloproteinase inhibitor 3), implicated in extracellular matrix maintenance and also known to interact with LRP1.

CONCLUSIONS:

Our findings support allele-specific
LRP1
expression repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased
LRP1
expression in smooth muscle cells to remodel the extracellular matrix enhanced by TGF-β as a potential mechanism of this pleiotropic locus for vascular diseases.
An Archaeology of Image Processing Tools: From the Optical Printer to the Sandin Image Processor
Authors: Lauritzen Kasper
Published: October 2024

This article employs a media archaeology framework to critically examine the evolution of image processing in film and video production. The author illustrates how different tools constitute distinct creative practices by comparing the optical printer and Dan Sandin’s Image Processor. Through detailed analysis of these machines, he challenges traditional narratives of technological progression, suggesting a more complex relationship between analog and digital media forms. The discussion extends to the implications of these tools in shaping film and video aesthetics and methodologies, urging a reconsideration of how technology influences artistic expression and perception in media.
A Piano for Visuals: Affordances of Scan Processing Instruments
Authors: Holzer Derek
Published: October 2024

The analog technology of scan processing was developed and used during the 1970s as a method of electronic image animation. Because their real time modes of operation strongly resemble those of electronic musical instruments, scan processors can be considered instruments with which to compose and play moving images. Although cheaper digital tools replaced them in commercial studios during the 1980s, scan processing has a distinctive aesthetic that continues to inspire both visual artists and instrument designers. This article examines the way that scan processing instruments’ affordances arise from specific combinations of the user, technology, and situation by surveying a number of technical and artistic use cases involving two different instruments: the VP-8 Image Analyzer and the Rutt/Etra Video Synthesizer. The article also demonstrates how reenacting an instrument works through its historical affordances using current technological means to address present-day contexts.
Justice, Equity, and Approaches for Sharing Benefits from Deep Sea Mining Operations in the Area
Authors: Friedman Shani
Published: October 2024

This article critically examines the current benefit-sharing regime on the international seabed (the Area) and the proposed modalities for benefit-sharing. The United Nations Convention on the Law of the Sea contains few and vague rules on this issue. The only obligation is that benefit-sharing should be ‘equitable’ and the interests of developing States must be considered. To determine what may constitute equitable sharing the practice of other law of the sea legal regimes are examined and proposed distribution mechanisms are critically analysed. The article offers a unique perspective by trying to identify the scope of the vague equitable criterion for sharing or distributing benefits, rather than referring to it as a general goal or principle. Doing so, the article offers a practical account for the feasibility of different distribution modalities, which may yield new insights for institutional design to better deal with challenges in this well-researched but still unclear issue.
Transcriptomic response of Hermetia illucens L. (Diptera: Stratiomyidae) to wounding and Gram-negative bacterial infection
Authors: Shah P.N. , Maistrou S. , Willemsen I. , van Loon J.J.A. , Dicke M.
Published: October 2024

The larvae of the black soldier fly (BSFL), Hermetia illucens L. (Diptera: Stratiomyidae), are of economic interest due to their use as livestock feed component. Unraveling their response to a bacterial infection will allow us to gain a better insight into their biology. In the current study, we used RNA-Seq analysis to unravel the transcriptomic response of BSFL to wounding and infection by a Gram-negative bacterium, Pseudomonas protegens Pf-5. Five-day-old BSFL were subjected to three treatments, i.e. untreated, PBS-injection, and bacteria-injection (5000 CFU per larva) and samples were collected at three time points (2 h, 6 h, and 13 h) post- treatment. Wounding induced expression of genes encoding recognition molecules and signaling pathway genes such as PGRP-SA, and Relish, and antimicrobial peptides (AMPs) such cecropin, defensin, and attacin. At 2 h, wounding resulted in a significant upregulation of immunity-related genes whereas genes encoding for resilin and cuticle proteins were significantly downregulated. At 6 h, the expression of immunity-related genes reduced in response to wounding whereas their expression increased in infected larvae. At 13 h, the expression of immunity-related genes reduced drastically in response to wounding, while their expression increased significantly in infected larvae. Conversely, the expression of metabolism-related genes, such as trypsin and chymotrypsin, was significantly upregulated in wounded larvae at 13 h, while their expression was significantly reduced in infected larvae. Increased investments in immunity-related processes in infected BSF larvae correlated with the downregulation of genes associated with metabolic processes indicative of a trade-off. Various immunity-related genes, including those encoding cecropin, defensin, attacin, and PGRP-SA, were consistently induced only during pathogen infection, indicating their role in immunity against Gram-negative bacteria. In this study, we report multiple genes that are significantly upregulated post-bacterial infection in BSFL that may be utilized as biomarkers to monitor insect health in mass production facilities.
Improving egg quality in laying hens using calcium salt of black soldier fly larvae oil
Authors: Anas M.A , Aprianto M.A. , Muhlisin M. , Kurniawati A. , Hanim C. , Budiariati V. , Montha N.
Published: October 2024

Black soldier fly larvae (BSFL) oil has gained attention as a potential substitute for vegetable oil in feed formulations designed to improve productivity and product quality. This study aimed to investigate the impact of supplementation BSFL oil calcium salt (BSFLO-SCa) on the egg quality and gene expression involved in fat metabolism in laying hens. A total of sixty 40-wk-old ISA Brown laying hens were divided into three distinct groups: a control group (T0) that received a basic diet, and two treatment groups that were supplemented with 1% (T1) and 2% (T2) BSFLO-SCa. Each group consisted of 5 replicates, with 4 laying hens per replicate. The study indicated that the inclusion of 2% of BSFLO-SCa significantly increased egg albumen weight, height, ratio, eggshell weight, and thickness (). The inclusion of 1 and 2% of BSFLO-SCa increased the yolk lightness (L*) and yellowness (b*), but redness (a*) was decreased (). Moreover, BSFLO-SCa supplementation with 1 and 2% reduced () egg fat and cholesterol. Analysis of fatty acid profiles showed significantly increased medium-chain fatty acid (MCFA) and polyunsaturated fatty acid (PUFA) (), while monosaturated fatty acid (MUFA) reduced () with 2% BSFLO-SCa. Gene expression related to lipid metabolism, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), as well as cholesterol synthesis gene expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) were downregulated (). In conclusion, the inclusion of 2% BSFLO-SCa in the diet improved quality and reduced fat and cholesterol content in eggs from laying hens. This improvement was accompanied by downregulation of key genes involved in lipid metabolism.
Innocence and Knowledge Acquisition: Epiphanies of Knowledge in Olga Tokarczuk’s “Podróż Ludzi Księgi” [The Journey of the Book-People]
Authors: Kazibut Agnieszka , Kazibut Radosław
Published: October 2024

Innocence and Knowledge Acquisition: Epiphanies of Knowledge in Olga Tokarczuk’s Podróż Ludzi Księgi [The Journey of the Book-People]
The Journey and the Book are the hidden but central characters in Olga Tokarczuk’s debut novel, Podróż ludzi Księgi [The Journey of the Book-People] (1993). In Tokarczuk’s novel, the three dimensions of the journey correspond to the material, the psychological, and the esoteric religious. This paper identifies and discusses these interrelated planes of Tokarczuk’s story.
 
Niewinność i poznanie. Epifanie wiedzy w Podróży ludzi Księgi Olgi Tokarczuk
Podróż i Księga to ukryci, ale główni bohaterowie debiutanckiej powieści Olgi Tokarczuk Podróż ludzi Księgi (1993). W powieści tej korespondują trzy wymiary wędrówki: materialny, psychologiczny oraz ezoteryczno-religijny. W artykule te trzy powiązane ze sobą płaszczyzny opowieści zostały zidentyfikowane i przedyskutowane.
Beyond Morbidity and Mortality Conference: How Do We Learn From Special Cases?
Authors: Cohen Michael B. , Garvey Emily A. , Kohn Jocelyn L. , Setzen Sean A. , Grundfast Kenneth M. , Platt Michael P.
Published: October 2024

Objective:

Physicians experience scary cases in the course of usual medical practice. Cases of near misses, legal and ethical dilemmas, or unique clinical challenges are great sources of education. However, there is no format for presentation and dissemination of cases that do not meet criteria for morbidity and mortality (M&M) conferences. The Scary Cases Conference is an innovative educational forum for scrutiny and analysis of these challenging clinical cases. Scary Cases differs from traditional Morbidity and Mortality conferences as it explores outcomes beyond the scope of medical or surgical errors.

Methods:

From 2011 to 2021: 11 regional and 10 national “Otolaryngology Scary Cases” conferences and mini-seminars were held. The cases presented were analyzed for case specialty, area of management deemed troublesome, and compared to M&M conference criteria.

Results:

187 cases were presented. 62% percent of cases included traditional medical problems, whereas 21% involved legal issues, and 17% focused on ethical dilemmas. For the cases with medical problems, 31% involved airway obstruction, 17% nerve injuries, and 17% malignancy. 49% of cases would have met criteria for presentation at traditional M&M conferences. Of all the “scary cases,” 25% were near misses and 26% represented ethical or legal dilemmas which would not be classified as morbitidy, mortality, or near miss.

Conclusions:

The Scary Cases provides a forum conducive to learning amongst peers and experts. It allows medical and surgical specialties to share the cases deemed most impactful. The M&M conference would only include half of such cases, but could be expanded beyond the traditional scope in the future.
Understanding Alcohol and Illicit Drug Use in Young College Students: A Qualitative Work from India Based on Social Norms Theory
Authors: Ghosh Abhishek , George Blessy B. , Vij Jatina , Pillai Renjith R. , Soundappan Kathirvel , Sharma Mamta , Basu Debasish
Published: October 2024

Background and Objectives:

Substance use among young college students in India poses public health challenges. This study seeks to uncover the motivation behind alcohol and illicit drug consumption, applying social norms theory.

Methods:

This qualitative research utilized the framework method to analyze data from 14 college students (18–24 years) across various disciplines. Participants were selected using purposive sampling to ensure diversity in demographics and perspectives. Data collection was conducted online. The study used a combination of in-depth interviews (n = 14) and focused group discussions (n = 2). We used AtLAS.ti to facilitate data analysis. We used a mixed inductive and deductive coding approach. A mind map was generated to visualize the complex interplay between social norms and other individual and external mediators.

Results:

We identified 10 themes, 20 subthemes, and 42 codes. The themes revealed descriptive (e.g., media and modernization) and injunctive (e.g., availability and legality) social norms that facilitate substance use and social disapproval and stigma that might deter young people from using substances. Family and institutional support were also found to play a protective role. The individuals also weigh the personal consequences (e.g., health and academic harm) and advantages (e.g., coping and relaxation) of substance use, which can influence their decision to use substances. Gendered norms and subtle differences in the social norms between alcohol and illicit drugs were also identified.

Conclusion:

Our study illuminates culturally tailored substance use prevention/intervention strategies that operate at the social, individual, and policy levels.
Evaluation of Frontal QRS-T Angle in Children With ADHD and Healthy Controls
Authors: Kılıçaslan Fethiye , Tan Aybike , Tanriverdi Zulkif
Published: October 2024

Introduction:

Conflicting findings exist regarding the link between attention deficit hyperactivity disorder (ADHD) and cardiovascular diseases. This study aimed to evaluate the frontal QRS-T (fQRS-T) angle and its correlation with symptom severity in children diagnosed with ADHD.

Methods:

The study population consisted of 172 patients diagnosed with ADHD (120 drug naive and 52 drug positive) and 82 healthy controls. ADHD symptoms were assessed using the Atilla Turgay DSM-IV-Based Screening and Assessment Scale for Disruptive Conduct Disorders (T-DSM-IV-Scale). The fQRS-T angle and corrected QT (QTc) interval were obtained from the automated reports of 12-lead electrocardiography device for each patient.

Results:

QTc interval and fQRS-T angle were significantly different among the groups. Post hoc analyses showed that QTc interval and fQRS-T angle of ADHD drug naive and ADHD drug positive patients were significantly higher than the healthy control groups. However, there was no significant difference between drug naive and drug positive patients regarding QTc interval and fQRS-T angle. Both QTc interval and fQRS-T angle showed positive correlations with the severity of ADHD symptoms (r = 0.263, p = .001 and r = 0.175, p = .023 respectively).

Conclusion:

We found that fQRS-T angle was significantly wider in children with ADHD. Therefore, we suggest that fQRS-T angle may help in cardiovascular risk assessment in children with ADHD.
Synthesis of M + 4 Stable Isotopomers of Ergometrine and Ergometrinine
Authors: Braun Birgit , Köppen Robert , Wedler Christine , Theil Fritz
Published: October 2024

The priority ergot alkaloids ergometrine and ergometrinine are highly toxic mycotoxins naturally occurring in different types of grains (i.e. rye, wheat, rice), as well as grain-based foods and, therefore, have gained increasing importance for food safety over the last years. The application of HPLC-MS/MS for the analysis of ergot alkaloids in food presupposes the availability of isotopically labelled internal standards. Thus, a multistep synthesis was developed for ergometrine-( N- 13CD3) and its epimer ergometrinine-( N- 13CD3) with a mass shift of four units compared with the parent compounds. The synthesis is based on the preparation of stable isotope labelled lysergic acid that was coupled with ( S)-alaninol. The chemical synthesis of both compounds has been achieved in six steps with an overall yield of 1 % (ergometrine-( N- 13CD3)) and 0.6 % (ergometrinine-( N- 13CD3)), respectively. Structural identification was performed by MS analysis as well as 1H and 13C NMR.
Higher hair cortisol levels associated with previous cardiovascular events and cardiovascular risks in a large cross-sectional population study
Authors: Faresjö Åshild , Theodorsson Elvar , Stomby Andreas , Quist Helena , Jones Michael P. , Östgren Carl Johan , Dahlqvist Per , Faresjö Tomas
Published: October 2024

Background

Stress is today a common feature of patients seeking medical care and a growing public health issue in society. A method has been developed to measure biological chronic stress by Hair Cortisol Concentrations (HCC). This biomarker, for chronic stress, captures information about cumulative cortisol levels over the course of several months. Long-term stress might be one of the factors contributing to the onset of cardiovascular conditions and also affecting different risk factors. The aim of this study was to analyse the association between Hair Cortisol Concentrations and previous cardiovascular diseases and cardiovascular risk factors.

Methods

The method of measuring chronic stress by Hair Cortisol Concentration was applied in a large Swedish national observational cross-sectional study. A population-based random sample of N = 4,821 Swedish middle-aged men and women was analysed for hair cortisol levels in relation to diagnosed previous cardiovascular diseases and biologically measured cardiovascular risk factors.

Results

Long-term stress, measured by hair cortisol, was significantly associated with the classical cardiovascular risk factors hypertension and high cholesterol, but not smoking. Those with elevated HCC levels also had a significantly increased pre-history of myocardial infarction, type 2 diabetes, atrial fibrillation and by-pass surgery, but not regarding stroke, angina pectoris or sleep apnoea. Higher HCC was significantly associated (p < 0.001) with Body mass index and waist circumference, but only for females. HCC was also associated with the risk markers leukocytes, and high-sensitivity CRP, indicating a possible linkage between HCC and inflammation and hypothetically also the bodily immune defense. No association was found between perceived stress and HCC.

Conclusions

An overall conclusion of our results is that health care should put more emphasis on patients reporting that they have been exposed to long term stress. Altogether, these analyses of Hair cortisol levels in a large middle-aged population show that chronically elevated cortisol levels represent a relevant and significant factor associated with cardiovascular diseases and classical cardiovascular risk factors.
Daily snuff use during pregnancy, gestational length and birth weight; register-based study
Authors: Lie Rolv T. , Magnus Maria C. , Gjessing Håkon K. , Wilcox Allen J. , Håberg Siri E.
Published: October 2024

Background

Snuff is a smokeless source of nicotine that is common in Scandinavia and increasingly used by women of fertile age. Persistent use of snuff during pregnancy has been associated with adverse pregnancy outcomes. Emerging data from the Medical Birth Registry of Norway distinguishes between occasional use and daily use. We provide preliminary estimates of associations between frequency of snuff and gestational length and birth weight.

Methods

Data on snuff use during pregnancies delivered in 2020 and 2021 were available for the west and central regions of Norway. Associations of snuff use with gestational length and birth weight at term (39–41 weeks) were estimated using quantile regression at the 25th, the 50th and the 75th percentiles, with adjustments for mother’s age, pre-pregnancy weight, and parity. We compared associations with the pregnancy outcomes according to maternal snuff and cigarette use.

Results

12.4% of 18 042 non-smoking women reported daily use of snuff before pregnancy, and 4.6% reported continuing use during pregnancy, with 1.2% still reporting daily use in the last trimester. Women with daily use through the last trimester delivered babies with a median gestational length reduced by 3.4 days (95% CI: -5.0 to -1.7 days) compared with women who never used snuff. The reduction was even stronger at the 25th percentile of gestational age. The median term birth weight was reduced by 44 g (95% CI: -134 to 46 g). These associations were much weaker for women who quit snuff at some point during pregnancy or used snuff only occasionally. Mothers who smoked daily through the last trimester had a median gestational length reduced by 2.1 days (95% CI: -2.7 to -1.4) and a median term birth weight reduced by 294 g (95% CI: -325 to -262) compared with never-smokers.

Conclusions

Daily snuff use through the last trimester reduced the median gestational length by more than three days. Snuff reduced birth weight, but not as much as smoking, suggesting that the predominant effect of smoking on fetal growth is not through nicotine but through the additional toxic chemicals in cigarettes or by reduced oxygen supply to the fetus.
Marginal bone loss and soft tissue health around two-implant mandibular overdenture retained with milled versus selective laser melted cobalt chromium bar: a randomized clinical trial
Authors: El-Asfahani Iman Adel , Abd El-Moatty Reem , Mohamed Gehan Fekry , Hussein Hussein Abdelhady
Published: October 2024

Background

To assess marginal bone loss and soft tissue health around two-implant mandibular overdenture retained with milled versus selective laser-melted cobalt chromium (Co-Cr) bars.

Method

This research was set to be a parallel, triple-blinded, randomised controlled trial. Twenty completely edentulous patients received new conventional complete dentures according to conventional techniques. Two implants were placed at mandibular canine areas bilaterally, and patients were randomly allocated into two equal groups: the milled Co-Cr bar group and the selective laser melted (SLM) Co-Cr bar group. Marginal bone loss (MBL), modified plaque index (mPI), modified gingival index (mGI), and probing depth (PD) were evaluated at 0-month (baseline), 6-month, and 12-month follow-up visits. Repeated measures ANOVA test and Bonferroni’s post-hoc test were used for parametric data as PD, while for non-parametric data as MBL, mGI, and mPI, Mann-Whitney U test and Friedman’s test were used. A P-value ≤ 0.05 was set as the statistical level of significance. The study protocol was approved by the Faculty Research Ethics Committee at Minia University (636 4/10/2022). Registration for the clinical trial was made retrospectively on clinicaltrials.gov with ID NCT06401200 at 04/30/2024.

Results

The follow-up period (one year) was completed without a dropout. Regarding MBL, no statistically significant difference was found between the two groups throughout the study. However, the milled group showed significantly increased MBL from 0- to 6-month follow up period. In both groups, mPI increased significantly from 0- to 6-months post-loading. On the other hand, no statistically significant difference between the two groups was found regarding mPI and mGI throughout the study follow-up periods. The PD was significantly lower in the milled compared to the SLM group at the 6- and 12-month follow up period.

Conclusion

Two-implant mandibular overdenture retained with milled or SLM Co-Cr bar can provide an acceptable treatment option for completely edentulous patients regarding marginal bone loss and soft tissue outcomes.
Effects of mandarin peel powder on growth, biochemical, immune, and intestinal health in Oreochromis niloticus at suboptimal temperatures
Authors: Reda Rasha M. , El-Rahim Mostafa I. Abd , Elkerdawy Dawlat A. , Metwally Mohamed M. M. , Said Nermin
Published: October 2024

This 60-day study aimed to examine the efficacy of a diet supplemented with mandarin peel powder (MP) in enhancing the health and survival of Oreochromis niloticus under suboptimal temperature conditions (21 ℃). One hundred and eighty Nile tilapia fish (22.51 ± 0.04 g) were randomly distributed into four experimental groups; each of 3 replicates (15 fish per replicate). The first group (CONT) received a basal diet without MP. The second (MP10%), third (MP15%), and fourth (MP20%) groups were fed diets containing 10, 15, and 20% MP powder, respectively. At the end of the feeding trail, growth performance, serum growth hormone, α-amylase enzyme, lysozyme activity, nitric oxide, protease activity, globulin, serum levels of IL-1ß, antioxidant status, and intestinal histology were measured. The results showed insignificant differences between CONT, MP15%, and MP20% groups in the final body weight and specific growth rate. The growth hormones in the MP15% and MP20% groups did not show a significant difference compared to fish fed a normal basal diet (CONT). However, the amylase enzymes were significantly greater in both groups. The MP20% and MP15% groups showed a significant increase in antioxidant, lysozyme, nitric oxide, and protease activities compared to CONT. The results also showed that fish that were fed a diet with MP had significantly less of the pro-inflammatory cytokine interleukin-1 beta, and their intestinal villi got wider, especially in the MP20% group. It could be concluded that feeding tilapia on a diet with 20% MP is an effective strategy to improve their health when the temperature is below 21 °C. This is because the fish exhibit higher levels of antioxidant activity, reduced pro-inflammatory responses, and improved intestinal health without difference in the growth performance in compared to control group.
Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma
Authors: Lavoro Alessandro , Falzone Luca , Gattuso Giuseppe , Conti Giuseppe N. , Caltabiano Rosario , Madonna Gabriele , Capone Mariaelena , McCubrey James A. , Ascierto Paolo A. , Libra Massimo , Candido Saverio
Published: October 2024

Background

Cancer onset and progression are driven by genetic and epigenetic alterations leading to oncogene activation and the silencing of tumor suppressor genes. Among epigenetic mechanisms, DNA methylation (methDNA) is gaining growing interest in cancer. Promoter hypomethylation is associated with oncogene activation while intragenic methDNA can be involved in transcriptional elongation, alternative spicing, and the activation of cryptic start sites. Several genes involved in the modulation of the tumor microenvironment are regulated by methDNA, including the Solute Carrier Family 22 Member 17 (SLC22A17), which is involved in iron trafficking and extracellular matrix remodeling cooperating with the Gelatinase-Associated Lipocalin (NGAL) ligand. However, the exact role of intragenic methDNA in cancer has not been fully investigated. Therefore, the aim of the present study is to explore the role of methDNA in the regulation of SLC22A17 in cutaneous melanoma (CM), used as a tumor model.

Methods

Correlation and differential analyses between SLC22A17 expression and methDNA were performed using the data contained in The Cancer Genome Atlas and Gene Expression Omnibus databases. Functional studies on melanoma cell lines treated with 5-Azacytidine (5-Aza) were conducted to assess the correlation between methDNA and SLC22A17 expression. A validation study on the diagnostic potential of the in silico-identified SLC22A17 methDNA hotspot was finally performed by analyzing tissue samples obtained from CM patients and healthy controls.

Results

The computational analyses revealed that SLC22A17 was significantly downregulated in CM, and its expression was related to promoter hypomethylation and intragenic hypermethylation. Moreover, SLC22A17 overexpression and hypermethylation of two intragenic methDNA hotspots were associated with a better clinical outcome in CM patients. The correlation between SLC22A17 methDNA and expression was confirmed in 5-Aza-treated cells. In agreement with in silico analyses, the SLC22A17 promoter methylation hotspot showed higher methDNA levels in CM samples compared to nevi. In addition, the methDNA levels of this hotspot were positively correlated with advanced CM.

Conclusions

The SLC22A17 methDNA hotspot could represent a promising biomarker for CM, highlighting the regulatory role of methDNA on SLC22A17 expression. These results pave the way for the identification of novel epigenetic biomarkers and therapeutic targets for the management of CM patients.
Exploring transparent reporting and data availability in systematic reviews to identify subgroup evidence: imaging for suspected hepatocellular carcinoma in the non-cirrhotic liver
Authors: Oerbekke Michiel S. , de Man Robert A. , van Vilsteren Frederike G. I. , Nijkamp Maarten W. , Tjwa Eric , Gaasterland Charlotte M. W. , van der Laan Maarten J. , Hooft Lotty
Published: October 2024

We aim to illustrate the role of complete and transparent reporting coupled with access to data sourced from published systematic reviews, especially assisting in the identification of evidence for subgroups within the context of a rare disease. To accomplish this principle, we provide a real-world example encountered during the revision of the Dutch clinical practice guideline for hepatocellular carcinoma. Specifically, we retrieved insights from two Cochrane reviews to identify direct evidence concerning the diagnostic test accuracy of computed tomography and magnetic resonance imaging for detecting hepatocellular carcinomas in suspected patients without liver cirrhosis. Through reusing the Cochrane review authors’ efforts already undertaken in their exhaustive literature search and selection, we successfully identified relevant direct evidence for this subgroup of suspected patients without cirrhosis and performed an evidence synthesis within the constraints of limited resources for the guideline revision. This approach holds the potential for replication in other subgroups in the context of rare diseases, contingent on the transparent and complete reporting of systematic reviews, as well as the availability and accessibility of their extracted data. Consequently, we underscore the importance of adhering to established reporting guidelines for systematic reviews, while simultaneously advocating for increased availability and accessibility to data. Such practices would not only increase the transparency and reproducibility of systematic reviews but could also increase reusability of their data. In turn, the increased reusability could result in reduced resource utilization in other sectors such as the guideline developing community as we show in our example.
Resilience and coping during protracted conflict: a comparative analysis of general and evacuees populations
Authors: Marciano Hadas , Kimhi Shaul , Eshel Yohanan , Adini Bruria
Published: October 2024

Background

On October 7th, 2023, Hamas launched a surprise attack on Israel, triggering a conflict with Israel in the Gaza Strip. This ongoing war, now six months old, has also seen threats from Hezbollah in Lebanon, as well as from Yemen and Iran. The precarious security situation along Israel’s southern and northern borders led to extensive evacuations, with residents relocating within Israel under uncertain conditions concerning their return and property safety. This study compares resilience (societal, SR; community, CR; and individual, IR), hope, morale, distress symptoms (anxiety and depression symptoms), and perceived danger between general Hebrew-speaking adults and evacuee adults a few months post-conflict initiation.

Methods

Data was collected using structured self-reported questionnaires focusing on resilience and coping strategies, administered through two online panel companies. The general population data was collected from January 14–21, 2024 (N = 1,360), and the evacuees’ data from March 1–9, 2024 (N = 372; 133 from the north, 239 from the south).

Results

Evacuees reported lower SR and CR, hope, and morale, and higher distress symptoms and perceived danger compared to the general population. No differences in IR were found. Regression analyses identified different primary predictors of SR for each group: hope for the general population and governmental support for evacuees. Additionally, IR significantly predicted outcomes only among evacuees, whereas age, religiosity, and education were significant predictors solely in the general population. One notable similarity emerged: CR served as the second most influential predictor in both samples.

Conclusions

The entire population of Israel is affected by the ongoing war, yet evacuees endure a disproportionately severe impact, with potential for increased harm as the conflict persists. The adjustment to a new wartime emergency routine is more complex for evacuees than for the general population. It is crucial for policy and decision-makers to address the distinct differences between evacuees and the general populace to effectively meet their specific needs. Yet, it should be acknowledged that the evacuees represent a heterogenic group, necessitating a detailed subdivision into subgroups to accurately assess and address their unique challenges.
Development and Portability of a Text Mining Algorithm for Capturing Disease Progression in Electronic Health Records of Patients With Stage IV Non–Small Cell Lung Cancer
Authors: Verschueren M.V. , Abedian Kalkhoran H. , Deenen M. , van den Borne B.E.E.M. , Zwaveling J. , Visser L.E. , Bloem L.T. , Peters B.J.M. , van de Garde E.M.W.
Published: October 2024

PURPOSE

The objective was to develop and evaluate the portability of a text mining algorithm for prospectively capturing disease progression in electronic health record (EHR) data of patients with metastatic non–small cell lung cancer (mNSCLC) treated with immunochemotherapy.

METHODS

This study used EHR data from patients with mNSCLC receiving immunochemotherapy (between October 1, 2018, and December 31, 2022) in four Dutch hospitals. A text mining algorithm for capturing disease progression was developed in hospitals 1 and 2 and then transferred to hospitals 3 and 4 to evaluate portability. Performance metrics were calculated by comparing its outcomes with manual chart review. In addition, data were simulated to come available over time to assess performance in real-time applications. Median progression-free survival (PFS) was calculated using the Kaplan-Meier method to compare text mining with manual chart review.

RESULTS

During development and portability, the text mining algorithm performed well in capturing disease progression, with all performance scores >90%. When real-time performance was simulated, the performance scores in all four hospitals exceeded 90% from week 15 after the start of follow-up. Although the exact progression dates varied in 46 patients of 157 patients with progressive disease, the number of patients labeled with progression too early (n = 24) and too late (n = 22) was well balanced with discrepancies ranging from –116 to 384 days. Nevertheless, the PFS curves constructed with text mining and manual chart review were highly similar for each hospital.

CONCLUSION

In this study, an accurate text mining algorithm for capturing disease progression in the EHR data of patients with mNSCLC was developed. The algorithm was portable across different hospitals, and the performance over time was good, making this an interesting approach for prospective follow-up of multicenter cohorts.
Novel oleanolic acid derivative ZQL-4c as a target for SCD to modulate lipid metabolism reprogramming to overcome trastuzumab resistance in HER2 positive breast cancer.
Authors: Ma Yiwen , Wang Shisheng , Li Xiaorui , Guo Xiangyu , Jiang Cui , Sun Tao
Published: October 2024

e13009

Background:
Approximately 15% to 20% of patients with breast cancer are characterized as Human epidermal growth factor2 (HER2) positive with a high recurrence rate and a poor survival outcome. With the development and application of anti-HER2 drugs such as trastuzumab, the prognosis of patients with HER2-positive breast cancer has improved significantly. However, more than 30% of patients still experience treatment failure, recurrence, and distant metastasis due to drug resistance. It is therefore important to develop new drugs to overcome trastuzumab resistance and investigate the precise mechanism. Oleanolic acid (OA), one of the most common pentacyclic triterpenoids, has been shown to have significant benefits in treating tumors. Still, its clinical application is limited due to its poor bioavailability and target uncertainty.
Methods:
We synthesized ZQL-4c, a novel derivative of oleanolic acid with anti-tumor activity, which can target the reprogramming function of lipid metabolism of Stearoyl-CoA desaturase (SCD) to overcome resistance to trastuzumab in HER2 positive breast cancer, along with a panel from Dalian University of Technology.
Results:
After exploring the anti-tumor effects of ZQL-4c in trastuzumab-resistant tumors, we assessed overcoming resistance through the combination of ZQL-4c and trastuzumab. To further identify the SCD target of ZQL-4c, we used multi-omics association and molecular docking technology and established drug-resistant tumor models with SCD overexpression in vivo and ex vivo. We found that targeting SCD could inhibit de novo lipid synthesis, thus inducing lipotoxicity-mediated apoptosis and exerting the effect of overcoming resistance to trastuzumab.
Conclusions:
In summary, our observations that the novel oleanolic acid derivative ZQL-4c inhibits apoptosis induced by lipotoxicity by targeting SCD provides an attractive future direction for treating HER2-positive trastuzumab-resistant breast cancer.
Phase Ib Study for the Combination of Doxorubicin, Dacarbazine, and Nivolumab as the Upfront Treatment in Patients With Advanced Leiomyosarcoma: A Study by the Spanish Sarcoma Group (GEIS)
Authors: Martin-Broto Javier , Diaz-Beveridge Roberto , Moura David , Ramos Rafael , Martinez-Trufero Javier , Carrasco Irene , Sebio Ana , González-Billalabeitia Enrique , Gutierrez Antonio , Fernandez-Jara Javier , Hernández-Vargas Laura , Cruz Josefina , Valverde Claudia , Hindi Nadia
Published: October 2024

PURPOSE

Doxorubicin, alongside a select group of cytotoxic agents, is capable of inducing an adaptive immune response via a well-established peculiar type of tumor cell death called immunogenic cell death (ICD). We hypothesize that combining doxorubicin and dacarbazine with nivolumab may enhance therapeutic efficacy by exerting synergy in the ICD circuit. We hereby present a phase Ib trial with this combination.

PATIENTS AND METHODS

Patients with advanced leiomyosarcoma and anthracycline-naïve were eligible. The initial dose level consisted of doxorubicin 75 mg/m
2
once on day 1, once every three weeks, followed by dacarbazine 400 mg/m
2
once on days 1 and 2, once every three weeks, plus nivolumab 360 mg once on day 2, once every 3 weeks, for six courses and then 1 year of nivolumab. A (–1) dose level was the same regimen but with nivolumab 240 mg. A classic 3 + 3 phase-I design was used to determine the recommended phase-II dose (RP2D). Secondary end points included overall response rate, safety profile, survival, and translational research.

RESULTS

From January 2002 to July 2023, 24 patients were enrolled and 23 were evaluable for efficacy, excluding one patient because of noncompliant dose. All patients were treated with the initial dose level, then the RP2D. Toxicity was mild, with the most frequent being grade 4 toxicity neutropenia (16.7%) and thrombocytopenia (8.3%), while no grade 5 toxicity occurred. The centrally reviewed objective response rate was as follows: partial response 56.5%, stable disease 39.1%, and progression 4.4%. The 6-month progression-free survival (PFS) rate was 80% (95% CI, 63 to 98). Dynamic increases of HMGB1 in blood significantly correlated with longer PFS.

CONCLUSION

This scheme of doxorubicin, dacarbazine, and nivolumab is feasible and well tolerated. Clinical activity is encouraging and the prognostic impact of HMGB1 supports the relevance of ICD activation. Further clinical research is already underway with this concept in leiomyosarcoma.
Chronic Pain Psychology in Neurology Practice
Authors: Serdarevic Mirsad
Published: October 2024

OBJECTIVE

This article reviews the latest literature regarding chronic pain epidemiology and describes pain-specific psychological factors associated with the development and maintenance of chronic pain, mental health conditions that co-occur with chronic pain, and advances in the psychobehavioral treatment of chronic pain, including established treatments (ie, cognitive behavioral therapy [CBT], acceptance and commitment therapy, and mindfulness-based stress reduction) and emerging treatments (ie, pain reprocessing therapy).

LATEST DEVELOPMENTS

In addition to CBT and acceptance and commitment therapy for pain, numerous other psychological treatment modalities have been integrated into chronic pain management, including mindfulness-based stress reduction, mindfulness meditation, chronic pain self-management, relaxation response, pain neuroscience education, biofeedback, hypnosis, and, more recently, integrative psychological treatment for centralized pain. This article gives an overview of these methods and contextualizes their use within the standard psychological treatment of chronic pain.

ESSENTIAL POINTS

Guided by the biopsychosocial treatment model, pain psychologists use numerous evidence-based psychological methods to treat patients with chronic pain conditions. Familiarity with the psychological tools available for pain management will aid neurologists and their patients in navigating the psychological aspects of living with chronic pain.
Spine Pain
Authors: Williams Vernon B.
Published: October 2024

OBJECTIVE

Spine pain is one of the most common presenting concerns in health care settings. This article reviews clinical strategies for evaluating and managing patients with spine pain.

LATEST DEVELOPMENTS

Minimally invasive interventional procedures, virtual reality, predictive analytics, neuromodulation, and other evolving technologies are significantly impacting the management of spine pain. Advances in modern pain science have also led to effective skills and treatment strategies, including patient interviews and queries for insight regarding pain, education, and cognitive restructuring, and adjusting the timing of examination (after reeducation) and examination techniques to encourage the experience of movement in the absence of assumed tissue damage. An evolving understanding of the influence of patient-centric thoughts, framing, emotional status, and cognitive restructuring’s influence on the brain’s response to perceived threat are important aspects of spine pain management.

ESSENTIAL POINTS

The correlation of clinical presentations with structural abnormalities is necessary but insufficient to evaluate and manage spine pain. Modern pain science acknowledges pain as a subjective experience but recognizes a critical distinction between tissue damage, nociception, and the experience of pain. What and how we communicate with patients, as well as evolving neuromodulation technologies, augment conventional approaches.
Use of Sugammadex in “Cannot Intubate, Cannot Ventilate” Scenarios: A Systematic Review of Case Reports
Authors: Abou Nafeh Nancy G. , Aouad Marie T. , Khalili Amro F. , Serhan Fatima G. , Sokhn Anthony M. , Kaddoum Roland N.
Published: October 2024

After an induction dose of rocuronium, sugammadex in a dose of 16 mg.kg−
1 has been shown to provide early reversal of the neuromuscular blockade. However, the use of sugammadex to rescue a “cannot intubate, cannot ventilate” (CICV) scenario remains controversial. The aim of this systematic review was to discuss case reports describing the use of sugammadex as a rescue reversal in CICV scenarios and analyze the influencing factors potentially shaping the outcome of such reversal. The study has been registered on International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024514255). We conducted a systematic review of the literature using PubMed, Medline, and Embase. Records were included if they were case reports or case series published in peer-reviewed journals, describing the administration of sugammadex as a rescue reversal in CICV scenarios, and including clinical outcomes and details of the management. Sources were last searched on November 30, 2023. The articles selected were initially screened based on their titles and abstracts, and then complete articles were examined to determine their eligibility and compliance with the inclusion criteria. Two independent authors evaluated the quality of the individual studies using the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports. Eight articles were included in our review. In all patients, CICV scenarios were declared minutes following induction. In 6/8 cases (75%), adequate spontaneous ventilation was restored after the administration of sugammadex. In the remaining 2 cases, sugammadex administration resulted in an obstructed pattern of breathing, and surgical airway was the successful rescue technique. There was wide variability in the sugammadex dose with a median (range) of 14 (5–16) mg.kg−1 and median timing (range) from rocuronium administration of 6 (2–10) minutes.

This case-report-based review is susceptible to reporting bias and may not encompass all pertinent data and adverse events. Also, cases with both favorable and unfavorable outcomes may have not been published, and the heterogeneity of cases limits the ability to draw definitive conclusions. In summary, although these case reports suggest that sugammadex might be helpful in CICV scenarios, further research is needed to confirm its effectiveness. However, due to the rare occurrence of CICV events, gathering sufficient data for conclusive evidence may be challenging.