bluuebunny/crossref_metadata_2025_split huggingface dataset:
Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy
Authors: Adhikarla Vikram , Awuah Dennis , Caserta Enrico , Minnix Megan , Kuznetsov Maxim , Krishnan Amrita , Wong Jefferey Y. C. , Shively John E. , Wang Xiuli , Pichiorri Flavia , Rockne Russell C. 
Published: April 2024

IntroductionCancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. MethodsUsing a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. ResultsTherapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. DiscussionMathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.
Unravelling B cell heterogeneity: insights into flow cytometry-gated B cells from single-cell multi-omics data
Authors: Pernes Jane I. , Alsayah Atheer , Tucci Felicia , Bashford-Rogers Rachael J. M. 
Published: April 2024

IntroductionB cells play a pivotal role in adaptive immunity which has been extensively characterised primarily via flow cytometry-based gating strategies. This study addresses the discrepancies between flow cytometry-defined B cell subsets and their high-confidence molecular signatures using single-cell multi-omics approaches.MethodsBy analysing multi-omics single-cell data from healthy individuals and patients across diseases, we characterised the level and nature of cellular contamination within standard flow cytometric-based gating, resolved some of the ambiguities in the literature surrounding unconventional B cell subsets, and demonstrated the variable effects of flow cytometric-based gating cellular heterogeneity across diseases.ResultsWe showed that flow cytometric-defined B cell populations are heterogenous, and the composition varies significantly between disease states thus affecting the implications of functional studies performed on these populations. Importantly, this paper draws caution on findings about B cell selection and function of flow cytometric-sorted populations, and their roles in disease. As a solution, we developed a simple tool to identify additional markers that can be used to increase the purity of flow-cytometric gated immune cell populations based on multi-omics data (AlliGateR). Here, we demonstrate that additional non-linear CD20, CD21 and CD24 gating can increase the purity of both naïve and memory populations.DiscussionThese findings underscore the need to reconsider B cell subset definitions within the literature and propose leveraging single-cell multi-omics data for refined characterisation. We show that single-cell multi-omics technologies represent a powerful tool to bridge the gap between surface marker-based annotations and the intricate molecular characteristics of B cell subsets.
Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program
Authors: van Leeuwen Leanne P. M. , Grobben Marloes , GeurtsvanKessel Corine H. , Ellerbroek Pauline M. , de Bree Godelieve J. , Potjewijd Judith , Rutgers Abraham , Jolink Hetty , van de Veerdonk Frank L. , van Gils Marit J. , de Vries Rory D. , Dalm Virgil A. S. H. ,   VACOPID Research Group
Published: April 2024

PurposePrevious studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.MethodsThis study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections.ResultsAfter booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer.ConclusionOur study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.
Patient-reported assessment of medical care for chronic inflammatory skin diseases: an enterprise-based survey
Authors: Wolk Kerstin , Schielein Maximilian , Maul Julia-Tatjana , Widmayer Fontaine , Wanke Kerstin , Fischmann Wolfgang , Nathan Petra , Sabat Robert 
Published: April 2024

BackgroundChronic inflammatory skin diseases (CISDs) are among the most common diseases in the Western world. Current estimates of medical care for CISDs are primarily based on surveys among patients in medical care facilities and on health insurance data.AimSurvey-based examination to what extent CISD patients in health-aware environment consider their skin disease to be controlled.MethodsThe survey of CISD patients was carried out in 2022 among the employees of a pharmaceutical company located in Germany and Switzerland. Software-based, anonymous, self-reported questionnaires were used.ResultsThe number of employees, who answered the questionnaire, was 905. Of these, 222 participants (24.5%) reported having at least one CISD. 28.7% of participants with CISD described their disease as being hardly or not controlled. Regarding the nature of disease, more than one third of participants suffering from hidradenitis suppurativa (HS) or psoriasis fell into the hardly/not controlled category. In contrast, the largest proportion of participants with chronic spontaneous urticaria (43%) or atopic dermatitis (42%) considered their CISD to be completely or well controlled. Only 35.5% of CISD sufferers stated that they were currently under medical care for their skin condition. Being under medical care, however, had no influence on the extent CISD sufferers considered their skin disease to be controlled. The number of active CISD episodes but not the total number of symptomatic days per year was negatively associated with poor disease control (p = 0.042 and p = 0.856, respectively). Poor disease control had a negative effect on the personal and professional lives of those affected, as deduced from its positive association with the extent of daily activity impairment and presenteeism (p = 0.005 and p = 0.005, respectively). Moreover, 41.4 and 20.7% of participants with hardly/not controlled disease stated that their CISD had a moderate and severe or very severe impact on their overall lives (p &lt; 0.001), respectively. A severe or very severe impact of their CISD on their overall life was most commonly reported by participants with HS.ConclusionMedical care for CISDs, even in an environment with high socio-economic standard and high health-awareness, still appears to be limited and has a negative impact on individuals and society.
ED50 of remimazolam combined with different doses butorphanol for first trimester artificial abortion
Authors: Chen Jinming , Li Xiaoling , Hu Zilan , Zheng Yuling , Mai Ying , Zhang Zhongqi 
Published: April 2024

IntroductionRemimazolam (RMZ) is a novel intravenous sedative drug of ultra-short benzodiazepine. The optimal dose of RMZ plus butorphanol for sedation during first trimester artificial abortion is unknown. Therefore, the present study aimed to evaluate the median effective dose (ED50) of RMZ combined with different doses of butorphanol on the sedative effect for first-trimester artificial abortion.MethodsSixty-one female patients were randomly assigned to Group B10 (31 patients) and Group B15 (30 patients). RMZ was administered 5 min after IV butorphanol at doses of 10 μg/kg (Group B10) and 15 μg/kg (Group B15). Cervical dilatation at the time of using a cervical dilating rod, if the patient has body movement and affects the gynecologist’s operation, we define it as “Ineffective.” Therefore, the dose of RMZ was increased in the next patient. Otherwise, it was defined as “Effective,” and the dose of RMZ was reduced in the next patient. According to the pre-experiment, the first dose of RMZ in the first patient was 0.35 mg/kg, and the adjacent geometric dose ratio was 0.9. The centered isotonic regression was performed to determine the ED50 of RMZ. The total RMZ dose administered, recovery time, and anesthesia-related adverse events were all recorded.ResultsThe ED50 (90% CI) of RMZ was 0.263 (0.215–0.310) mg/kg in Group B10, and 0.224 (0.191–0.261) mg/kg in Group B15, respectively. The recovery time in Group B10 was significantly shorter than in Group B15 (9.8 ± 2.3 vs. 12.5 ± 3.6 min, p ≤ 0.001). There was no significant difference in the incidence rate of all anesthesia-related adverse events between the two groups (p &gt; 0.05).ConclusionThe ED50 of RMZ combined with a 10 μg/kg or 15 μg/kg dose of butorphanol was 0.263 and 0.224 mg/kg during painless first trimester artificial abortion. However, RMZ combined with a 10 μg/kg dose of butorphanol seems to have a shorter recovery time.Clinical trial registrationhttps://www.chictr.org.cn/bin/project/edit?pid=166623.
Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice
Authors: Berlanga-Acosta Jorge , Arteaga-Hernandez Ernesto , Garcia-Ojalvo Ariana , Duvergel-Calderin Dayanis , Rodriguez-Touseiro Marisol , Lopez-Marin Laura , Suarez-Alba Jose , Fuentes-Morales Dasha , Mendoza-Fuentes Osmany , Fernández-Puentes Sheyla , Nuñez-Figueredo Yanier , Guillen-Nieto Gerardo 
Published: April 2024

Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100 µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2 months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for “malignancy drivers,” which ultimately implement a carcinogenesis process in otherwise healthy mice.
Establishing a nutrition calculation model for catering food according to the influencing factors of energy and nutrient content in food processing
Authors: Li Nan , Cong Liangzi , Wang Heng , Chen Yamin , Liu Zhaowei , Li Mingliang , Yang Dong , Li Huzhong , Fang Haiqin 
Published: April 2024

ObjectiveThis study aimed to establish an accurate and efficient scientific calculation model for the nutritional composition of catering food to estimate energy and nutrient content of catering food.MethodsWe constructed a scientific raw material classification database based on the Chinese food composition table by calculating the representative values of each food raw material type. Using China’s common cooking methods, we cooked 150 dishes including grains, meat, poultry, fish, eggs, and vegetables and established a database showing the raw and cooked ratios of various food materials by calculating the ratio of raw to cooked and the China Total Diet Research database. The effects of various cooking methods on the nutritional composition of catering food were analyzed to determine correction factors for such methods on the nutritional components. Finally, we linked the raw material classification, raw and cooked ratio, and nutritional component correction factor databases to establish a model for calculating the nutritional components of catering food. The model was verified with nine representative Chinese dishes.ResultsWe have completed the construction of an accurate and efficient scientific calculation model for the nutritional composition of catering food, which improves the accuracy of nutrition composition calculation.ConclusionThe model constructed in this study was scientific, accurate, and efficient, thereby promising in facilitating the accurate calculation and correct labeling of nutritional components in catering food.
Home capillary sampling and screening for type 1 diabetes, celiac disease, and autoimmune thyroid disease in a Swedish general pediatric population: the TRIAD study
Authors: Naredi Scherman Maria , Lind Alexander , Hamdan Samia , Lundgren Markus , Svensson Johan , Pociot Flemming , Agardh Daniel 
Published: April 2024

ObjectiveTo screen a general pediatric population for type 1 diabetes (T1D), celiac disease (CD), and autoimmune thyroid disease (AITD) after home capillary sampling.MethodsSwedish schoolchildren between 6–9 years and 13–16 years of age were invited to screening by taking a capillary sample at home. Samples were returned by mail and assessed for autoantibodies associated with T1D, CD, and AITD. Persistently autoantibody-positive children were referred for clinical follow-up.ResultsOf 19,593 invited, 3,527 (18.0%) consented to participate and 2,315/3,527 (65.6%) returned a blood sample of sufficient volume. Hemolysis occurred in 830/2,301 (36.1%) samples. After exclusion of 42 children with previously known T1D, CD, or AITD, and two autoantibody-positive children who declined a confirmatory sample, 2,271/19,593 (11.6%) were included. 211/2,271 (9.3%) had persistent autoantibodies: 60/2,271 (2.6%) with T1D autoantibodies, 61/2,271 (2.7%) with CD autoantibodies, and 99/2,271 (4.4%) with AITD autoantibodies; 9/2,271 (0.4%) were autoantibody positive for ≥1 disease. After clinical follow-up, 3/2,271 (0.1%) were diagnosed with T1D, 26/2,271 (1.1%) with CD, and 6/2,271 (0.3%) with AITD. Children with a first-degree relative (FDR) with T1D, CD, and/or AITD, had higher occurrence of autoantibodies compared to children without an FDR (63/344, 18.3%, vs. 148/1,810, 8.2%) (p &lt; 0.0001, OR 2.52, 95% CI 1.83–3.47), and higher occurrence of screening-detected diagnosis (14/344, 4.1%, vs. 21/1,810, 1.2%) (p &lt; 0.0001, OR 3.61, 95% CI 1.82–7.18). Half of these children screened positive for another disease than the FDR.ConclusionScreening for T1D, CD, and AITD by home capillary sampling in a Swedish general pediatric population detected autoimmunity in 9.3% and undiagnosed disease in 1.5%.
Bismuth subsalicylate, probiotics, rifaximin and vaccines for the prevention of travelers’ diarrhea: a systematic review and network meta-analysis
Authors: Fan Hao , Liu I-Chun , Gao Lei , Wu Lanka 
Published: April 2024

Background: Bismuth subsalicylate (BSS), probiotics, rifaximin, and vaccines have been proposed as preventive modalities for patients with travelers’ diarrhea (TD), but their comparative effectiveness for prevention has rarely been studied. We aimed to perform a systematic review and network meta-analysis to test whether one of these modalities is more effective than the others in reducing the incidence of TD.Methods: We searched Pubmed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and clinical registries from inception of the databases through 18 November 2023, without language restriction, for randomized controlled trials (RCTs) evaluating the efficacy of BSS, probiotics, rifaximin, and vaccines in preventing TD. The primary outcome was the incidence of TD and the safety outcome was the incidence of adverse events. The relative ratio (RR) was used to assess the effect of the modalities, and RR estimates between any two of the modalities were calculated and pooled using a frequentist network meta-analysis model.Results: Thirty-one studies (recruiting 10,879 participants) were included in the analysis. Sixteen were judged to have a low risk of bias. In the aggregate analysis, BSS and rifaximin were more effective than placebo and other treatment modalities, which was further confirmed in the individual analysis. The comparison between rifaximin and placebo achieved high confidence, while the comparisons between BSS and placebo, ETEC and probiotics, and rifaximin and vaccines achieved moderate confidence. BSS had a higher rate of adverse events compared with other treatments.Conclusion: Rifaximin had a relative lower TD incidence and lower adverse event rate, and the evidence was with moderate confidence.Systematic Review Registration:https://osf.io/dxab6, identifier.
Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation
Authors: Kidane Yared H. , Lee Franklin H. , Smith Matthew F. , Wang Chunbo , Mirza Jacqueline Barbera , Sharma Saachi , Lobo Alejandro A. , Dewan Krish C. , Chen Jengwei , Diaz Thomas E. , Pla Michelle Mendiola , Foster Matthew W. , Bowles Dawn E. 
Published: April 2024

Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion) develop cardiovascular dysfunction by 12 months post-radiation.Methods: To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8 months post-radiation.Results: Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted p-value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted p-value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR5-ion irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis.Discussion: These findings suggest that a single exposure to GCR5-ion results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice.