bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodality local consolidative treatment versus conventional care of advanced lung cancer after first-line systemic anti-cancer treatment: study protocol for the RAMON multicentre randomised controlled trial with an internal pilot
Authors: Beard Chloe , Rogers Chris A , Fleming Leah , Conibear John , Evison Matthew , Newsom-Davis Thomas , Barwick Tara , Mills Nicola , Stokes Elizabeth A , De Sousa Paulo , Batchelor Tim , Rawlinson Janette , Baos Sarah , Harris Rosie , Lim Eric 
Published: December 2023

IntroductionLung cancer is the most common cause of cancer death worldwide and most patients present with extensive disease. One-year survival is improving but remains low (37%) despite novel systemic anti-cancer treatments forming the current standard of care. Although new therapies improve survival, most patients have residual disease after treatment, and little is known on how best to manage it. Therefore, residual disease management varies across the UK, with some patients receiving only maintenance systemic anti-cancer treatment while others receive local consolidative treatment (LCT), alongside maintenance systemic anti-cancer treatment. LCT can be a combination of surgery, radiotherapy and/or ablation to remove all remaining cancer within the lung and throughout the body. This is intensive, expensive and impacts quality of life, but we do not know if it results in better survival, nor the extent of impact on quality of life and what the cost might be for healthcare providers. The RAMON study (RAdical Management Of Advanced Non-small cell lung cancer) will evaluate the acceptability, effectiveness and cost-effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer.Methods and analysisRAMON is a pragmatic open multicentre, parallel group, superiority randomised controlled trial. We aim to recruit 244 patients aged 18 years and over with advanced non-small-cell lung cancer from 40 UK NHS hospitals. Participants will be randomised in a 1:1 ratio to receive LCT alongside maintenance treatment, or maintenance treatment alone. LCT will be tailored to each patient’s specific disease sites. Participants will be followed up for a minimum of 2 years. The primary outcome is overall survival from randomisation.Ethics and disseminationThe West of Scotland Research Ethics Committee (22/WS/0121) gave ethical approval in August 2022 and the Health Research Authority in September 2022. Participants will provide written informed consent before participating in the study. Findings will be presented at international meetings, in peer-reviewed publications, through patient organisations and notifications to patients.Trial registration numberISRCTN11613852.
The epidemiology of primary FSGS including cluster analysis over a 20-year period
Authors: McDonnell Thomas , Storrar Joshua , Chinnadurai Rajkumar , Heal Calvin , Chrysochou Constantina , Ritchie James , Rainone Francesco , Poulikakos Dimitrios , Kalra Philip , Sinha Smeeta 
Published: December 2023

Abstract
Introduction
Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of nephrotic syndrome in adults. This epidemiological study describes a renal centre’s 20-year experience of primary FSGS.

Methods
Patients were identified with a diagnosis of primary FSGS after exclusion of known secondary causes. In this retrospective observational study, data was collected for baseline demographics, immunosuppression and outcomes. A two-step cluster analysis was used to identify natural groupings within the dataset.

Results
The total cohort was made up of 87 patients. Those who received immunosuppression had lower median serum albumin than those who did not- 23g/L vs 40g/L (p<0.001) and higher median urine protein creatinine ratios (uPCR)- 795mg/mmol vs 318mg/mmol (p <0.001). They were more likely to achieve complete remission (62% vs 40%, p=0.041), but relapsed more 48.6% vs 22% (p=0.027). Overall 5 year mortality was 10.3% and 5 year progression to RRT was seen in 17.2%. Complete remission was observed in 49.4%. The 2-step cluster analysis separated the cohort into 3 clusters: cluster 1 (n=26) with ‘nephrotic-range proteinuria’; cluster 2 (n=43) with ‘non-nephrotic-range proteinuria’; and cluster 3 (n=18) with nephrotic syndrome. Immunosuppression use was comparable in clusters 1 and 3, but lower in cluster 2 (77.8% and 69.2% vs 11.6%, p<0.001). Rates of complete remission were greatest in clusters 1 and 3 vs cluster 2: 57.7% and 66.7% vs 37.2%.

Conclusion
People who received immunosuppression had lower serum albumin and achieved remission more frequently, but were also prone to relapse. Our cluster analysis highlighted 3 FSGS phenotypes: a nephrotic cluster that clearly require immunosuppression; a cohort with preserved serum albumin and non-nephrotic range proteinuria who will benefit from supportive care; and lastly a cluster with heavy proteinuria but serum albumin > 30g/L. This group may still have immune mediated disease and thus could potentially benefit from immunosuppression.

Trial registration
This study protocol was reviewed and approved by the ‘Research and Innovation committee of the Northern Care Alliance NHS Group’, study approval number (Ref: ID 22HIP54).
Cross-cultural adaptation and validation of the Chinese version of the Malocclusion Impact Scale for Early Childhood (MIS-EC/C)
Authors: Chen Qiao 
Published: December 2023

Abstract
Background
The Malocclusion Impact Scale for Early Childhood (MIS-EC) is a newly developed questionnaire used to measure the parental perceptions of the impact of malocclusion on oral health-related quality of life (OHRQoL) of preschool children aged 3–5 years. This study describes the cross-cultural adaptation and validation of the MIS-EC questionnaire into Chinese version (MIS-EC/C).

Methods
The MIS-EC/C was developed in accordance with international standards. The scale was then evaluated in a cross-sectional study comprising 210 preschool children aged 3–5 years. The reliability of the MIS-EC/C was tested using internal consistency and test-retest reliability analyses. Cross-cultural validity, discriminant validity and convergent validity were tested.

Results
The Cronbach’s α value and intraclass correlation coefficient (ICC) value for the MIS-EC/C were 0.943 and 0.873, respectively. Confirmatory factor analysis indicated that the fitting indicators of the two-factor model all reached the standard. The MIS-EC/C can differentiate preschool children with malocclusion from those without malocclusion. In addition, there is a good relationship between the MIS-EC/C and the general oral health question.

Conclusion
The MIS-EC/C is a reliable and effective assessment tool for assessing the effect of malocclusion on the OHRQoL of preschool children in China.
Excitatory neurons in the lateral parabrachial nucleus mediate the interruptive effect of inflammatory pain on a sustained attention task
Authors: Zheng Huan-Yu , Chen Yu-Meng , Xu Yao , Cen Cheng , Wang Yun 
Published: December 2023

Abstract
Background
Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood.

Methods
We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits.

Results
Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain.

Conclusions
Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.
Learning from cerebrospinal fluid drug-resistant HIV escape-associated encephalitis: a case report
Authors: Kang Jing , Wang Ziqiu , Zhou Ying , Wang Wen , Wen Ying 
Published: December 2023

Abstract
Background
In the era of antiretroviral therapy (ART), central nervous system (CNS) complications in patients with human immunodeficiency virus (HIV) infection are sometimes associated with cerebrospinal fluid (CSF) viral escape. Here, we reported a case of persistent CNS viral escape with recurrent symptomatic encephalitis, which had ultimate stabilization achieved by a combination of ART adjustment and corticosteroids.

Case presentation
A 27-year-old man with HIV infection complained of recurrent headaches during the last year. His magnetic resonance imaging (MRI) presented diffused bilateral white matter lesions, and laboratory tests confirmed elevated CSF protein level, lymphocytic pleocytosis, and detectable CSF HIV RNA (774 copies/mL). Plasma HIV RNA was well suppressed with tenofovir, lamivudine, and lopinavir/ritonavir. Prednisone 60 mg once daily was initiated to reduce intracranial inflammation, followed by a good clinical response, with CSF HIV RNA still detectable (31.1 copies/mL). During the gradual tapering of prednisone, his headache relapsed, and booming viral loads were detected in both CSF (4580 copies/mL) and plasma (340 copies/mL) with consistent drug-resistant mutations. Thereupon, prednisone was resumed and the ART regimen was switched to zidovudine, lamivudine, and dolutegravir according to drug resistance tests. Persistent clinical recovery of symptoms, neuroimaging, and laboratory abnormalities were observed in the follow-up visits.

Conclusion
CSF and plasma HIV RNA and further drug resistance tests should be monitored in HIV-infected patients with neurologic symptoms, as opportunistic infections or tumors can be ruled out. ART optimization using a sensitive regimen may be crucial for addressing CSF viral escape and the related encephalitis.
Integration of (S)-2,3-oxidosqualene enables E. coli to become Iron Man E. coli with improved overall tolerance
Authors: Sun Wenjie , Chen Yun , Li Mengkun , Shah Syed Bilal , Wang Tianfu , Hou Jin , Bai Linquan , Feng Yan , Tan Zaigao 
Published: December 2023

Abstract
Background
While representing a model bacterium and one of the most used chassis in biomanufacturing, performance of Escherichia coli is often limited by severe stresses. A super-robust E. coli chassis that could efficiently tolerant multiple severe stresses is thus highly desirable. Sterols represent a featured composition that distinguishes eukaryotes from bacteria and all archaea, and play a critical role in maintaining the membrane integrity of eukaryotes. All sterols found in nature are directly synthesized from (S)-2,3-oxidosqualene. However, in E. coli, (S)-2,3-oxidosqualene is not present.

Results
In this study, we sought to introduce (S)-2,3-oxidosqualene into E. coli. By mining and recruiting heterologous enzymes and activation of endogenous pathway, the ability of E. coli to synthesize (S)-2,3-oxidosqualene was demonstrated. Further analysis revealed that this non-native chemical confers E. coli with a robust and stable cell membrane, consistent with a figurative analogy of wearing an “Iron Man’s armor”-like suit. The obtained Iron Man E. coli (IME) exhibited improved tolerance to multiple severe stresses, including high temperature, low pH, high salt, high sugar and reactive oxygen species (ROS). In particular, the IME strain shifted its optimal growth temperature from 37 °C to 42–45 °C, which represents the most heat-resistant E. coli to the best of our knowledge. Intriguingly, this non-native chemical also improved E. coli tolerance to a variety of toxic feedstocks, inhibitory products, as well as elevated synthetic capacities of inhibitory chemicals (e.g., 3-hydroxypropionate and fatty acids) due to improved products tolerance. More importantly, the IME strain was effectively inhibited by the most commonly used antibiotics and showed no undesirable drug resistance.

Conclusions
Introduction of the non-native (S)-2,3-oxidosqualene membrane lipid enabled E. coli to improve tolerance to various stresses. This study demonstrated the effectiveness of introducing eukaryotes-featured compound into bacteria for enhancing overall tolerance and chemical production.
Repopulating Kupffer cells originate directly from hematopoietic stem cells
Authors: Fan Xu , Lu Pei , Cui Xiang-Hua , Wu Peng , Lin Wei-Ran , Zhang Dong , Yuan Shong-Zong , Liu Bing , Chen Fang-Yan , You Hong , Wei Han-Dong , He Fu-Chu , Jia Ji-Dong , Jiang Ying 
Published: December 2023

Abstract
Background
Kupffer cells (KCs) originate from yolk-sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at a steady state and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adults remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence.

Methods
We first traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models, respectively. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC-depletion in mice. Finally, we traced the fate of hematopoietic stem cells (HSCs) in an HSC-specific fate-mapping mouse model, in the context of chronic liver inflammation induced by repeated carbon tetrachloride treatment.

Results
By using fate-mapping mouse models, we found no evidence that repopulating KCs originate from preexisting KCs or MOs and found that in response to KC-depletion, HSCs proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Then, in the chronic liver inflammation context, we confirmed that repopulating KCs originated directly from HSCs.

Conclusion
Taken together, these findings provided in vivo fate-mapping evidence that repopulating KCs originate directly from HSCs, which presents a completely novel understanding of the cellular origin of repopulating KCs and shedding light on the divergent roles of KCs in liver homeostasis and diseases.
Umbilical cord-derived mesenchymal stem cell sheets transplanted subcutaneously enhance cell retention and survival more than dissociated stem cell injections
Authors: Nakao Mitsuyoshi , Matsui Makoto , Kim Kyungsook , Nishiyama Nobuhiro , Grainger David W. , Okano Teruo , Kanazawa Hideko , Nagase Kenichi 
Published: December 2023

Abstract
Background
Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) sheets have recently attracted attention as an alternative approach to injected cell suspensions for stem cell therapy. However, cell engraftment and cytokine expression levels between hUC-MSC sheets and their cell suspensions in vivo have not yet been compared. This study compares hUC-MSC in vivo engraftment efficacy and cytokine expression for both hUC-MSC sheets and cell suspensions.

Methods
hUC-MSC sheets were prepared using temperature-responsive cell culture; two types of hUC-MSC suspensions were prepared, either by enzymatic treatment (trypsin) or by enzyme-free temperature reduction using temperature-responsive cell cultureware. hUC-MSC sheets and suspensions were transplanted subcutaneously into ICR mice through subcutaneous surgical placement and intravenous injection, respectively. hUC-MSC sheet engraftment after subcutaneous surgical transplantation was investigated by in vivo imaging while intravenously injected cell suspensions were analyzing using in vitro organ imaging. Cytokine levels in both transplant site tissues and blood were quantified by enzyme-linked immunosorbent assay.

Results
After subcutaneous transplant, hUC-MSC sheets exhibited longer engraftment duration than hUC-MSC suspensions. This was attributed to extracellular matrix (ECM) and cell–cell junctions retained in sheets but enzymatically altered in suspensions. hUC-MSC suspensions harvested using enzyme-free temperature reduction exhibited relatively long engraftment duration after intravenous injection compared to suspensions prepared using trypsin, as enzyme-free harvest preserved cellular ECM. High HGF and TGF-β1 levels were observed in sheet-transplanted sites compared to hUC-MSC suspension sites. However, no differences in human cytokine levels in murine blood were detected, indicating that hUC-MSC sheets might exert local paracrine rather than endocrine effects.

Conclusions
hUC-MSC sheet transplantation could be a more effective cell therapeutic approach due to enhanced engraftment and secretion of therapeutic cytokines over injected hUC-MSC suspensions.
In vivo safety and biodistribution profile of Klotho-enhanced human urine-derived stem cells for clinical application
Authors: Kim Sang-Heon , Lee Sung-Hoon , Jin Jeong-Ah , So Hyung-Joon , Lee Jae-Ung , Ji Min-Jae , Kwon Eun-Joong , Han Pyo-Sung , Lee Hong-Ki , Kang Tae-Wook 
Published: December 2023

Abstract
Background
Urine-derived stem cells (UDSCs) can be easily isolated from urine and possess excellent stem cell characteristics, making them a promising source for cell therapeutics. Due to their kidney origin specificity, UDSCs are considered a superior therapeutic alternative for kidney diseases compared to other stem cells. To enhance the therapeutic potential of UDSCs, we developed a culture method that effectively boosts the expression of Klotho, a kidney-protective therapeutic factor. We also optimized the Good Manufacturing Practice (GMP) system to ensure stable and large-scale production of clinical-grade UDSCs from patient urine. In this study, we evaluated the in vivo safety and distribution of Klotho-enhanced UDSCs after intravenous administration in accordance with Good Laboratory Practice (GLP) regulations.

Methods
Mortality and general symptoms were continuously monitored throughout the entire examination period. We evaluated the potential toxicity of UDSCs according to the administration dosage and frequency using clinical pathological and histopathological analyses. We quantitatively assessed the in vivo distribution and retention period of UDSCs in major organs after single and repeated administration using human Alu-based qPCR analysis. We also conducted long-term monitoring for 26 weeks to assess the potential tumorigenicity.

Results
Klotho-enhanced UDSCs exhibited excellent homing potential, and recovered Klotho expression in injured renal tissue. Toxicologically harmful effects were not observed in all mice after a single administration of UDSCs. It was also verified that repeated administration of UDSCs did not induce significant toxicological or immunological adverse effects in all mice. Single and repeated administrated UDSCs persisted in the blood and major organs for approximately 3 days and cleared in most organs, except the lungs, within 2 weeks. UDSCs that remained in the lungs were cleared out in approximately 4–5 weeks. There were no significant differences according to the variation of sex and administration frequency. The tumors were found in the intravenous administration group but they were confirmed to be non-human origin. Based on these results, it was clarified that UDSCs have no tumorigenic potential.

Conclusions
Our results demonstrate that Klotho-enhanced UDSCs can be manufactured as cell therapeutics through an optimized GMP procedure, and they can be safely administered without causing toxicity and tumorigenicity.
Centella asiatica lowers body fat accumulation via regulating cholesterol homeostasis- and lipid metabolism-related genes in mice with high-fat, high-sugar diet-induced obesity
Authors: Chang Yeok Boo , Ahn Yejin , Seo Daebang , Bae Soohyun , Suh Hyung Joo , Hong Yang Hee , Jung Eun Young 
Published: December 2023

AbstractTo understand the mechanisms involved in the anti-obesity effects Centella asiatica (CA), we examined body weight, serum levels, white adipose tissue (WAT) weight, histological analysis, and the expression of cholesterol homeostasis- and lipid metabolism-related genes in mice with high-fat, high-sugar diet (HFHSD)-induced obesity that were orally treated with CA for 12 weeks. Eight-week-old, male C57BL/6J mice were assigned to the following four groups (8 mice/group): NOR, normal diet; HFHSD (Control), HFHSD; CA-L, HFHSD + CA 300 mg/kg; CA-H, HFHSD+CA 600 mg/kg. The suspension of powdered CA leaf was fed using oral gavage. CA treatment significantly attenuated HFHSD-induced increase in body weight gain, serum glucose, triacylglycerol, and WAT weight (p < 0.05). Compared to that in HFHSD, adipocyte diameter and macrovesicular area of epididymal WAT significantly decreased with CA treatment (p < 0.05). The mRNA expression levels of peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), cluster of differentiation 36 (CD36), 3- hydroxyl-3-methylglutaryl CoA reductase (HMGCR), and stearoyl CoA desaturase 1 (SCD 1) were significantly downregulated in the CA-H compared to the HFHSD (p < 0.05). CA exerts anti-obesity effects by lowering body fat accumulation via regulating gene expression and thus, is a potential lipid-lowering agent.