bluuebunny/crossref_metadata_2025 huggingface dataset:
NanoLuc Binary Technology as a methodological approach: an important new tool for studying the localization of androgen receptor and androgen receptor splice variant V7 homo and heterodimers
Authors: Guzman Juan , Weigelt Katrin , Neumann Angela , Tripal Philipp , Schmid Benjamin , Winter Zoltán , Palmisano Ralph , Culig Zoran , Cronauer Marcus V. , Muschler Paul , Wullich Bernd , Taubert Helge , Wach Sven
Published: March 2024

Background

The androgen/androgen receptor (AR)-signaling axis plays a central role in prostate cancer (PCa). Upon androgen-binding the AR dimerizes with another AR, and translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. Consequently, treatments for PCa are commonly based on androgen deprivation therapy (ADT). The clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. Clinical failure of ADT is often characterized by the synthesis of a constitutively active AR splice variant, termed AR-V7. AR-V7 mRNA expression is considered as a resistance mechanism following ADT. AR-V7 no longer needs androgenic stimuli for nuclear entry and/or dimerization.

Methods

Our goal was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology under androgen stimulation and deprivation conditions.

Results

Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 homodimers localize in the nucleus. However, after androgen stimulation, all the AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers were localized in the nucleus.

Conclusions

We showed that AR-FL and AR-V7 form heterodimers that localize to the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus.
ART1 knockdown decreases the IL-6-induced proliferation of colorectal cancer cells
Authors: Lin Ting , Zhang Shuxian , Tang Yi , Xiao Ming , Li Ming , Gong Hanjuan , Xie Hailun , Wang Yalan
Published: March 2024

Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.
Renal toxicity of ifosfamide in children with cancer: an exploratory study integrating aldehyde dehydrogenase enzymatic activity data and a wide-array urinary metabolomics approach
Authors: Febvey-Combes Olivia , Guitton Jérôme , Marec-Berard Perrine , Faure-Conter Cécile , Blanc Ellen , Chabaud Sylvie , Conjard-Duplany Agnès , Schell Matthias , Derain Dubourg Laurence
Published: March 2024

Background

Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity.

Methods

The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified.

Results

The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24–102), given over a median of 7 cycles (range: 4–14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children.

Conclusions

Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.
The cost of illness and burden of suicide and suicide attempts in France
Authors: Segar Laeticia Blampain , Laidi Charles , Godin Ophélia , Courtet Philippe , Vaiva Guillaume , Leboyer Marion , Durand-Zaleski Isabelle
Published: March 2024

Background

With 11,558 deaths and 200,000 suicide attempts in 2019, France is among the European countries most affected. The aim of this study was to determine the costs and burden of suicides and suicide attempts in France (population 67 million).

Methods

We estimated direct costs, comprising healthcare, as well as post-mortem costs including autopsy, body removal, funeral expenses, police intervention and support groups; indirect costs comprised lost productivity, daily allowances; the burden of disease calculations used a monetary value for death and disability based on incidence data. Data was obtained from the national statistics, health and social care database, registries, global burden of disease, supplemented by expert opinion. We combined top down and bottom up approaches.

Results

The total costs and burden of suicides and suicide attempts was estimated at €18.5 billion and €5.4 billion, respectively. Direct costs were €566 million and €75 million; indirect costs were €3.8 billion and €3.5 billion; monetary value for death and disability was €14.6 billion and €1.3. The monetary value for death and disability represented 79.1% and 24.8% of total costs for suicide and suicide attempt respectively.

Some costs were based upon expert opinion, caregivers’ burden was not counted and pre COVID data only is reported.

Conclusions

In France, the total cost and burden of suicides and suicide attempts was several billion €, suggesting major potential savings from public health interventions.
Ischemic heart disease-related mortality in Brazil, 2006 to 2020. A study of multiple causes of death
Authors: Bastos Luiz A. V. M. , Villela Paolo B. , Bichara Jose L. P. , do Nascimento Emilia M. , Bastos Eduardo L. V. M. , de B Pereira Basilio , Oliveira Glaucia M. M.
Published: March 2024

Context

Both the aging of the population and the increase in noncommunicable diseases may influence the progression and outcomes culminating in death, changing the evolution of ischemic heart diseases (IHDs) and their associated causes. Using the multiple causes of death method could help understand the magnitude of these relationships and enable better targeting of investments in health.

Objectives

To evaluate the mortality from IHD in Brazil between 2006 and 2020 using the method of multiple causes and identify differences in the distribution pattern of IHD mortality by sex and geographic region.

Methods

Based on information extracted from death certificates (DCs) obtained from the database of the Department of Informatics of the Unified Health System (DATASUS), we used the multiple causes method to analyze the causes of death associated with IHD when IHD was defined as the underlying cause of death (UC) and the causes of death listed as the UC when IHD was recorded in any other lines of the DC, from 2006 to 2020, in Brazil. Subsequently, the proportion of these causes of death and differences between sexes and geographic regions were evaluated, with statistical relevance analyzed using the chi-square test, and the dependence between factors illustrated using stacked bar charts and small-world network graphs.

Results

When IHD was listed as the UC of death, the most frequent associated causes of death were, in descending order of frequency, acute myocardial infarction (AMI), arterial hypertension (AH), chronic ischemic heart disease (CHID), heart failure (HF), and diabetes mellitus (DM). When IHD was mentioned in any line of the DC, the most frequent UCs of death were AMI followed by DM, CIHD, chronic obstructive pulmonary disease (COPD), stroke, dyslipidemia, and, in the year 2020, COVID-19. The most frequent cause of death in women were DM as the UC and associated cause of death, AH as the UC, and CIHD and Alzheimer's disease as associated causes of death, while the most frequent causes of death in men were substance dependence as the UC and associated cause of death, and cancer as an associated cause of death. The most frequent causes of death were DM and stroke in the North and Northeast, dyslipidemia and obesity in the Midwest, Alzheimer's disease in the South and Southeast, and atherosclerotic heart disease (AHD) and COPD in the South.

Conclusions

Several diseases – including AMI, AH, CIHD, HF, and DM – were the most frequent associated causes of death when IHD was recorded as the UC. In contrast, AMI, DM, CIHD, COPD, and stroke were the most frequent UCs when IHD was listed as an associated cause of death. The degree of these associations varied between sexes and geographic regions.
Marginalisation and distrust in the context of the COVID-19 vaccination programme: experiences of communities in a northern UK city region
Authors: Gillibrand Stephanie , Kapadia Dharmi , Watkinson Ruth , Issa Basma , Kwaku-Odoi Charles , Sanders Caroline
Published: March 2024

Background

There are clear inequalities in COVID − 19 vaccination rates amongst marginalised groups, with lower rates for some minoritised ethnic and religious groups, younger people, those living in more deprived areas, and with lower socio-economic status. Existing research focuses on psychological and socio-economic factors that influence vaccine uptake and does not explore broader social and historical contexts. Understanding inequalities in COVID-19 vaccine uptake requires a critical examination of the drivers of, and barriers to, vaccination.

Methods

We present findings from a co-designed qualitative research study undertaken during the COVID-19 pandemic. Focus groups and interviews were used to examine the context underpinning responses to the COVID-19 vaccination in Greater Manchester, particularly focussing on experiences of marginalisation. Thematic framework analysis was used to analyse the data.

Results

We found that the public’s responses to the COVID-19 vaccination programme are intertwined with a longstanding history of institutional distrust and disenfranchisement, resulting from experiences of marginalisation and social inequalities. This was exacerbated further by the disproportionate impacts of the COVID-19 pandemic on minoritised ethnic groups, younger people, and those with existing health conditions.

Conclusions

Histories of structural inequalities experienced by minoritised groups invoked feelings of suspicion and scepticism at the motivations of the agencies behind the vaccination rollout. This highlights the need for a contextualised analysis of attitudes to vaccines, considering pre-existing inequalities, which may be especially relevant for conceptualising public responses to the vaccination programme. Finally, our study shows the important ways in which public (dis)trust can impact public health policies. We recommend this should be incorporated into responses to future public health crises.
Relationship between loneliness and internet addiction: a meta-analysis
Authors: Wang Yue , Zeng Youlai
Published: March 2024

Background

In the digital age, the Internet has become integrated into all aspects of people’s work, study, entertainment, and other activities, leading to a dramatic increase in the frequency of Internet use. However, excessive Internet use has negative effects on the body, psychology, and many other aspects. This study aims to systematically analyze the research findings on the relationship between loneliness and Internet addiction to obtain a more objective, comprehensive effect size.

Methods

This study employed a comprehensive meta-analysis of empirical research conducted over the past two decades to investigate the relationship between loneliness and Internet addiction, with a focus on the moderating variables influencing this relationship. This meta-analysis adopted a unique approach by categorizing moderating variables into two distinct groups: the objective characteristics of research subjects and the subjective characteristics of researchers. It sheds light on the multifaceted factors that influence the relationship between loneliness and Internet addiction.

Results

A literature search in web of science yielded 32 independent effect sizes involving 35,623 subjects. Heterogeneity testing indicated that a random effects model was appropriate. A funnel plot and Begg and Mazumdar’s rank correlation test revealed no publication bias in this meta-analysis. Following the effect size test, it was evident that loneliness was significantly and positively correlated with Internet addiction (r = 0.291,p < 0.001). The moderating effect analysis showed that objective characteristics significantly affected the relationship. However, subjective characteristics did not affect the relationship.

Conclusions

The study revealed a moderately positive correlation between loneliness and Internet addiction. Moreover, this correlation’s strength was found to be influenced by various factors, including gender, age, grade, and the region of the subjects. However, it was not affected by variables such as the measurement tool, research design, or research year (whether before or after COVID-19).
Incidence and sequence of scoliosis and windswept hip deformity: which comes first in 4148 children with cerebral palsy? A longitudinal cohort study
Authors: Casey Jackie , Rosenblad Andreas , Agustsson Atli , Lauge-Pedersen Henrik , Rodby-Bousquet Elisabet
Published: March 2024

Background

The aim was to analyse whether scoliosis or windswept hip deformity (WSH) occurs first for children with cerebral palsy (CP).

Methods

This longitudinal cohort study using data from 1994 − 2020 (26 years) involved 41,600 measurements of 4148 children (2419 [58.3%] boys) with CP born 1990 − 2018 and registered into the Swedish CP follow-up program. Children were followed from a mean age of 2.8 [SD 1.4] years, until they developed either scoliosis or WSH or were removed at surgery.

Results

WSH developed first in 16.6% of the children (mean age 8.1 [SD 5.0] years), and scoliosis in 8.1% (mean age 8.1 [SD 4.9] years). The incidence of WSH was higher than scoliosis across all levels I–V of the Gross Motor Function Classification System (GMFCS), both sexes, and for those with dyskinetic (20.0%) or spastic (17.0%) CP. The incidence of scoliosis was highest (19.8%) and developed earliest in children with GMFCS level V (mean age 5.5 [SD 3.5] years), and in children with dyskinetic (17.9%) CP (mean age 7.0 [SD 4.7] years).

Conclusions

WSH presents earlier than scoliosis in most children with CP. Children with higher GMFCS level or dyskinetic CP are more likely to develop these deformities at a younger age.
Coping with breast cancer during medical and occupational rehabilitation: a qualitative study of strategies and contextual factors
Authors: Heidkamp Paula , Hiltrop Kati , Breidenbach Clara , Kowalski Christoph , Pfaff Holger , Geiser Franziska , Ernstmann Nicole
Published: March 2024

Purpose

This study aimed to gain a deeper understanding of the coping processes of breast cancer survivors (BCSs) during medical and occupational rehabilitation after acute treatment.

Methods

This study is part of the mixed-methods Breast Cancer Patients’ Return to Work study conducted in Germany. Data were collected through semistructured interviews with 26 female BCSs 5–6 years after their diagnosis. A qualitative content analysis was conducted to investigate the coping strategies and contextual factors of coping of BCSs.

Results

The participants used different strategies for coping with their breast cancer, namely, approach- versus avoidance-oriented coping and emotion- versus problem-focused coping. During the medical rehabilitation process, coping behavior was used mainly to address disease management and its consequences. During the occupational rehabilitation process, most coping strategies were used to overcome discrepancies between the patient’s current work capacity and the job requirements. The contextual factors of coping were in the health, healthcare, work-related, and personal domains.

Conclusion

The study findings provide in-depth insights into the coping processes for BCSs during the rehabilitation phase and highlight the importance of survivorship care after acute cancer treatment.

Implications for Cancer survivors

The results indicate that BCSs employ approach- and avoidance-oriented strategies to cope with their cancer during rehabilitation. As both attempts are helpful in the short term to cope with physical and emotional consequences of the cancer, healthcare and psychosocial personnel should respect the coping strategies of BCSs while also being aware of the potential long-term negative impact of avoidance-oriented coping on the rehabilitation process.
The economic burden of obesity in 4 south-eastern European countries associated with obesity-related co-morbidities
Authors: Athanasakis Kostas , Bala Cornelia , Kokkinos Alexander , Simonyi Gabor , Karoliová Klaudia Hálová , Basse Amaury , Bogdanovic Miodrag , Kang Malvin , Low Kaywei , Gras Adrien
Published: March 2024

Objective

To provide an assessment of the cost burden of obesity across a spectrum of obesity-related comorbidities (ORCs) for four countries in South-Eastern Europe (SEE).

Methods

A micro-costing analysis from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Czech Republic, Greece, Hungary, and Romania. A survey was administered to obtain healthcare resource use and unit cost data. Cost estimates were validated by local steering committees which comprised at least one public sector clinician and a panel of independent industry experts.

Results

Chronic kidney disease and cardiovascular diseases were the costliest ORCs across all 4 countries, where annual cost burden per ORC exceeded 1,500 USD per patient per year. In general, costs were driven by the tertiary care resources allocated to address treatment-related adverse events, disease complications, and associated inpatient procedures.

Conclusions

Our findings confirm that the high prevalence of obesity and its comorbidities result in substantial financial burden to all 4 SEE public payers. By quantifying the burden of obesity from a public healthcare perspective, our study aims to support policy efforts that promote health education and promotion in combating obesity in the region.
The role of sialidase Neu1 in respiratory diseases
Authors: Mei Shiran , Li Dingding , Wang Aoyi , Zhu Guoxue , Zhou Bingwen , Li Nian , Qin Yi , Zhang Yanliang , Jiang Shujun
Published: March 2024

Neu1 is a sialidase enzyme that plays a crucial role in the regulation of glycosylation in a variety of cellular processes, including cellular signaling and inflammation. In recent years, numerous evidence has suggested that human NEU1 is also involved in the pathogenesis of various respiratory diseases, including lung infection, chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. This review paper aims to provide an overview of the current research on human NEU1 and respiratory diseases.
Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study
Authors: Chiu Li-Chung , Lee Chung-Shu , Hsu Ping-Chih , Li Hsin-Hsien , Chan Tien-Ming , Hsiao Ching-Chung , Kuo Scott Chih-Hsi , Ko How-Wen , Lin Shu-Min , Wang Chun-Hua , Lin Horng-Chyuan , Chu Pao-Hsien , Yen Tzung-Hai
Published: March 2024

Background

Cadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19).

Methods

We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed.

Results

A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060–2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 μg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118–25.580], p = 0.036).

Conclusions

Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.
Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism
Authors: Zhao Yuying , Tan Hanxu , Zhang Juping , Zhan Dandan , Yang Bowen , Hong Shicui , Pan Bo , Wang Neng , Chen Tongkai , Shi Yafei , Wang Zhiyu
Published: March 2024

Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

Graphical Abstract
HairNet2: deep learning to quantify cotton leaf hairiness, a complex genetic and environmental trait
Authors: Farazi Moshiur , Conaty Warren C. , Egan Lucy , Thompson Susan P. J. , Wilson Iain W. , Liu Shiming , Stiller Warwick N. , Petersson Lars , Rolland Vivien
Published: March 2024

Background

Cotton accounts for 80% of the global natural fibre production. Its leaf hairiness affects insect resistance, fibre yield, and economic value. However, this phenotype is still qualitatively assessed by visually attributing a Genotype Hairiness Score (GHS) to a leaf/plant, or by using the HairNet deep-learning model which also outputs a GHS. Here, we introduce HairNet2, a quantitative deep-learning model which detects leaf hairs (trichomes) from images and outputs a segmentation mask and a Leaf Trichome Score (LTS).

Results

Trichomes of 1250 images were annotated (AnnCoT) and a combination of six Feature Extractor modules and five Segmentation modules were tested alongside a range of loss functions and data augmentation techniques. HairNet2 was further validated on the dataset used to build HairNet (CotLeaf-1), a similar dataset collected in two subsequent seasons (CotLeaf-2), and a dataset collected on two genetically diverse populations (CotLeaf-X). The main findings of this study are that (1) leaf number, environment and image position did not significantly affect results, (2) although GHS and LTS mostly correlated for individual GHS classes, results at the genotype level revealed a strong LTS heterogeneity within a given GHS class, (3) LTS correlated strongly with expert scoring of individual images.

Conclusions

HairNet2 is the first quantitative and scalable deep-learning model able to measure leaf hairiness. Results obtained with HairNet2 concur with the qualitative values used by breeders at both extremes of the scale (GHS 1-2, and 5-5+), but interestingly suggest a reordering of genotypes with intermediate values (GHS 3-4+). Finely ranking mild phenotypes is a difficult task for humans. In addition to providing assistance with this task, HairNet2 opens the door to selecting plants with specific leaf hairiness characteristics which may be associated with other beneficial traits to deliver better varieties.
Effectiveness and safety of tourniquet utilization for civilian vascular extremity trauma in the pre-hospital settings: a systematic review and meta-analysis
Authors: Ko Ying-Chih , Tsai Tou-Yuan , Wu Chien-Kai , Lin Kai-Wei , Hsieh Ming-Ju , Lu Tzu-Pin , Matsuyama Tasuku , Chiang Wen-Chu , Ma Matthew Huei-Ming
Published: March 2024

Background

Tourniquets (TQ) have been increasingly adopted in pre-hospital settings recently. This study examined the effectiveness and safety of applying TQ in the pre-hospital settings for civilian patients with traumatic vascular injuries to the extremities.

Materials and methods

We systematically searched the Ovid Embase, PubMed, and Cochrane Central Register of Controlled Trials databases from their inception to June 2023. We compared pre-hospital TQ (PH-TQ) use to no PH-TQ, defined as a TQ applied after hospital arrival or no TQ use at all, for civilian vascular extremity trauma patients. The primary outcome was overall mortality rate, and the secondary outcomes were blood product use and hospital stay. We analyzed TQ-related complications as safety outcomes. We tried to include randomized controlled trials (RCTs) and non-randomized studies (including non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies, and case-control studies), if available. Pooled odds ratios (ORs) were calculated and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.

Results

Seven studies involving 4,095 patients were included. In the primary outcome, pre-hospital TQ (PH-TQ) use significantly decrease mortality rate in patients with extremity trauma (odds ratio [OR], 0.48, 95% confidence interval [CI] 0.27–0.86, I2 = 47%). Moreover, the use of PH-TQ showed the decreasing trend of utilization of blood products, such as packed red blood cells (mean difference [MD]: -2.1 [unit], 95% CI: -5.0 to 0.8, I2 = 99%) or fresh frozen plasma (MD: -1.0 [unit], 95% CI: -4.0 to 2.0, I2 = 98%); however, both are not statistically significant. No significant differences were observed in the lengths of hospital and intensive care unit stays. For the safety outcomes, PH-TQ use did not significantly increase risk of amputation (OR: 0.85, 95% CI: 0.43 to 1.68, I2 = 60%) or compartment syndrome (OR: 0.94, 95% CI: 0.37 to 2.35, I2 = 0%). The certainty of the evidence was very low across all outcomes.

Conclusion

The current data suggest that, in the pre-hospital settings, PH-TQ use for civilian patients with vascular traumatic injury of the extremities decreased mortality and tended to decrease blood transfusions. This did not increase the risk of amputation or compartment syndrome significantly.
Later aorta operation after aortic valve replacement for bicuspid aortic valve
Authors: Hachiro Kohei , Takashima Noriyuki , Suzuki Tomoaki
Published: March 2024

Background

We investigated long-term outcomes, particularly later aorta operations and overall death in patients who underwent aortic valve replacement for bicuspid aortic valve without aortic surgery.

Methods

Between January 2002 and December 2022, 274 patients underwent aortic valve replacement for bicuspid aortic valve at our institution. Of them, 181 patients who did not undergo aortic surgery, in accordance with current guidelines, were analyzed retrospectively.

Results

The median follow-up duration was 6.1 (2.0–10.6) years, and follow-up was completed in 97.8% of pateints. There were 3 patients (1.7%) who underwent later aorta operation during follow-up period. The cumulative later aorta operation rate at 10 years adjusting overall death as competing risk was 16.3%, and the estimated rates of freedom from overall death at 10 years was 83.7%. Fine-Gray competing risk regression model showed that aortic valve stenosis was only the predictor of later aorta operation (hazard ratio 8.477; p = 0.012). In multivariable Cox models, predictors of overall death were aortic valve stenosis (hazard ratio: 8.270, 95% confidence interval: 1.082–63.235; p = 0.042) and operation time (hazard ratio: 1.011, 95% confidence interval: 1.004–1.017; p = 0.002).

Conclusions

Patients with bicuspid aortic valve with ascending aortic diameter less than 45 mm are at low risk of later aorta operation after isolated aortic valve replacement.
Anaplastic thyroid cancer spheroids as preclinical models to test therapeutics
Authors: Hu Jiangnan , Liu Kaili , Ghosh Chandrayee , Khaket Tejinder Pal , Shih Helen , Kebebew Electron
Published: March 2024

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for ATC spheroid culture is yet to be developed. In this study, we created an efficient and cost-effective 3D tumor spheroids culture system from human ATC cells and existing cell lines that better mimic patient tumors and that can enhance our understanding of in vivo treatment response. We found that patient-derived ATC cells and cell lines can readily form spheroids in culture with a unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and discohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAFWT ATC spheroids grew in a cohesive pattern, while BRAFV600E-mutant ATC spheroids had a discohesive organization. In the patient-derived BRAFV600E-mutant ATC spheroids, we observed both growth patterns, but mostly the discohesive type. Histologically, ATC spheroids had a similar morphology to the patient’s tumor through H&E staining and proliferation marker staining. Moreover, RNA sequencing analysis revealed that the gene expression profile of tumor cells derived from the spheroids closely matched parental patient tumor-derived cells in comparison to monolayer cultures. In addition, treatment response to combined BRAF and MEK inhibition in BRAFV600E-mutant ATC spheroids exhibited a similar sensitivity to the patient clinical response. Our study provides a robust and novel ex vivo spheroid model system that can be used in both established ATC cell lines and patient-derived tumor samples to better understand the biology of ATC and to test therapeutics.
LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4
Authors: Li Zhenchong , Ma Zuyi , Wang Shujie , Yan Qian , Zhuang Hongkai , Zhou Zixuan , Liu Chunsheng , Chen Yubin , Han Mingqian , Wu Zelong , Huang Shanzhou , Zhou Qi , Hou Baohua , Zhang Chuanzhao
Published: March 2024

Background

Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis.

Methods

The expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People’s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied.

Results

LINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models.

Conclusion

We demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.
Lipopolysaccharide regulation of antiinflammatory tristetraprolin family and proinflammatory gene expression in mouse macrophages
Authors: Cao Heping
Published: March 2024

Objective

Tristetraprolin (TTP/ZFP36) family proteins exhibit antiinflammatory effects by destabilizing proinflammatory mRNAs. Previous studies showed that bacterial endotoxin lipopolysaccharides (LPS) stimulated TTP and tumor necrosis factor (TNF) gene expression, but less was known about LPS effects on TTP homologues and other proinflammatory gene expression in macrophages. The objective was to investigate LPS regulation of TTP family gene and TTP-targeted gene expression in mouse RAW264.7 macrophages using much higher concentrations of LPS and much longer treatment time than previous studies.

Results

MTT assay showed that LPS was not toxic to the cells under LPS treatment up to 1000 ng/mL for 2–24 h. LPS mildly affected the soluble protein content in the cells. qPCR assay showed that LPS stimulated TTP mRNA rapidly but not sustainably with 40, 10, and 3 fold of the DMSO control after 2, 8 and 24 h treatment, respectively. Immunoblotting confirmed qPCR results on LPS stimulation of TTP gene expression in the mouse macrophages. LPS exhibited minimal effects on ZFP36L1, ZFP36L2 and ZFP36L3 mRNA levels. LPS increased mRNA levels of TNF, COX2, GM-CSF, INFγ and IL12b up to 311, 418, 11, 9 and 4 fold, respectively. This study demonstrated that LPS did not affect macrophage viability, dramatically increased antiinflammatory TTP gene expression as well as proinflammatory TNF and COX2 gene expression but had only mild effects on TTP homologues and other proinflammatory cytokine gene expression in the mouse macrophages.
Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer’s disease
Authors: Verma Parul , Ranasinghe Kamalini , Prasad Janani , Cai Chang , Xie Xihe , Lerner Hannah , Mizuiri Danielle , Miller Bruce , Rankin Katherine , Vossel Keith , Cheung Steven W. , Nagarajan Srikantan S. , Raj Ashish
Published: March 2024

Background

Alzheimer’s disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).

Methods

SGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).

Results

Patients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.

Conclusions

These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.
A novel reporting workflow for automated integration of artificial intelligence results into structured radiology reports
Authors: Jorg Tobias , Halfmann Moritz C. , Stoehr Fabian , Arnhold Gordon , Theobald Annabell , Mildenberger Peter , Müller Lukas
Published: March 2024

Objectives

Artificial intelligence (AI) has tremendous potential to help radiologists in daily clinical routine. However, a seamless, standardized, and time-efficient way of integrating AI into the radiology workflow is often lacking. This constrains the full potential of this technology. To address this, we developed a new reporting pipeline that enables automated pre-population of structured reports with results provided by AI tools.

Methods

Findings from a commercially available AI tool for chest X-ray pathology detection were sent to an IHE-MRRT-compliant structured reporting (SR) platform as DICOM SR elements and used to automatically pre-populate a chest X-ray SR template. Pre-populated AI results could be validated, altered, or deleted by radiologists accessing the SR template. We assessed the performance of this newly developed AI to SR pipeline by comparing reporting times and subjective report quality to reports created as free-text and conventional structured reports.

Results

Chest X-ray reports with the new pipeline could be created in significantly less time than free-text reports and conventional structured reports (mean reporting times: 66.8 s vs. 85.6 s and 85.8 s, respectively; both p < 0.001). Reports created with the pipeline were rated significantly higher quality on a 5-point Likert scale than free-text reports (p < 0.001).

Conclusion

The AI to SR pipeline offers a standardized, time-efficient way to integrate AI-generated findings into the reporting workflow as parts of structured reports and has the potential to improve clinical AI integration and further increase synergy between AI and SR in the future.

Critical relevance statement

With the AI-to-structured reporting pipeline, chest X-ray reports can be created in a standardized, time-efficient, and high-quality manner. The pipeline has the potential to improve AI integration into daily clinical routine, which may facilitate utilization of the benefits of AI to the fullest.

Key points

• A pipeline was developed for automated transfer of AI results into structured reports.

• Pipeline chest X-ray reporting is faster than free-text or conventional structured reports.

• Report quality was also rated higher for reports created with the pipeline.

• The pipeline offers efficient, standardized AI integration into the clinical workflow.

Graphical Abstract
Dapagliflozin promotes white adipose tissue browning though regulating angiogenesis in high fat induced obese mice
Authors: Xiang Lin , Liu Min , Xiang Guangda , Yue Ling , Zhang Junxia , Xu Xiaoli , Dong Jing
Published: March 2024

Browning of white adipose tissue (WAT) is become an appealing target for therapeutics in the treatment of obesity and related metabolic diseases. Dapagliflozin is widely used in the treatment of type 2 diabetes, and it is also found that the drug exhibits regulate systemic metabolism such as obesity, insulin resistance and hepatic steatosis. However, the precise role of dapagliflozin on WAT remodeling remains to be elucidated. The current study aimed to explore the role of dapagliflozin on WAT browning in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice (n = 6 per group) were used to establish obesity model by following feeding with HFD for 6 weeks. The mice were randomly treated with or without dapagliflozin for the experimental observation. The volume and fat fraction of WAT were quantified, H&E, UCP-1 staining and immunohistochemistry were conducted to investigate the white-to-brown fat conversion and angiogenesis in WAT respectively. Quantitative real-time polymerase chain reaction (qPCR) was employed to explore the mRNA expression levels of genes related to fat browning and angiogenesis in WAT. Subsequently, 3T3-L1 cells were used to explore the effect of dapagliflozin on preadipocytes differentiation in vitro. Our results demonstrated that dapagliflozin could reduce body weight gain and promote WAT browning in HFD induced obese mice via regulating lipogenesis and angiogenesis in WAT. Furthermore, dapagliflozin reduce cells differentiation, up-regulate the expression of WAT browning and angiogenesis genes in 3T3-L1 adipocytes in vitro. In conclusion, dapagliflozin can potentially promote WAT browning in HFD induced obese mice via improving lipogenesis and angiogenesis in WAT.
Quantitative characteristics and influencing factors of Tibetan Buddhist religious space with monasteries as the carrier: a case study of U-Tsang, China
Authors: Fang Subin , Zhao Yaolong , Liu Xinxin , Yang Yao
Published: March 2024

Tibetan Buddhism has an inseparable connection with the spatial characteristics, development process, and human-natural environment of the Tibetan Plateau. This paper takes monasteries as carriers of Tibetan Buddhist culture in U-Tsang region which is one of the traditional geographical units of Tibet. Using geospatial analysis methods, this study explores the spatial quantification characteristics of Tibetan Buddhist monasteries and qualitatively and quantitatively analyzes the factors that influence the spatial distribution of monasteries. The results indicate that: (1) Political activities of human society influence the pattern of political power. Under the unique context of Tibetan theocracy system, the scope of political authority has a significant influence and affects the religious spatial pattern in the U-Tsang region throughout history. The distribution of monasteries in the U-Tsang region shows significant spatial differences at three sub-regional scales. (2) The religious spatial pattern in the U-Tsang is the result of the diverse interaction of human-natural factors. The results indirectly endorse that religious space is an inevitable product of the interaction between humans and the environment. (3) The religious spatial distribution patterns in the three major Tibetan regions have distinct characteristics, closely related to the superior conditions of their respective historical and geographical environments.