bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage
Authors: Chang Hanxiao , Li Zheng , Zhang Weiwei , Lin Chao , Shen Yuqi , Zhang Guangjian , Mao Lei , Ma Chencheng , Liu Ning , Lu Hua
Published: January 2024

Primary subarachnoid hemorrhage (SAH) is a type of acute stroke, accounting for approximately 10% of cases, with high disability and mortality rate. Early brain injury (EBI) is a critical factor in determining SAH mortality; however, there are no effective treatment interventions for EBI. Based on our results, the transmission of cyclic GMP-AMP (cGAMP) from neurons to microglia is a key molecular event that triggers type I interferon response, amplifies neuroinflammation, and leads to neuronal apoptosis. Abnormal intracytoplasmic mitochondrial DNA (mtDNA) is the initiating factor of the cGAS-cGAMP-STING signaling axis. Overall, the cGAS-cGAMP-STING signaling axis is closely associated with neuroinflammation after subarachnoid hemorrhage. Targeting cGAS triggered by cytoplasmic mtDNA may be useful for comprehensive clinical treatment of patients after SAH. Further studies targeting cGAS-specific antagonists for treating SAH are warranted.
Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer
Authors: Hussain Zainab , Bertran Thomas , Finetti Pascal , Lohmann Eugenie , Mamessier Emilie , Bidaut Ghislain , Bertucci François , Rego Moacyr , Tomasini Richard
Published: January 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) remains a clinically challenging cancer, mainly due to limited therapeutic options and the presence of a highly prominent tumor microenvironment (TME), facilitating tumor progression. The TME is predominated by heterogeneous populations of cancer-associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), in constant communication with each other and with tumor cells, influencing many tumoral abilities such as therapeutic resistance. However how the crosstalk between CAFs and macrophages evolves following chemotherapeutic treatment remains poorly understood, limiting our capacity to halt therapeutic resistance.

Methods

We combined biological characterization of macrophages indirectly cocultured with human PDAC CAFs, under FOLFIRINOX treatment, with mRNAseq analyses of such macrophages and evaluated the relevance of the specific gene expression signature in a large series of primary PDAC patients to search for correlation with overall survival (OS) after FOLFIRINOX chemotherapy.

Results

Firstly, we demonstrated that CAFs polarize naïve and M1 macrophages towards an M2-like phenotype with a specific increase of CD200R and CD209 M2 markers. Then, we demonstrated that CAFs counteract the pro-inflammatory phenotype induced by the FOLFIRINOX on Macrophages. Indeed, we highlighted that, under FOLFIRINOX, CAFs limit the FOLFIRINOX-induced cell death of macrophages and further reinforce their M2 phenotype as well as their immunosuppressive impact through specific chemokines production. Finally, we revealed that under FOLFIRINOX CAFs drive a specific macrophage gene expression signature involving SELENOP and GOS2 that correlates with shortened OS in FOLFIRINOX-treated PDAC patients.

Conclusion

Our study provides insight into the complex interactions between TME cells under FOLFIRINOX treatment. It suggests potential novel candidates that could be used as therapeutic targets in combination with FOLFIRINOX to prevent and alleviate TME influx on therapeutic resistance as well as biomarkers to predict FOLFIRINOX response in PDAC patients.
Characterization of gastric cancer-stimulated signaling pathways and function of CTGF in cancer-associated fibroblasts
Authors: Choi Kyoung-Min , Kim Boram , Lee Su-Min , Han Jisoo , Bae Ha-Song , Han Su-Bhin , Lee Dagyeong , Ham In-Hye , Hur Hoon , Kim Eunjung , Kim Jae-Young
Published: January 2024

Background

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC.

Methods

Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay.

Results

We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model.

Conclusions

This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC.
Development and content validity of an application to assess 24-hour movement behaviors in 0–4-year-old children involving end-users and key stakeholders: the My Little Moves app
Authors: Arts Jelle , Chinapaw Mai J. M. , Gubbels Jessica S. , Verhoeff Arnoud P. , Brons Annette , Veldman Sanne , Lettink Annelinde , Altenburg Teatske M.
Published: January 2024

Background

Recently, research focus has shifted to the combination of all 24-h movement behaviors (physical activity, sedentary behavior and sleep) instead of each behavior separately. Yet, no reliable and valid proxy-report tools exist to assess all these behaviors in 0–4-year-old children. By involving end-users (parents) and key stakeholders (researchers, professionals working with young children), this mixed-methods study aimed to 1) develop a mobile application (app)-based proxy-report tool to assess 24-h movement behaviors in 0–4-year-olds, and 2) examine its content validity.

Methods

First, we used concept mapping to identify activities 0–4-year-olds engage in. Parents (n = 58) and professionals working with young children (n = 21) generated a list of activities, sorted related activities, and rated the frequency children perform these activities. Second, using multidimensional scaling and cluster analysis, we created activity categories based on the sorted activities of the participants. Third, we developed the My Little Moves app in collaboration with a software developer. Finally, we examined the content validity of the app with parents (n = 14) and researchers (n = 6) using focus groups and individual interviews.

Results

The app has a time-use format in which parents proxy-report the activities of their child, using eight activity categories: personal care, eating/drinking, active transport, passive transport, playing, screen use, sitting/lying calmly, and sleeping. Categories are clarified by providing examples of children’s activities. Additionally, 1–4 follow-up questions collect information on intensity (e.g., active or calm), posture, and/or context (e.g., location) of the activity. Parents and researchers considered filling in the app as feasible, taking 10–30 min per day. The activity categories were considered comprehensive, but alternative examples for several activity categories were suggested to increase the comprehensibility and relevance. Some follow-up questions were considered less relevant. These suggestions were adopted in the second version of the My Little Moves app.

Conclusions

Involving end-users and key stakeholders in the development of the My Little Moves app resulted in a tailored tool to assess 24-h movement behaviors in 0–4-year-olds with adequate content validity. Future studies are needed to evaluate other measurement properties of the app.
Potential roles of the interactions between gut microbiota and metabolites in LPS-induced intrauterine inflammation (IUI) and associated preterm birth (PTB)
Authors: Jia Bei , Tang Lijun , Liu Huibing , Chen Wenqian , Chen Qian , Zhong Mei , Yin Ailan
Published: January 2024

Background

Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in preterm birth (PTB) pathophysiology, increasing the incidence of neurodevelopmental disorders. Gut microbiota and metabolite profile alterations have been reported to be involved in PTB pathophysiology.

Method and results

In this study, IUI-exposed PTB mouse model was established and verified by PTB rate and other perinatal adverse reactions; LPS-indued IUI significantly increased the rates of PTB, apoptosis and inflammation in placenta tissue samples. LPS-induced IUI caused no significant differences in species richness and evenness but significantly altered the species abundance distribution. Non-targeted metabolomics analysis indicated that the metabolite profile of the preterm mice was altered, and differential metabolites were associated with signaling pathways including pyruvate metabolism. Furthermore, a significant positive correlation between Parasutterella excrementihominis and S4572761 (Nb-p-coumaroyltryptamine) and Mreference-1264 (pyruvic acid), respectively, was observed. Lastly, pyruvic acid treatment partially improved LPS-induced IUI phenotypes and decreased PTB rates and decreased the apoptosis and inflammation in placenta tissue samples.

Conclusion

This study revealed an association among gut microbiota dysbiosis, metabolite profile alterations, and LPS-induced IUI and PTB in mice models. Our investigation revealed the possible involvement of gut microbiota in the pathophysiology of LPS-induced IUI and PTB, which might be mediated by metabolites such as pyruvic acid. Future studies should be conducted to verify the findings through larger sample-sized animal studies and clinical investigations.
The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-induced kidney injury
Authors: Yan Xinzhou , Xia Yuqi , Li Bojun , Ye Zehua , Li Lei , Yuan Tianhui , Song Baofeng , Yu Weimin , Rao Ting , Ning Jinzhuo , Lin Fangyou , Mei Shuqin , Mao Zhiguo , Zhou Xiangjun , Li Wei , Cheng Fan
Published: January 2024

Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.

Graphical Abstract
Bladder cancer risk stratification with the Oncuria 10-plex bead-based urinalysis assay using three different Luminex xMAP instrumentation platforms
Authors: Furuya Hideki , Sakatani Toru , Tanaka Sunao , Murakami Kaoru , Waldron Richard T. , Hogrefe Wayne , Rosser Charles J.
Published: January 2024

Background

No single marker of bladder cancer (BC) exists in urine samples with sufficient accuracy for disease diagnosis and treatment monitoring. The multiplex Oncuria BC assay noninvasively quantifies the concentration of 10 protein analytes in voided urine samples to quickly generate a unique molecular profile with proven BC diagnostic and treatment-tracking utility. Test adoption by diagnostic and research laboratories mandates reliably reproducible assay performance across a variety of instrumentation platforms used in different laboratories.

Methods

We compared the performance of the clinically validated Oncuria BC multiplex immunoassay when data output was generated on three different analyzer systems. Voided urine samples from 36 subjects (18 with BC and 18 Controls) were reacted with Oncuria test reagents in three 96-well microtiter plates on Day 1, and consecutively evaluated on the LED/image-based MagPix, and laser/flow-based Luminex 200 and FlexMap 3D (all xMAP instruments from Luminex Corp., Austin, TX) on Day 2. The BC assay uses magnetic bead-based fluorescence technology (xMAP, Multi-analyte profiling; Luminex) to simultaneously quantify 10 protein analytes in urine specimens [i.e., angiogenin (ANG), apolipoprotein E (ApoE), carbonic anhydrase IX (CA9), CXCL8/interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-10 (MMP-10), serpin A1/alpha-1 anti-trypsin (A1AT), serpin E1/plasminogen activator inhibitor-1 (PAI-1), CD138/syndecan-1 (SDC1), and vascular endothelial growth factor-A (VEGF-A)]. All three analyzers quantify fluorescence signals generated by the Oncuria assay.

Results

All three platforms categorized all 10 analytes in identical samples at nearly identical concentrations, with variance across systems typically < 5%. While the most contemporary instrument, the FlexMap 3D, output higher raw fluorescence values than the two comparator systems, standard curve slopes and analyte concentrations determined in urine samples were concordant across all three units. Forty-four percent of BC samples registered ≥ 1 analyte above the highest standard concentration, i.e., A1AT (n = 7/18), IL-8 (n = 5), and/or ANG (n = 2), while only one control sample registered an analyte (A1AT) above the highest standard concentration.

Conclusion

Multiplex BC assays generate detailed molecular signatures useful for identifying BC, predicting treatment responsiveness, and tracking disease progression and recurrence. The similar performance of the Oncuria assay across three different analyzer systems supports test adaptation by clinical and research laboratories using existing xMAP platforms.

Trial Registration: This study was registered at ClinicalTrials.gov as NCT04564781, NCT03193528, NCT03193541, and NCT03193515.
Prospective study to characterize adalimumab exposure in pediatric patients with rheumatic diseases
Authors: Welzel Tatjana , Golhen Klervi , Atkinson Andrew , Gotta Verena , Ternant David , Kuemmerle-Deschner Jasmin B. , Michler Christine , Koch Gilbert , van den Anker Johannes N. , Pfister Marc , Woerner Andreas
Published: January 2024

Background

In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2–8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate.

Methods

A two-center prospective study in PRD patients aged 2–18 years treated with adalimumab and methotrexate (GA-M) or adalimumab alone (GA) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1–9 (maximum concentration; Cmax), and 10–14 days (minimum concentration; Cmin) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized Cmin were compared between GA-M and GA using a standard t-test.

Results

Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. GA-M included more females (71.4%; GA 35.7%, p = 0.13). At first study visit, children in GA-M had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to GA (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in GA-M had a 27% higher median overall exposure compared to GA, although median Cmin adalimumab values were statistically not different (p = 0.3). Cmin values ≥ 8 mg/L (upper limit RA) were more frequently observed in GA-M versus GA (79% versus 64%). Overall, a wide range of Cmin values was observed in PRD (0.5 to 26 mg/L).

Conclusion

This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure.

Trial registration

NCT04042792, registered 02.08.2019.
Pediatrics severe low back pain by disc herniation: an uncommon entity
Authors: Tiendrebeogo/Zabsonre Wendlassida Joelle Stéphanie , Zabsonre Denlewende Sylvain , Kabore Fulgence , Sanou Abdoulaye , Haro Yakouba , Zoungrana Inoussa , Ouedraogo Dieu-Donné
Published: January 2024

Background

Common severe back pain due to disc herniation is rare in the paediatric population which involves children under eighteen years of age. Paediatric lumbar disc herniation (LDH) cannot be considered the same disease as in adults, as it has potentially different natural and clinical backgrounds. The treatment of pediatric LDH is the other particularity of this condition. Indeed, in children, delaying surgery for a conservative treatment is justified. We report 3 cases treated in 8 years.

Case presentation

Three patients, two of whom were 14 years of age and one 17 years of age, were admitted for L5 or S1 lumbosciatica. A CT scan showed a lumbar disc herniation L5S1 associated with bi-isthmic lysis (and a transitional abnormality in 1 case or spina bifida occulta in 1 other case). The last patient had an magnetic resonance imaging (MRI) that showed a herniated L4L5 disc. The diagnosis of low back pain disc herniation was retained in two patients and that of disabling low back disc in one patient. Percutaneous discolysis in the two hyperalgesic cases and epidural corticosteroid infiltration in the disabling case were effective on lumbosciatica.

Conclusion

Paediatric common lomw back pain caused by a disc herniation with a hyperalgic or disabling character posed a therapeutic problem which were solved by the invasive approaches that must be given priority nowadays with children.
Helicobacter pylori infection and Parkinson’s Disease: etiology, pathogenesis and levodopa bioavailability
Authors: Wei Bang-rong , Zhao Yu-jia , Cheng Yu-feng , Huang Chun , Zhang Feng
Published: January 2024

Parkinson’s disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.
Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake
Authors: Wu Kay L. H. , Wu Chih-Wei , Chen Lee-Wei , Chang Hsiao-Huang , Cheng Ching-Li , Wu Cai-Yi , Lee Yu-Chi , Chen I-Chun , Hung Chun-Ying , Liu Wen-Chung
Published: January 2024

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.
Preliminary exploration of herbal tea products based on traditional knowledge and hypotheses concerning herbal tea selection: a case study in Southwest Guizhou, China
Authors: Long Xiaofeng , Ranjitkar Sailesh , Waldstein Anna , Wu Huan , Li Qingqing , Geng Yanfei
Published: January 2024

Background

Herbal tea usually refers to “beverage plants that do not belong to the genus Camellia”, and it holds a significant historical legacy as a traditional beverage among specific regions and ethnic groups. In light of this, our research aims to investigate and analyze the traditional knowledge pertaining to herbal tea plants used by local people in the Qianxinan Buyi and Miao Autonomous Prefecture, Guizhou Province. We also initiated preliminary efforts to create tea products from herbal tea leaves using various processing techniques. Additionally, we attempted to test hypotheses to elucidate how local people select herbal tea plants.

Methods

Data related to the use of herbal tea plants in this study were collected through semi-structured interviews and participatory observations in four villages in Qianxinan. Quantitative indicators, including the relative frequency of citation (RFC) and the relative importance (RI) value, were calculated, and the availability of plants was also evaluated. General linear model was performed to examine the relationship between the frequency of citation and resource availability, as well as the correlation between the relative frequency of citation and the relative importance, to test both the resource availability hypothesis and the versatility hypothesis. Centella asiatica tea was processed using techniques from green tea, black tea and white tea, with a preliminary sensory evaluation conducted.

Results

A total of 114 plant species were documented as being used for herbal teas by local residents, representing 60 families and 104 genera. Of these, 61% of herbal tea plants were found growing in the wild, and 11 species were exotic plants. The family with the highest number of species was Asteraceae (20 species). The study identified 33 major medicinal functions of herbal tea, with clearing heat-toxin and diuresis being the most common functions. General linear model revealed a strong correlation (correlation coefficient of 0.72, p < 0.001) between the frequency of citation and plant availability, as well as a significant correlation (correlation coefficient of 0.63, p < 0.001) between RFC and RI. Under different processing conditions, the characteristics of Centella asiatica tea exhibited variations and were found to be suitable for consumption.

Conclusion

The consumption of herbal tea serves as a preventive measure against common ailments for local residents. The resource availability hypothesis, diversification hypothesis and the versatility hypothesis were shown to provide some insight into “how and why local communities select plants for use.” Exotic herbal tea plants in the study area also possess valuable therapeutic properties. The processing and production of Centella asiatica herbal tea products hold promising prospects.
Stereotactic body radiotherapy for early-stage lung cancer: a systematic review on the choice of photon energy and linac flattened/unflattened beams
Authors: Gill Ashlesha , Hirst Andrew L , Rowshanfarzad Pejman , Gill Suki , Bucknell Nicholas , Dass Joshua , Sabet Mahsheed
Published: January 2024

SBRT is an effective local treatment for patients with early-stage non-small cell lung cancer (NSCLC). This treatment is currently used in patients who have poor lung function or who decline surgery. As SBRT usually has small PTV margins, reducing the beam-on-time (BOT) is beneficial for accurate dose delivery by minimising intrafraction motion as well as improved patient comfort. Removal of the linear accelerator flattening filter can provide a higher dose rate which results in a faster treatment. In addition, the choice of photon energy can also affect the dose distribution to the target and the organs-at-risk (OAR). In this systematic review, studies analysing the choice of various photon beam energies, with a flattening filter or flattening filter free (FFF), were compared for their overall dosimetric benefit in the SBRT treatment for early-stage NSCLC. It was found that FFF treatment delivers a comparatively more conformal dose distribution, as well as a better homogeneity index and conformity index, and typically reduces BOT by between 30 and 50%. The trade-off may be a minor increase in monitor units for FFF treatment found in some studies but not others. Target conformity and OAR sparing, particularly lung doses appear better with 6MV FFF, but 10MV FFF was marginally more advantageous for skin sparing and BOT reduction. The favourable beam modality for clinical use would depend on the individual case, for which tumour size and depth, radiotherapy technique, as well as fractionation scheme need to be taken into account.
Social skills interventions for Thai adolescents with Autism Spectrum Disorder (ASD): a qualitative study of the perceptions and experiences of Thai adolescents, their caregivers and healthcare professionals
Authors: Tawankanjanachot Nadlada , Truesdale Maria , Orachon Pornpun , Kidd Lisa
Published: January 2024

Background

Social skills interventions (SSIs) are effective for enhancing social skills and decreasing mental health problems in adolescents with autism spectrum disorder (ASD). However, these interventions have been designed and their effectiveness has been established in Western countries. Lack of culturally acceptable SSIs for Asian nations is a possible barrier to implementing effective and tailored interventions that address the unique requirements of ASD individuals across countries and cultures. This study aims to explore the needs and preferences of adolescents with ASD, their caregivers, and healthcare professionals (HPs) in Thailand regarding the components, delivery formats, and cultural adaptation required for an outpatient-based social skills intervention.

Methods

Qualitative data was collected via three focus groups of HPs (n = 20) and 24 paired interviews with adolescents with ASD and their caregivers from a child psychiatric hospital in Thailand. Purposive sampling was employed, and thematic analysis was used to analyse the data.

Results

Nine themes emerged from the data generated by HPs, and seven from adolescents with ASD and their caregivers. SSIs for Thai adolescents with ASD and their caregivers should emphasise specific social skills training and assess the abilities of adolescents as required. Incorporating various learning strategies is important. Parental involvement is essential and provides knowledge of an adolescent’s symptoms and coaching skills, which are best used to support their adolescents. Cultural considerations include the need for social knowledge of Thai culture, promoting assertiveness and praising parents’ abilities, implementing a programme in time to not interrupt academic achievement, and renaming a programme from social skills intervention to social communication intervention. Barriers to implementing a programme included HPs’ need for specialised training and education and decreased workload. Also, the caregivers’ and adolescents’ stigma reduced attendance in a programme. Increased extra compensation and relocation days off are provided as policy support for staff who deliver the intervention.

Conclusion

The results suggest that SSIs for Thai adolescents with ASD should be tailored to meet the needs for specific knowledge, skills, and parental collaboration as coaches for their adolescents. Additionally, it should incorporate Thai culture. It is necessary to consider staff knowledge, workload, and stigma in order to reduce barriers to implementation in practice.
Modulation of synaptic transmission through O-GlcNAcylation
Authors: Han Seunghyo , Kim Jun-Nyeong , Park Chan Ho , Byun Jin-Seok , Kim Do-Yeon , Ko Hyoung-Gon
Published: January 2024

O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission.
EIF4A3-mediated biogenesis of circSTX6 promotes bladder cancer metastasis and cisplatin resistance
Authors: Wei Wenjie , Liu Kan , Huang Xing , Tian Shuo , Wang Hanfeng , Zhang Chi , Ye Jiali , Dong Yuhao , An Ziyan , Ma Xin , Wang Baojun , Huang Yan , Zhang Xu
Published: January 2024

Background

Cisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa.

Methods

CircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity.

Results

We identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors.

Conclusion

These studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.
Video versus direct laryngoscopy in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials
Authors: Araújo Beatriz , Rivera André , Martins Suzany , Abreu Renatha , Cassa Paula , Silva Maicon , Gallo de Moraes Alice
Published: January 2024

Background

The utilization of video laryngoscopy (VL) has demonstrated superiority over direct laryngoscopy (DL) for intubation in surgical settings. However, its effectiveness in the intensive care unit and emergency department settings remains uncertain.

Methods

We systematically searched PubMed, Embase, Cochrane, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) comparing VL versus DL in critically ill patients. Critical setting was defined as emergency department and intensive care unit. This systematic review and meta-analysis followed Cochrane and PRISMA recommendations. R version 4.3.1 was used for statistical analysis and heterogeneity was examined with I2 statistics. All outcomes were submitted to random-effect models.

Results

Our meta-analysis of 14 RCTs, compromising 3981 patients assigned to VL (n = 2002) or DL (n = 1979). Compared with DL, VL significantly increased successful intubations on the first attempt (RR 1.12; 95% CI 1.04–1.20; p < 0.01; I2 = 82%). Regarding adverse events, VL reduced the number of esophageal intubations (RR 0.44; 95% CI 0.24–0.80; p < 0.01; I2 = 0%) and incidence of aspiration episodes (RR 0.63; 95% CI 0.41–0.96; p = 0.03; I2 = 0%) compared to DL.

Conclusion

VL is a more effective and safer strategy compared with DL for increasing successful intubations on the first attempt and reducing esophageal intubations in critically ill patients. Our findings support the routine use of VL in critically ill patients.

Registration CRD42023439685 https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023439685. Registered 6 July 2023.
Accounting for diverse transposable element landscapes is key to developing and evaluating accurate de novo annotation strategies
Authors: Gozashti Landen , Hoekstra Hopi E.
Published: January 2024

Transposable elements (TEs) are important drivers of genome evolution. Nonetheless, TE annotation remains a complex and challenging task. As more genomes from phylogenetically diverse species are published, a comprehensive pipeline for accurate annotation of diverse TEs is increasingly important. Recently, (Ou et al. Genome Biol. 20:275, 2019) developed a new comprehensive pipeline, Extensive De novo Transposable element Annotator (EDTA), and benchmarked its performance on the genomes of three species: maize, wheat, and fruit fly. Because TE landscapes can vary tremendously across species, we tested EDTA’s performance on four additional genomes with different TE landscapes: mouse, zebrafish, zebra finch, and chicken. Our analysis reveals that EDTA faces challenges with repeat classification in these genomes and underperforms overall relative to its benchmark dataset. Notably, EDTA consistently misclassifies nonLTR retrotransposons as DNA transposons, resulting in erroneous TE annotations for species with considerable repertoires of nonLTR retrotransposons. Overall, we set expectations for EDTA’s performance on genomes spanning additional diversity, urge caution when using EDTA on genomes with divergent TE repertoires from the species on which it was initially benchmarked, and hope to motivate the development of methods that are robust to both the diversity of TEs and TE landscapes observed across species.
FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases
Authors: Breeze Charles E. , Haugen Eric , Gutierrez-Arcelus María , Yao Xiaozheng , Teschendorff Andrew , Beck Stephan , Dunham Ian , Stamatoyannopoulos John , Franceschini Nora , Machiela Mitchell J. , Berndt Sonja I.
Published: January 2024

The majority of disease-associated variants identified through genome-wide association studies are located outside of protein-coding regions. Prioritizing candidate regulatory variants and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb (https://forgedb.cancer.gov/; https://forge2.altiusinstitute.org/files/forgedb.html; and https://doi.org/10.5281/zenodo.10067458), a standalone and web-based tool that integrates multiple datasets, delivering information on associated regulatory elements, transcription factor binding sites, and target genes for over 37 million variants. FORGEdb scores provide researchers with a quantitative assessment of the relative importance of each variant for targeted functional experiments.
Efficacy and safety of heparin for sepsis-induced disseminated intravascular coagulation (HepSIC): study protocol for a multicenter randomized controlled trial
Authors: Sun Yini , Ding Renyu , Sun Hao , Liang Yingjian , Ma Xiaochun
Published: January 2024

Background

Disseminated intravascular coagulation (DIC) occurs in 30–50% of septic patients and contributes to high mortality in the intensive care unit (ICU). However, there are few proven interventions for coagulation disorder management in sepsis. Experimental and clinical data have demonstrated that sepsis could benefit from unfractionated heparin (UFH) treatment. To date, there are no large multicenter trials to determine the safety and efficacy of UFH in septic patients with suspected DIC.

Methods

A multicenter, double-blinded, placebo-controlled randomized trial is designed to recruit 600 patients who met sepsis 3.0 criteria and suspected DIC. Participants will be randomized (1:1) to receive UFH or saline via continuous intravenous administration for 7 days within 6 h of enrolment. The primary outcome is ICU mortality. The secondary outcome includes 28-day all-cause mortality, the improvement of Sequential Organ Failure Assessment scores, and the incidence of major hemorrhage. Investigators, participants, and statisticians will be blinded to the allocation.

Discussion

The HepSIC trial is to evaluate the efficacy and safety of UFH on sepsis-related DIC across different areas of China. The small dosage of UFH administration would offer a new potential approach for treating sepsis-related coagulation disorders.

Ethics and dissemination

Ethical approval was granted by all the ethics committees of 20 participant centers. Results will be disseminated via peer-reviewed publications and presented at conferences.

Trial registration

ClinicalTrials.gov NCT02654561. Registered on 13 January 2016.
Experiences and challenges with the new European Clinical Trials Regulation
Authors: Patrick-Brown Thale D. J. H. , Bourner Josephine , Kali Sabrina , Trøseid Marius , Yazdanpanah Yazdan , Olliaro Piero , Olsen Inge Christoffer
Published: January 2024

Background

The new European Medicines Agency (EMA) Clinical Trials Information System (CTIS), based on the Clinical Trials Regulation (CTR EU 536/2014), came into full effect on 31 January 2022 and was intended to provide an easier, more streamlined approach to the registration of clinical trials taking place in Europe. Using the experience gained on the new regulatory framework from three multi-national European clinical research studies of outbreak-prone infectious diseases, this article describes the advantages and shortcomings of the new clinical trial submission procedure.

Methods

We report the time to approval, size of the application dossier, and number of requests for information (RFIs) for each study. We also explore the experience of each study within the regulatory framework and its use of CTIS to document the real-world, practical consequences of the system on individual studies. The study assesses the experience of three multi-country studies conducted in Europe working within the EU and non-EU regulatory environments.

Results

While the time to regulatory and ethical approval has improved since the implementation of the new regulation, the timelines for approvals are still unacceptably slow, particularly for studies being conducted in the context of an evolving outbreak. Within the new regulatory approval procedure, there is evidence of conflicting application requirements, increased document burden, barriers to submitting important modifications, and debilitating technical hurdles.

Conclusions

CTIS promised to lower the administrative bar, but unfortunately this has not been achieved. There are challenges that need to be urgently confronted and addressed for international research collaborators to effectively manage health crises in the future. While the value of multi-national outbreak research is clear, the limitations and delays imposed by the system, which raise challenging ethical questions about the regulation, are prejudicial to all clinical research, especially publicly funded academic studies. This report is relevant to both regulators and clinical researchers. It is hoped that these findings can help improve pan-European clinical trials, especially for the purpose of epidemic preparedness and response.

Trial registration

This paper references experiences gained during management of three pan-European trials: EU-SolidAct’s Bari-SolidAct (CT No. 2022-500385-99-00 - 15 March 2022) and AXL-SolidAct (CT No. 2022-500363-12-00 - 19 April 2022), and MOSAIC (CT No. 2022-501132-42-00 - 22 June 2022).
Ectoparasites of European hedgehogs (Erinaceus europaeus) in Germany and their health impact
Authors: Schütte Karolin , Springer Andrea , Brandes Florian , Reuschel Maximilian , Fehr Michael , Strube Christina
Published: January 2024

Background

The European hedgehog (Erinaceus europaeus) is known for high levels of ectoparasitism that not only represents a health risk for the animals themselves, but also for pet animals and humans as hedgehogs are frequently taken into human care. In the present study, patterns of ectoparasite infestation were assessed in hedgehogs taken into care at northern German animal rehabilitation centres.

Methods

Ectoparasites (ticks, fleas and mites) of 498 hedgehogs were collected over a period of 3 years from July 2018 to May 2021. Species were identified based on morphological characteristics and also via amplification and sequencing of the partial cytochrome c oxidase subunit 2 (COX-2) gene for fleas of the family Ceratophyllidae. Seasonal changes in infestation patterns as well as correlations with animal age, body weight and health status were assessed using generalised linear models.

Results

Infestation with ticks, fleas and mites occurred throughout the year. Overall, 86.5% (431/498) of the examined hedgehogs were infested with ticks, 91.4% (455/498) with fleas and 17.7% (88/498) with mites.Ixodes ricinus and Ixodes hexagonus/Ixodes canisuga were the most common tick species detected, with the additional occurrence of one Ixodes frontalis. Significant seasonal changes were observed for I. ricinus, but not for I. hexagonus/I. canisuga. Additionally, I. ricinus nymph prevalence declined significantly as of 2020, probably as a consequence of the climate change-related drought as of 2018. In hedgehogs with flea infestations, Archaeopsylla erinacei, Ceratophyllus sciurorum, Nosopsyllus fasciatus and Ctenocephalides felis were identified. In all cases of mite infestation, Caparinia tripilis was detected, in addition to specimens of the family Macronyssidae and free-living mites of the family Acaridae. Statistical analyses showed correlations regarding the factors month, year, body weight and age, but no correlation was evident regarding the health status of the animals.

Conclusions

With a detected infestation rate of 98.6%, almost all of the examined hedgehogs were infested with at least one ectoparasite species. The seasonal activity patterns of the different ectoparasite species together with the complex annual cycle of hedgehogs lead to different seasonal patterns in ectoparasite prevalence and infestation intensities. Due to the risk of transmission of zoonotic pathogens as well as the possible negative impact on the host itself, hedgehogs should be treated against ectoparasites when taken into care facilities.

Graphical Abstract