bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous targeting of Tim3 and A2a receptors modulates MSLN-CAR T cell antitumor function in a human cervical tumor xenograft model
Authors: Soltantoyeh Tahereh , Akbari Behnia , Shahosseini Zahra , Mirzaei Hamid Reza , Hadjati Jamshid 
Published: May 2024

IntroductionChimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo.MethodsSecond-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model.ResultsIn vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in miceConclusionThese findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.
Interleukin-1 regulates follicular T cells during the germinal center reaction
Authors: Belbezier Aude , Engeroff Paul , Fourcade Gwladys , Vantomme Hélène , Vaineau Romain , Gouritin Bruno , Bellier Bertrand , Brocheriou Isabelle , Tchitchek Nicolas , Graff-Dubois Stephanie , Klatzmann David 
Published: May 2024

IntroductionAntibody production and the generation of memory B cells are regulated by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that both Tfh and Tfr cells express the IL-1R1 agonist receptor, whereas only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. We aimed to investigate the role of IL-1 receptors in the regulation of B cell responses by Tfh and Tfr.MethodsWe generated mice with IL-1 receptors inactivated in Tfh or Tfr and measured antibody production and cell activation after immunisation.ResultsWhile IL-1β levels are increased in the draining lymph node after immunisation, antigen-specific antibody levels and cell phenotypes indicated that IL-1β can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, expression of IL-1R2 and IL-1Ra on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs also regulate the antibody response to autoantigens and its associated pathophysiology in an experimental lupus model.DiscussionCollectively, our results show that IL-1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunisation. Further mechanistic studies should unravel these complex interactions between IL-1β and follicular helper and regulatory T cells and provide new avenues for therapeutic intervention.
Causal links between gut microbiomes, cytokines and risk of different subtypes of epilepsy: a Mendelian randomization study
Authors: Qiu Youjia , Song Bingyi , Xie Minjia , Tao Yuchen , Yin Ziqian , Wang Menghan , Ma Chao , Chen Zhouqing , Wang Zhong 
Published: May 2024

ObjectiveRecent research suggests a potential link between the gut microbiome (GM) and epilepsy. We undertook a Mendelian randomization (MR) study to determine the possible causal influence of GM on epilepsy and its various subtypes, and explore whether cytokines act as mediators.MethodsWe utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM, cytokines, and four epilepsy subtypes. Furthermore, we assessed whether cytokines mediate the relationship between GM and epilepsy. Significant GMs were further investigated using transcriptomic MR analysis with genes mapped from the FUMA GWAS. Sensitivity analyses and reverse MR were conducted for validation, and false discovery rate (FDR) correction was applied for multiple comparisons.ResultsWe pinpointed causal relationships between 30 GMs and various epilepsy subtypes. Notably, the Family Veillonellaceae (OR:1.03, 95%CI:1.02–1.05, p = 0.0003) consistently showed a strong positive association with child absence epilepsy, and this causal association endured even after FDR correction (p-FDR &lt; 0.05). Seven cytokines were significantly associated with epilepsy and its subtypes. A mediating role for cytokines has not been demonstrated. Sensitivity tests validated the primary MR analysis outcomes. Additionally, no reverse causality was detected between significant GMs and epilepsy. Of the mapped genes of notable GMs, genes like BLK, FDFT1, DOK2, FAM167A, ZSCAN9, RNGTT, RBM47, DNAJC21, SUMF1, TCF20, GLO1, TMTC1, VAV2, and RNF14 exhibited a profound correlation with the risk factors of epilepsy subtypes.ConclusionOur research validates the causal role of GMs and cytokines in various epilepsy subtypes, and there has been no evidence that cytokines play a mediating role between GM and epilepsy. This could provide fresh perspectives for the prevention and treatment of epilepsy.
Marine microalgae Schizochytrium demonstrates strong production of essential fatty acids in various cultivation conditions, advancing dietary self-sufficiency
Authors: Literáková Petra , Zavřel Tomáš , Búzová Diana , Kaštánek Petr , Červený Jan 
Published: May 2024

IntroductionPolyunsaturated fatty acids (PUFAs) are essential nutrients that humans obtain from their diet, primarily through fish oil consumption. However, fish oil production is no longer sustainable. An alternative approach is to produce PUFAs through marine microalgae. Despite the potential of algae strains to accumulate high concentrations of PUFAs, including essential fatty acids (EFAs), many aspects of PUFA production by microalgae remain unexplored and their current production outputs are frequently suboptimal.MethodsIn this study, we optimized biomass and selected ω-3 PUFAs production in two strains of algae, Schizochytrium marinum AN-4 and Schizochytrium limacinum CO3H. We examined a broad range of cultivation conditions, including pH, temperature, stirring intensity, nutrient concentrations, and their combinations.ResultsWe found that both strains grew well at low pH levels (4.5), which could reduce bacterial contamination and facilitate the use of industrial waste products as substrate supplements. Intensive stirring was necessary for rapid biomass accumulation but caused cell disruption during lipid accumulation. Docosahexaenoic acid (DHA) yield was independent of cultivation temperature within a range of 28–34°C. We also achieved high cell densities (up to 9 g/L) and stable DHA production (average around 0.1 g/L/d) under diverse conditions and nutrient concentrations, with minimal nutrients required for stable production including standard sea salt, glucose or glycerol, and yeast extract.DiscussionOur findings demonstrate the potential of Schizochytrium strains to boost industrial-scale PUFA production and make it more economically viable. Additionally, these results may pave the way for smaller-scale production of essential fatty acids in a domestic setting. The development of a new minimal culturing medium with reduced ionic strength and antibacterial pH could further enhance the feasibility of this approach.
High serum klotho levels are inversely associated with the risk of low muscle mass in middle-aged adults: results from a cross-sectional study
Authors: Xie Yilian , Huang Kai , Li Hui , Kong Weiliang , Ye Jiayuan 
Published: May 2024

ObjectiveMuscle mass gradually declines with advancing age, and as an anti-aging protein, klotho may be associated with muscle mass. This study aims to explore the relationship between klotho levels and muscle mass in the middle-aged population.MethodsUtilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2011 to 2018, we conducted a cross-sectional analysis on a cohort of individuals aged 40–59. Weighted multivariable analysis was employed to assess the correlation between klotho and low muscle mass, with stratified and Restricted Cubic Spline (RCS) analyses.ResultsThe cross-sectional investigation revealed a significant negative correlation between klotho levels and the risk of low muscle mass (Model 3: OR = 0.807, 95% CI: 0.712–0.915). A notable interaction between klotho and sex was observed, with a significant interaction effect (P for interaction = 0.01). The risk association was notably higher in females. The risk association was notably higher in females. Additionally, RCS analysis unveiled a significant linear relationship between klotho and low muscle mass (P for nonlinear = 0.9495, P for overall&lt;0.0001).ConclusionOur observational analysis revealed a noteworthy inverse relationship between klotho and low muscle mass, particularly prominent among female participants. This discovery provides crucial insights for the development of more effective intervention strategies and offers a new direction for enhancing muscle quality in the middle-aged population.
Assessing the role of advanced artificial intelligence as a tool in multidisciplinary tumor board decision-making for primary head and neck cancer cases
Authors: Schmidl Benedikt , Hütten Tobias , Pigorsch Steffi , Stögbauer Fabian , Hoch Cosima C. , Hussain Timon , Wollenberg Barbara , Wirth Markus 
Published: May 2024

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary approach in clinical practice, especially in tumor board discussions. In recent years, artificial intelligence has emerged as a tool to assist healthcare professionals in making informed decisions. This study investigates the application of ChatGPT 3.5 and ChatGPT 4.0, natural language processing models, in tumor board decision-making.MethodsWe conducted a pilot study in October 2023 on 20 consecutive head and neck cancer patients discussed in our multidisciplinary tumor board (MDT). Patients with a primary diagnosis of head and neck cancer were included. The MDT and ChatGPT 3.5 and ChatGPT 4.0 recommendations for each patient were compared by two independent reviewers and the number of therapy options, the clinical recommendation, the explanation and the summarization were graded.ResultsIn this study, ChatGPT 3.5 provided mostly general answers for surgery, chemotherapy, and radiation therapy. For clinical recommendation, explanation and summarization ChatGPT 3.5 and 4.0 scored well, but demonstrated to be mostly an assisting tool, suggesting significantly more therapy options than our MDT, while some of the recommended treatment modalities like primary immunotherapy are not part of the current treatment guidelines.ConclusionsThis research demonstrates that advanced AI models at the moment can merely assist in the MDT setting, since the current versions list common therapy options, but sometimes recommend incorrect treatment options and in the case of ChatGPT 3.5 lack information on the source material.
Characterization of prostatic cancer lesion and gleason grade using a continuous-time random-walk diffusion model at high b-values
Authors: Sheng Yurui , Chang Huan , Xue Ke , Chen Jinming , Jiao Tianyu , Cui Dongqing , Wang Hao , Zhang Guanghui , Yang Yuxin , Zeng Qingshi 
Published: May 2024

BackgroundDistinguishing between prostatic cancer (PCa) and chronic prostatitis (CP) is sometimes challenging, and Gleason grading is strongly associated with prognosis in PCa. The continuous-time random-walk diffusion (CTRW) model has shown potential in distinguishing between PCa and CP as well as predicting Gleason grading.PurposeThis study aimed to quantify the CTRW parameters (α, β &amp; Dm) and apparent diffusion coefficient (ADC) of PCa and CP tissues; and then assess the diagnostic value of CTRW and ADC parameters in differentiating CP from PCa and low-grade PCa from high-grade PCa lesions.Study typeRetrospective (retrospective analysis using prospective designed data).PopulationThirty-one PCa patients undergoing prostatectomy (mean age 74 years, range 64–91 years), and thirty CP patients undergoing prostate needle biopsies (mean age 68 years, range 46–79 years).Field strength/SequenceMRI scans on a 3.0T scanner (uMR790, United Imaging Healthcare, Shanghai, China). DWI were acquired with 12 b-values (0, 50, 100, 150, 200, 500, 800, 1200, 1500, 2000, 2500, 3000 s/mm2).AssessmentCTRW parameters and ADC were quantified in PCa and CP lesions.Statistical testsThe Mann-Whitney U test was used to evaluate the differences in CTRW parameters and ADC between PCa and CP, high-grade PCa, and low-grade PCa. Spearman’s correlation of the pathologic grading group (GG) with CTRW parameters and ADC was evaluated. The usefulness of CTRW parameters, ADC, and their combinations (Dm, α and β; Dm, α, β, and ADC) to differentiate PCa from CP and high-grade PCa from low-grade PCa was determined by logistic regression and receiver operating characteristic curve (ROC) analysis. Delong test was used to compare the differences among AUCs.ResultsSignificant differences were found for the CTRW parameters (α, Dm) between CP and PCa (all P&lt;0.001), high-grade PCa, and low-grade PCa (α:P=0.024, Dm:P=0.021). GG is correlated with certain CTRW parameters and ADC(α:P&lt;0.001,r=-0.795; Dm:P&lt;0.001,r=-0.762;ADC:P&lt;0.001,r=-0.790). Moreover, CTRW parameters (α, β, Dm) combined with ADC showed the best diagnostic efficacy for distinguishing between PCa and CP as well as predicting Gleason grading. The differences among AUCs of ADC, CTRW parameters and their combinations were not statistically significant (P=0.051–0.526).ConclusionCTRW parameters α and Dm, as well as their combination were beneficial to distinguish between CA and PCa, low-grade PCa and high-grade PCa lesions, and CTRW parameters and ADC had comparable diagnostic performance.
Development and validation of nomogram to predict overall survival and disease-free survival after surgical resection in elderly patients with hepatocellular carcinoma
Authors: Tian Yuan , Wang Yaoqun , Wen Ningyuan , Lin Yixin , Liu Geng , Li Bei 
Published: May 2024

BackgroundHepatocellular carcinoma (HCC) is one of the common causes of tumor death in elderly patients. However, there is a lack of individualized prognostic predictors for elderly patients with HCC after surgery.MethodWe retrospectively analyzed HCC patients over 65 years old who underwent hepatectomy from 2015 to 2018, and randomly divided them into training cohort and validation cohort in a ratio of 3:1. Univariate Cox regression was used to screen the risk factors related to prognosis. Prognostic variables were further selected by least absolute shrinkage and selection operator regression model (LASSO) and multivariate Cox regression to identify the predictors of overall survival (OS) and disease-free survival (DFS). These indicators were then used to construct a predictive nomogram. The receiver operating characteristic curve (ROC curve), calibration curve, consistency index (C-index) and decision analysis curve (DCA) were used to test the predictive value of these independent prognostic indicators.ResultA total of 188 elderly HCC patients who underwent hepatectomy were enrolled in this study. The independent prognostic indicators of OS included albumin (ALB), cancer embolus, blood loss, viral hepatitis B, total bilirubin (TB), microvascular invasion, overweight, and major resection. The independent prognostic indicators of DFS included major resection, ALB, microvascular invasion, laparoscopic surgery, blood loss, TB, and pleural effusion. In the training cohort, the ROC curve showed that the predictive values of these indicators for OS and DFS were 0.827 and 0.739, respectively, while in the validation cohort, they were 0.798 and 0.694. The calibration curve nomogram exhibited good prediction for 1-year, 2-year, and 3-year OS and DFS. Moreover, the nomogram models exhibited superior performance compared to the T-staging suggested by C-index and DCA.ConclusionThe nomogram established in this study demonstrate commendable predictive efficacy for OS and DFS in elderly patients with HCC after hepatectomy.Core Tip: The purpose of this retrospective study is to screen the risk factors of survival and recurrence in elderly patients with HCC after hepatectomy. The nomogram included cancer embolus, viral hepatitis B, overweight, major resection, ALB, microvascular invasion, laparoscopic surgery, blood loss, TB, and pleural effusion as predictors. The calibration curve of this nomogram was good, indicating credible predictive value and clinical feasibility.
“It's more than just a conversation about the heart”: exploring barriers, enablers, and opportunities for improving the delivery and uptake of cardiac neurodevelopmental follow-up care
Authors: Abell Bridget , Rodwell David , Eagleson Karen J. , Parsonage William , Auld Ben , Bora Samudragupta , Kasparian Nadine A. , Justo Robert , McPhail Steven M. 
Published: May 2024

IntroductionSurveillance, screening, and evaluation for neurodevelopmental delays is a pivotal component of post-surgical care for children with congenital heart disease (CHD). However, challenges exist in implementing such neurodevelopmental follow-up care in international practice. This study aimed to characterise key barriers, enablers, and opportunities for implementing and delivering outpatient cardiac neurodevelopmental follow-up care in Australia.Methodsan exploratory descriptive qualitative study was conducted with healthcare professionals across Australia who had lived experience of designing, implementing, or delivering neurodevelopmental care for children with CHD. Online semi-structured interviews were conducted using a guide informed by the Consolidated Framework for Implementation Research to explore contextual influences. Interview transcripts were analysed using a rapid qualitative approach including templated summaries and hybrid deductive-inductive matrix analysis.Resultsfifty-two participants were interviewed. Perceived barriers and enablers were organised into six higher-order themes: factors in the broader environmental, economic, and political context; healthcare system factors; organisational-level factors; provider factors; patient and family factors; and care model factors. The largest number of barriers occurred at the healthcare system level (service accessibility, fragmentation, funding, workforce), while service providers demonstrated the most enabling factors (interprofessional relationships, skilled teams, personal characteristics). Strategies to improve practice included building partnerships; generating evidence; increasing funding; adapting for family-centred care; and integrating systems and data.DiscussionAustralia shares many similar barriers and enablers to cardiac neurodevelopmental care with other international contexts. However, due to unique geographical and health-system factors, care models and implementation strategies will require adaption to the local context to improve service provision.
Can Chinese herbal medicine offer feasible solutions for newly diagnosed esophageal cancer patients with malnutrition? a multi-institutional real-world study
Authors: Lu Yi-Chin , Tseng Liang-Wei , Wu Chiao-En , Yang Ching-Wei , Yang Tsung-Hsien , Chen Hsing-Yu 
Published: May 2024

BackgroundEsophageal cancer (EC) is a major cause of cancer-related mortality in Taiwan and globally. Patients with EC are highly prone to malnutrition, which adversely affects their prognosis. While Chinese herbal medicine (CHM) is commonly used alongside conventional anti-cancer treatments, its long-term impact on EC patients with malnutrition remains unclear.MethodsThis study utilized a multi-center cohort from the Chang Gung Research Database, focusing on the long-term outcomes of CHM in EC patients with malnutrition between 1 January 2001, and 31 December 2018. Patients were monitored for up to 5 years or until death. Overall survival (OS) rates were calculated using the Kaplan-Meier method. Overlap weighting and landmark analysis were employed to address confounding and immortal time biases. Additionally, the study analyzed prescription data using a CHM network to identify key CHMs for EC with malnutrition, and potential molecular pathways were investigated using the Reactome database.ResultsEC patients with malnutrition who used CHM had a higher 5-year OS compared with nonusers (22.5% vs. 9% without overlap weighting; 24.3% vs. 13.3% with overlap weighting; log-rank test: p = 0.006 and 0.016, respectively). The median OS of CHM users was significantly longer than that of nonusers (19.8 vs. 12.9 months, respectively). Hazard ratio (HR) analysis showed a 31% reduction in all-cause mortality risk for CHM users compared with nonusers (HR: 0.69, 95% confidence interval: 0.50–0.94, p = 0.019). We also examined 665 prescriptions involving 306 CHM, with Hedyotis diffusa Willd. exhibiting the highest frequency of use. A CHM network was created to determine the primary CHMs and their combinations. The identified CHMs were associated with the regulation of immune and metabolic pathways, particularly in areas related to immune modulation, anti-cancer cachexia, promotion of digestion, and anti-tumor activity.ConclusionThe results of this study suggest a correlation between CHM use and improved clinical outcomes in EC patients with malnutrition. The analysis identified core CHMs and combinations of formulations that play a crucial role in immunomodulation and metabolic regulation. These findings lay the groundwork for more extensive research on the use of CHM for the management of malnutrition in patients with EC.