bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging
Authors: Leland Pamela , Kumar Dhiraj , Nimmagadda Sridhar , Bauer Steven R. , Puri Raj K. , Joshi Bharat H. 
Published: June 2023

Abstract
Background
Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products.

Methods
To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89Zirconium-oxine (89Zr-oxine) and characterized and compared their product attributes with non-labeled CAR-T cells. The 89Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, T cell subtype characterization and product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells.

Results
We observed that radiolabeling of CAR-T cells with 89Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells and subtypes such as CD4 + , CD8 + and scFV-IL-13Rα2 transgene positive T cell population were characterized and found similar to that of unlabeled cells as determined by TUNEL assay, caspase 3/7 enzyme and granzyme B activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion (PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells.

Conclusions
Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89Zr-oxine retain critical product attributes and suggest 89Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.
A quantitative method to measure geranylgeranyl diphosphate (GGPP) and geranylgeranyl monophosphate (GGP) in tomato (Solanum lycopersicum) fruit
Authors: Zita Wayne , Shanmugabalaji Venkatasalam , Ezquerro Miguel , Rodriguez-Concepcion Manuel , Kessler Felix , Glauser Gaetan 
Published: June 2023

Abstract
Background
Isoprenoids are a very large class of metabolites playing a key role in plant physiological processes such as growth, stress resistance, fruit flavor, and color. In chloroplasts and chromoplasts, the diterpene compound geranylgeranyl diphosphate (GGPP) is the metabolic precursor required for the biosynthesis of tocopherols, plastoquinones, phylloquinone, chlorophylls, and carotenoids. Despite its key role for the plant metabolism, reports on GGPP physiological concentrations in planta have been extremely scarce.

Results
In this study, we developed a method to quantify GGPP and its hydrolysis product geranylgeranyl monophosphate (GGP) from tomato fruit, using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS). Quantification was done by external calibration and the method was validated in terms of specificity, precision, accuracy, and detection and quantitation limits. We further demonstrate the validity of our approach by analysing GGPP contents in the ripe fruits of wild-type tomatoes and mutants defective in GGPP production. Finally, we also show that the sample preparation is key to prevent GGPP hydrolysis and mitigate its conversion to GGP.

Conclusion
Our study provides an efficient tool to investigate the metabolic fluxes required for GGPP supply and consumption in tomato fruit.
Technical guidelines for risk assessment of heavy metals in traditional Chinese medicines
Authors: Zuo Tian-Tian , Zhang Lei , Wang Ying , Nie Li-Xing , Shen Ming-Rui , Liu Li-Na , Yu Jian-Dong , Jin Hong-Yu , Wei Feng , Ma Shuang-Cheng 
Published: June 2023

Abstract
Background
Heavy metals are considered a global concern because they can deteriorate human health. This guideline aims to scientifically evaluate health risk of heavy metals in TCM and to propose a reference for decision making in developing TCM-related health policies.

Methods
Using a multidisciplinary approach, a steering committee oversaw the development of the guideline. To obtain a reasonable and accurate risk assessment, key exposure assessment parameters for TCM, e.g., exposure frequency (EF), exposure duration (ED), and daily ingestion rate (IR) were obtained from surveys. In addition, transfer rates for heavy metals from Chinese medicinal materials (CMM) to decoctions or preparations were examined.

Results
Based on the scientific theory of risk control, the guideline was designed systematically, and principles and procedures for the risk assessment of heavy metals in TCM were identified. The guideline can be utilized to assess the risk of heavy metals in CMM and Chinese patent medicines (CPM).

Conclusion
This guideline may help standardize the risk assessment of heavy metals in TCM, advance regulatory standards for heavy metals in TCM, and ultimately improve human health through scientific TCM usage in clinic.
Prevalence and influencing factors of sleep disorders among preschool children in Urumqi city: a cross-sectional survey
Authors: Gao Yongwei , Xu Peiru , Aizetiguli Maiming , Surong Shan , Zhu Zhaoxuan , Zhang Jing 
Published: June 2023

AbstractBackgroundSleep disorders refer to physiological and psychological states that cause adverse consequences due to the inability to fall asleep or poor sleep quality. The prevalence of sleep disorders varies greatly in different countries and regions due to different causes. This study aimed to investigate the prevalence and influencing factors of sleep disorders among preschool children in Urumqi city, China.MethodsA cross-sectional study was conducted with stratified random cluster sampling. Children aged 3–6 years old in one kindergarten randomly selected from each of the 8 districts of Urumqi from March to July 2022, and their parents were surveyed with a sleep quality questionnaire.ResultsThe prevalence of sleep disorders among preschool children in Urumqi was 14.29% (191/1336), and the prevalence of different symptoms was 42.81% for limb movements, 19.61% for snoring, 18.11% for bruxism, 16.39% for sleep talking, 12.57% for sweating, 11.60% for nocturnal awakening, 8.46% for nightmares, 6.89% for bed wetting, 3.74% for apnea, and 3.29% for sleepwalking. The prevalence of body movements, snoring, sweating, night-wake, nightmares, bed-wetting, apnea, and sleepwalking among different ethnicities were significantly different (P < 0.05). Multivariate analysis revealed that the major risk factors of sleep disorders were difficulty adapting to new environments, unwillingness to express emotions, inconsistent attitudes of the family toward children’s education, running before bedtime, strict family education methods, etc.ConclusionThe prevalence of sleep disorders in preschool children in Urumqi is lower than the average level reported in other studies. Many factors affect the prevalence of sleep disorders in preschool children, but it is necessary to focus on the ability to adapt to new environments, psychological problems, and the impact of family education on sleep disorders. Further studies on the prevention and treatment of sleep disorders are needed for different ethnicities.
Anticoagulation options for continuous renal replacement therapy in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials
Authors: Zhou Zhifeng , Liu Chen , Yang Yingying , Wang Fang , Zhang Ling , Fu Ping 
Published: June 2023

Abstract
Background
Continuous renal replacement therapy (CRRT) is a widely used standard therapy for critically ill patients with acute kidney injury (AKI). Despite its effectiveness, treatment is often interrupted due to clot formation in the extracorporeal circuits. Anticoagulation is a crucial strategy for preventing extracorporeal circuit clotting during CRRT. While various anticoagulation options are available, there were still no studies synthetically comparing the efficacy and safety of these anticoagulation options.

Methods
Electronic databases (PubMed, Embase, Web of Science, and the Cochrane database) were searched from inception to October 31, 2022. All randomized controlled trials (RCTs) that examined the following outcomes were included: filter lifespan, all-cause mortality, length of stay, duration of CRRT, recovery of kidney function, adverse events and costs.

Results
Thirty-seven RCTs from 38 articles, comprising 2648 participants with 14 comparisons, were included in this network meta-analysis (NMA). Unfractionated heparin (UFH) and regional citrate anticoagulation (RCA) are the most frequently used anticoagulants. Compared to UFH, RCA was found to be more effective in prolonging filter lifespan (MD 12.0, 95% CI 3.8 to 20.2) and reducing the risk of bleeding. Regional-UFH plus Prostaglandin I2 (Regional-UFH + PGI2) appeared to outperform RCA (MD 37.0, 95% CI 12.0 to 62.0), LMWH (MD 41.3, 95% CI 15.6 to 67.0), and other evaluated anticoagulation options in prolonging filter lifespan. However, only a single included RCT with 46 participants had evaluated Regional-UFH + PGI2. No statistically significant difference was observed in terms of length of ICU stay, all-cause mortality, duration of CRRT, recovery of kidney function, and adverse events among most evaluated anticoagulation options.

Conclusions
Compared to UFH, RCA is the preferred anticoagulant for critically ill patients requiring CRRT. The SUCRA analysis and forest plot of Regional-UFH + PGI2 are limited, as only a single study was included. Additional high-quality studies are necessary before any recommendation of Regional-UFH + PGI2. Further larger high-quality RCTs are desirable to strengthen the evidence on the best choice of anticoagulation options to reduce all-cause mortality and adverse events and promote the recovery of kidney function.
Trial registration The protocol of this network meta-analysis was registered on PROSPERO (CRD42022360263). Registered 26 September 2022.
Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis
Authors: Pedersen Janni Maria , Hansen Aida Solhøj , Skejø Cæcilie , Juul-Madsen Kristian , Junker Peter , Hørslev-Petersen Kim , Hetland Merete Lund , Stengaard-Pedersen Kristian , Østergaard Mikkel , Møller Bjarne Kuno , Dreyer Lene , Hauge Ellen-Margrethe , Hvid Malene , Greisen Stinne , Deleuran Bent 
Published: June 2023

Abstract
Background
Lymphocyte activation gene-3 (LAG-3) inhibits T cell activation and interferes with the immune response by binding to MHC-II. As antigen presentation is central in rheumatoid arthritis (RA) pathogenesis, we studied aspects of LAG-3 as a serological marker and mediator in the pathogenesis of RA. Since Galectin-3 (Gal-3) is described as an additional binding partner for LAG-3, we also aimed to study the functional importance of this interaction.

Methods
Plasma levels of soluble (s) LAG-3 were measured in early RA patients (eRA, n = 99) at baseline and after 12 months on a treat-to-target protocol, in self-reportedly healthy controls (HC, n = 32), and in paired plasma and synovial fluid (SF) from chronic RA patients (cRA, n = 38). Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were examined for LAG-3 expression by flow cytometry. The binding and functional outcomes of LAG-3 and Gal-3 interaction were assessed with surface plasmon resonance (SPR) and in cell cultures using rh-LAG3, an antagonistic LAG-3 antibody and a Gal-3 inhibitor.

Results
Baseline sLAG-3 in the plasma was increased in eRA compared to HC and remained significantly elevated throughout 12 months of treatment. A high level of sLAG-3 at baseline was associated with the presence of IgM-RF and anti-CCP as well as radiographic progression. In cRA, sLAG-3 was significantly increased in SF compared with plasma, and LAG-3 was primarily expressed by activated T cells in SFMCs compared to PBMCs. Adding recombinant human LAG-3 to RA cell cultures resulted in decreased cytokine secretion, whereas blocking LAG-3 with an antagonistic antibody resulted in increased cytokine secretion. By SPR, we found a dose-dependent binding between LAG-3 and Gal-3. However, inhibiting Gal-3 in cultures did not further change cytokine production.

Conclusions
sLAG-3 in the plasma and synovial fluid is increased in both early and chronic RA patients, particularly in the inflamed joint. High levels of sLAG-3 are associated with autoantibody seropositivity and radiographic progression in eRA, and LAG-3 plays a biologically active role in cRA by decreasing inflammatory cytokine production. This functional outcome is not affected by Gal-3 interference. Our results suggest that LAG-3 is a faceted regulator of inflammation in early and chronic RA.
Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/β-catenin signaling pathway
Authors: Xu Yuhui , Hu Jiali , Lv Qiaoying , Shi Chenyi , Qiu Mengdi , Xie Liying , Liu Wei , Yang Bingyi , Shan Weiwei , Cheng Yali , Zhao Bing , Chen Xiaojun 
Published: June 2023

AbstractBackgroundMesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.MethodsThe effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.ResultsOur results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.ConclusionsThe eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.
The global antimicrobial resistance response effort must not exclude marginalised populations
Authors: Adebisi Yusuff Adebayo , Ogunkola Isaac Olushola 
Published: June 2023

AbstractAntimicrobial resistance (AMR), a rising global health crisis causing about 700,000 deaths annually and potentially 10 million deaths by 2050, disproportionately impacts marginalised populations. Due to socioeconomic, ethnic, geographic, and other barriers, these communities often have restricted healthcare access, compounding the AMR threat. Unequal access to effective antibiotics, inadequate living conditions, and a lack of awareness exacerbate the crisis in marginalised communities, making them more susceptible to AMR. A broader, inclusive response is needed to ensure equitable access to antibiotics, improved living conditions, education, and policy changes to challenge the root socio-economic disparities. Ignoring marginalised populations in the fight against AMR is both a moral and strategic failure. Therefore, inclusivity must be a central tenet in combating AMR. This article not only critically dissects this prevailing oversight but also urgently calls for comprehensive action to address this significant shortcoming in our response efforts.
Blame or discovery? Walter Benjamin's Jetztzeit, Purdue Pharma LP and ‘our values and our historical understanding of psychiatrists’
Authors: Ikkos George 
Published: June 2023

SummaryThis commentary explores issues of professional identity, fairness and discovery in the history of psychiatry in the light of Walter Benjamin's (1892–1940) philosophy of history, especially his concept of Jetztzeit (now-time) and the profession's relationship with the founder and owners of Purdue Pharma LP.
A randomised phase II multicentre study of ipilimumab with temozolomide vs temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: Ipi-Glio.
Authors: Mulholland Paul James , Brown Nicholas Fraser , McBain Catherine , Brazil Lucy , Peoples Sharon , Jefferies Sarah , Harris Fiona , Plaha Puneet , Vinayan Anup , Brooks Claire , Hussain Samia , Dutton Susan J. , Ng Stasya , Levy Stephanie , Coutts Timothy 
Published: June 2023

LBA2023 Background: Median survival for patients with glioblastoma is less than a year. Standard treatment comprises surgical debulking if feasible followed by temozolomide (TMZ) chemoradiotherapy. The objective of this clinical trial is to evaluate whether the addition of the CTLA-4 immune checkpoint inhibitor ipilimumab (IPI) improves survival. Methods: Ipi-Glio is an academic phase II, open label, stratified randomised multicentre study of IPI + TMZ (Arm A) vs TMZ alone (Arm B), after surgery and radical radiotherapy with concomitant temozolomide in patients with recently diagnosed de-novo glioblastoma. Following completion of chemoRT, patients were randomised 2:1 Arm A:B, with stratification to extent of surgery and MGMT promotor methylation. IPI 3mg/kg was administered q3/52 for 4 cycles, and TMZ 150-200mg/m2 days 1-5 q4/52 for 6 cycles. Primary outcome was overall survival (OS), treatment difference reported as hazard ratio (HR) with 60% confidence intervals (CI) and OS at 18 months. Secondary outcomes were progression-free Survival (PFS) and safety. Results: 119 patients were randomly assigned, 79 to Arm A and 40 to Arm B, at seven centres in the UK between Jan 2019 and April 2021. Patient characteristics (Arm A vs B): median Age 53 vs 48 years; male sex 70% vs 65%; ECOG PS0 70 vs 70%, PS1 30 vs 30%; MGMT promotor methylation 39% vs 40%; IDH mutation 11% vs 10%; surgical gross total resection 61% vs 60%. PFS (Arm A vs B): median PFS 10.9 months (m) vs 12.5mo, HR 1.252 (60%CI 1.01-1.54, p=0.369); 18m PFS 22% (60%CI 17-27%) vs 43% (34-51%). Overall Survival (Arm A vs B): median OS 22.7 vs 26.4 months, HR 1.223 (60% CI 0.986-1.516, p=0.431); 18 month OS 53% (60%CI 48-58%) vs 64% (56-70%). Adverse events (AE) reported by CTCAE grade (Arm A vs B): total reported AEs 1058 vs 329; no. of reported AEs per patient: mean 13.5 (SD 10.1) vs mean 8.2 (SD 7.3). Conclusions: No improvement in PFS or OS was observed with the addition of ipilimumab to temozolomide. This study does not support further investigation of this regimen in this setting. Clinical trial information: ISRCTN84434175 .
Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial.
Authors: Conroy Thierry , Etienne Pierre-Luc , Rio Emmanuel , Evesque Ludovic , Mesgouez-Nebout Nathalie , Vendrely Veronique , Artignan Xavier , Bouche Olivier , Boileve Alice , Delaye Matthieu , Gargot Dany , Boige Valerie , Bonichon-Lamichhane Nathalie , Louvet Christophe , De La Fouchardiere Christelle , Morand Clotilde , Pezzella Veronica , Rullier Eric , Castan Florence , Borg Christophe 
Published: June 2023

LBA3504 Background: We have reported that neoadjuvant chemotherapy (NACT) with FOLFIRINOX followed by chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ACT) significantly improved outcomes in patients (pts) with locally advanced rectal cancer (LARC) compared with pts who received standard CRT, surgery, and ACT. We now report the primary and secondary endpoints with mature follow-up (F/U). Methods: PRODIGE 23 is a phase III randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, T location, and T extramural spread. Arm A pts received preoperative CRT (50 Gy, 2 Gy/fr; 25 fr + capecitabine), surgery, then ACT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX, then the same preoperative CRT, surgery and 3 mos of ACT, mFOLFOX6 or capecitabine. From 6/2012 to 6/2017, pts were randomly assigned in Arm A (n=230) and B (n=231) by 35 participating centers. Analysis was performed on intent-to-treat population. For survival outcomes, HR and 95% CI were estimated by a stratified Cox proportional hazard (PH) model. However, we observed non-PH. So we used the restricted mean survival time (RMST) to evaluate the treatment effect (Liang F & al Ann Oncol 2018, Pak K & al JAMA Oncol 2017). Results: With a median F/U of 82.2 mos, death was reported for 55 pts in arm A and 42 in Arm B. All survival endpoints were better for Arm B vs Arm A. The absolute increase in 5-year survival were 7.6% for Disease-Free Survival (DFS), 6.9% for Overall Survival (OS), 9.9% for Metastasis-Free Survival (MFS), and 5.7% for Cancer Specific Survival (CSS) in Arm B compared to Arm A. Survival results at 7 years are presented in the Table. 7-year cumulative incidence of locoregional relapses are 5.3% in arm B vs 8.1% in arm A (p= 0.38). Conclusions: NACT with mFOLFIRINOX followed by CRT, surgery, and ACT significantly improved all outcomes, including OS in pts with LARC vs those who received standard CRT, surgery, and ACT. Clinical trial information: NCT01804790 . [Table: see text]