bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trans-population graph-based coverage optimization of allogeneic cellular therapy
Authors: Israeli Sapir , Krakow Elizabeth F. , Maiers Martin , Summers Corinne , Louzoun Yoram 
Published: May 2023

BackgroundPre-clinical development and in-human trials of ‘off-the-shelf’ immune effector cell therapy (IECT) are burgeoning. IECT offers many potential advantages over autologous products. The relevant HLA matching criteria vary from product to product and depend on the strategies employed to reduce the risk of GvHD or to improve allo-IEC persistence, as warranted by different clinical indications, disease kinetics, on-target/off-tumor effects, and therapeutic cell type (T cell subtype, NK, etc.).ObjectiveThe optimal choice of candidate donors to maximize target patient population coverage and minimize cost and redundant effort in creating off-the-shelf IECT product banks is still an open problem. We propose here a solution to this problem, and test whether it would be more expensive to recruit additional donors or to prevent class I or class II HLA expression through gene editing.Study designWe developed an optimal coverage problem, combined with a graph-based algorithm to solve the donor selection problem under different, clinically plausible scenarios (having different HLA matching priorities). We then compared the efficiency of different optimization algorithms – a greedy solution, a linear programming (LP) solution, and integer linear programming (ILP) -- as well as random donor selection (average of 5 random trials) to show that an optimization can be performed at the entire population level.ResultsThe average additional population coverage per donor decrease with the number of donors, and varies with the scenario. The Greedy, LP and ILP algorithms consistently achieve the optimal coverage with far fewer donors than the random choice. In all cases, the number of randomly-selected donors required to achieve a desired coverage increases with increasing population. However, when optimal donors are selected, the number of donors required may counter-intuitively decrease with increasing population size. When comparing recruiting more donors vs gene editing, the latter was generally more expensive. When choosing donors and patients from different populations, the number of random donors required drastically increases, while the number of optimal donors does not change. Random donors fail to cover populations different from their original populations, while a small number of optimal donors from one population can cover a different population.DiscussionGraph-based coverage optimization algorithms can flexibly handle various HLA matching criteria and accommodate additional information such as KIR genotype, when such information becomes routinely available. These algorithms offer a more efficient way to develop off-the-shelf IECT product banks compared to random donor selection and offer some possibility of improved transparency and standardization in product design.
Interleukin 36 receptor-inducible matrix metalloproteinase 13 mediates intestinal fibrosis
Authors: Koop Kristina , Enderle Karin , Hillmann Miriam , Ruspeckhofer Laura , Vieth Michael , Sturm Gregor , Trajanoski Zlatko , Kühl Anja A. , Atreya Raja , Leppkes Moritz , Baum Patrick , Roy Janine , Martin Andrea , Neurath Markus F. , Neufert Clemens 
Published: May 2023

BackgroundFibrostenotic disease is a common complication in Crohn’s disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis.MethodsWe performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson’s Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis.ResultsBulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis.ConclusionTargeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.
Machine learning-based glycolysis-associated molecular classification reveals differences in prognosis, TME, and immunotherapy for colorectal cancer patients
Authors: Wang Zhenling , Shao Yu , Zhang Hongqiang , Lu Yunfei , Chen Yang , Shen Hengyang , Huang Changzhi , Wu Jingyu , Fu Zan 
Published: May 2023

BackgroundAerobic glycolysis is a process that metabolizes glucose under aerobic conditions, finally producing pyruvate, lactic acid, and ATP for tumor cells. Nevertheless, the overall significance of glycolysis-related genes in colorectal cancer and how they affect the immune microenvironment have not been investigated.MethodsBy combining the transcriptome and single-cell analysis, we summarize the various expression patterns of glycolysis-related genes in colorectal cancer. Three glycolysis-associated clusters (GAC) were identified with distinct clinical, genomic, and tumor microenvironment (TME). By mapping GAC to single-cell RNA sequencing analysis (scRNA-seq), we next discovered that the immune infiltration profile of GACs was similar to that of bulk RNA sequencing analysis (bulk RNA-seq). In order to determine the kind of GAC for each sample, we developed the GAC predictor using markers of single cells and GACs that were most pertinent to clinical prognostic indications. Additionally, potential drugs for each GAC were discovered using different algorithms.ResultsGAC1 was comparable to the immune-desert type, with a low mutation probability and a relatively general prognosis; GAC2 was more likely to be immune-inflamed/excluded, with more immunosuppressive cells and stromal components, which also carried the risk of the poorest prognosis; Similar to the immune-activated type, GAC3 had a high mutation rate, more active immune cells, and excellent therapeutic potential.ConclusionIn conclusion, we combined transcriptome and single-cell data to identify new molecular subtypes using glycolysis-related genes in colorectal cancer based on machine-learning methods, which provided therapeutic direction for colorectal patients.
One size does not fit all: an exploratory interview study on how translational researchers navigate the current academic reward system
Authors: Kools Farah R. W. , Fox Christine M. , Prakken Berent J. , van Rijen Harold V. M. 
Published: May 2023

IntroductionTranslational research is a subfield of the biomedical life sciences that focuses on clinically driven healthcare innovations. The workforce of this subfield, i.e., translational researchers, are diversely specialized and collaborate with a multitude of stakeholders from diverse disciplines in and outside academia in order to navigate the complex path of translating unmet clinical needs into research questions and ultimately into advancements for patient care. Translational researchers have varying responsibilities in the clinical, educational, and research domains requiring them to split their time two- or three-ways. Working between these domains and alongside peers who do not split their time as such, raises questions about the academic reward system used to recognize their performance, which mainly focuses on publication metrics within the research domain. What is unclear is how combining research tasks with tasks in the clinical and/or educational domains effects translational researchers and how they navigate the academic reward system.MethodsIn this exploratory interview study, semi-structured interviews were conducted to gain a deeper understanding of the current academic reward system for translational researchers. Stratified purposeful sampling was used to recruit 14 translational researchers from varying countries, subspecialties, and career stages. The interviews were coded after data collection was complete and arranged into three overarching result categories: intrinsic motivation, extrinsic factors, and ideal academic reward system and advice.ResultsWe found that these 14 translational researchers were intrinsically motivated to achieve their translational goals while working in settings where clinical work was reported to take priority over teaching which in turn took priority over time for research. However, it is the latter that was explained to be essential in the academic reward system which currently measures scientific impact largely based on publications metrics.ConclusionIn this study, translational researchers were asked about their thoughts regarding the current academic reward system. Participants shared possible structural improvements and ideas for specialized support on an individual, institutional, and also international level. Their recommendations focused on acknowledging all aspects of their work and led to the conclusion that traditional quantitative academic reward metrics do not fully align with their translational goals.
Skin infiltrating T-cell profile of drug reaction with eosinophilia and systemic symptoms (DRESS) reactions among HIV-infected patients
Authors: Chimbetete Tafadzwa , Choshi Phuti , Pedretti Sarah , Porter Mireille , Roberts Riyaadh , Lehloenya Rannakoe , Peter Jonathan 
Published: May 2023

IntroductionDrug Reaction with Eosinophilia Systemic Symptoms (DRESS) is more common in persons living with HIV (PLHIV), and first-line anti-TB drugs (FLTDs) and cotrimoxazole are the commonest offending drugs. Limited data is available on the skin infiltrating T-cell profile among DRESS patients with systemic CD4 T-cell depletion associated with HIV.Materials and methodsHIV cases with validated DRESS phenotypes (possible, probable, or definite) and confirmed reactions to either one or multiple FLTDs and/or cotrimoxazole were chosen (n = 14). These cases were matched against controls of HIV-negative patients who developed DRESS (n = 5). Immunohistochemistry assays were carried out with the following antibodies: CD3, CD4, CD8, CD45RO and FoxP3. Positive cells were normalized to the number of CD3+ cells present.ResultsSkin infiltrating T-cells were mainly found in the dermis. Dermal and epidermal CD4+ T-cells (and CD4+/CD8+ ratios) were lower in HIV-positive vs. negative DRESS; p &lt; 0.001 and p = 0.004, respectively; without correlation to whole blood CD4 cell counts. In contrast, no difference in dermal CD4+FoxP3+ T-cells was found in HIV-positive vs. negative DRESS, median (IQR) CD4+FoxP3+ T-cells: [10 (0–30) cells/mm2 vs. 4 (3–8) cells/mm2, p = 0.325]. HIV-positive DRESS patients reacting to more than one drug had no difference in CD8+ T-cell infiltrates, but higher epidermal and dermal CD4+FoxP3+ T-cell infiltrates compared to single drug reactors.ConclusionDRESS, irrespective of HIV status, was associated with an increased skin infiltration of CD8+ T-cells, while CD4+ T-cells were lower in HIV-positive DRESS compared to HIV-negative DRESS skin. While inter-individual variation was high, the frequency of dermal CD4+FoxP3+ T-cells was higher in HIV-positive DRESS cases reacting to more than one drug. Further research is warranted to understand the clinical impact of these changes.
HAIC as a potential therapy for esophageal cancer patients with liver metastasis: a retrospective cohort study
Authors: Dong Fengxiao , Cao Guang , Lu Zhihao 
Published: May 2023

MethodsThis was a single-arm historical cohort study of ESCC patients with synchronous or heterochronous LM between December 2014 and July 2021 at the Department of Gastrointestinal Oncology. The patients were treated with HAIC for LM, and regular image assessments were performed according to the judgment of the interventional physician. Liver progression-free survival (PFS), liver objective response rate (ORR), liver disease control rate (DCR), overall survival (OS), adverse events (AEs), treatment information, and basic characteristics were observed retrospectively.ResultsOverall, a total of 33 patients were enrolled in this study. All included patients received catheterized HAIC therapy, with a median of three (ranging from 2 to 6) sessions. The treatment response of liver metastatic lesions included partial response (PR) in 16 (48.5%) patients, stable disease (SD) in 15 (45.5%) patients, and progressive disease (PD) in two (6.1%) patients, for an ORR of 48.5% and a DCR of 93.9%. The median liver PFS was 4.8 months (95% confidence interval (CI): 3.0–6.6 months), and the median OS was 6.4 months (95% CI: 6.1–6.6 months). Patients who achieved PR at the liver metastasis site after HAIC were more likely to have a longer OS than those who achieved SD or PD. Grade 3 AEs occurred in 12 patients. The most common grade 3 AE was nausea, occurring in 10 (30.0%) patients, followed by abdominal pain in three (9.1%) patients. Only one patient showed grade 3 elevation of alanine aminotransferase (ALT)/aspartate aminotransferase (AST), and one patient suffered from grade 3 embolism syndrome AEs. Grade 4 adverse events, followed by abdominal pain, occurred in one patient.ConclusionHepatic arterial infusion chemotherapy might be an option as a regional therapy for ESCC patients with LM, as it is acceptable and tolerable.
Genomic representation predicts an asymptotic host adaptation of bat coronaviruses using deep learning
Authors: Li Jing , Tian Fengjuan , Zhang Sen , Liu Shun-Shuai , Kang Xiao-Ping , Li Ya-Dan , Wei Jun-Qing , Lin Wei , Lei Zhongyi , Feng Ye , Jiang Jia-Fu , Jiang Tao , Tong Yigang 
Published: May 2023

IntroductionCoronaviruses (CoVs) are naturally found in bats and can occasionally cause infection and transmission in humans and other mammals. Our study aimed to build a deep learning (DL) method to predict the adaptation of bat CoVs to other mammals.MethodsThe CoV genome was represented with a method of dinucleotide composition representation (DCR) for the two main viral genes, ORF1ab and Spike. DCR features were first analyzed for their distribution among adaptive hosts and then trained with a DL classifier of convolutional neural networks (CNN) to predict the adaptation of bat CoVs.Results and discussionThe results demonstrated inter-host separation and intra-host clustering of DCR-represented CoVs for six host types: Artiodactyla, Carnivora, Chiroptera, Primates, Rodentia/Lagomorpha, and Suiformes. The DCR-based CNN with five host labels (without Chiroptera) predicted a dominant adaptation of bat CoVs to Artiodactyla hosts, then to Carnivora and Rodentia/Lagomorpha mammals, and later to primates. Moreover, a linear asymptotic adaptation of all CoVs (except Suiformes) from Artiodactyla to Carnivora and Rodentia/Lagomorpha and then to Primates indicates an asymptotic bats-other mammals-human adaptation.ConclusionGenomic dinucleotides represented as DCR indicate a host-specific separation, and clustering predicts a linear asymptotic adaptation shift of bat CoVs from other mammals to humans via deep learning.
Comparative transcriptomic analysis of PK15 cells infected with a PRV variant and the Bartha-K/61 vaccine strain
Authors: Zhang Hongliang , Duan Xiaoxiao , Liu Gang , Li Yingguang , Dong Shaoming , Lin Jiaxu , Zhang Ruihua , Cai Xiulei , Shan Hu 
Published: May 2023

IntroductionPseudorabies virus (PRV) is a herpesvirus that can infect domestic animals, such as pigs, cattle and sheep, and cause fever, itching (except pigs), and encephalomyelitis. In particular, the emergence of PRV variants in 2011 have resulted in serious economic losses to the Chinese pig industry. However, the signaling pathways mediated by PRV variants and their related mechanisms are not fully understood.MethodsHere, we performed RNA-seq to compare the gene expression profiling between PRV virulent SD2017-infected PK15 cells and Bartha-K/61-infected PK15 cells.ResultsThe results showed that 5,030 genes had significantly different expression levels, with 2,239 upregulated and 2,791 downregulated. GO enrichment analysis showed that SD2017 significantly up-regulated differentially expressed genes (DEGs) were mainly enriched in the binding of cell cycle, protein and chromatin, while down-regulated DEGs were mainly enriched in ribosomes. KEGG enrichment analysis revealed that the pathways most enriched for upregulated DEGs were pathways in cancer, cell cycle, microRNAs in cancer, mTOR signaling pathway and autophagy-animal. The most down-regulated pathways of DEGs enrichment were ribosome, oxidative phosphorylation, and thermogenesis. These KEGG pathways were involved in cell cycle, signal transduction, autophagy, and virus-host cell interactions.DiscussionOur study provides a general overview of host cell responses to PRV virulent infection and lays a foundation for further study of the infection mechanism of PRV variant strain.
A functional metagenomics study of soil carbon and nitrogen degradation networks and limiting factors on the Tibetan plateau
Authors: Yang Chong , Zhang Hong , Zhao Xinquan , Liu Pan , Wang Lushan , Wang Wenying 
Published: May 2023

IntroductionThe Three-River Source Nature Reserve is located in the core area of the Qinghai-Tibetan Plateau, with the alpine swamp, meadow and steppe as the main ecosystem types. However, the microbial communities in these alpine ecosystems, and their carbon and nitrogen degrading metabolic networks and limiting factors remain unclear.MethodsWe sequenced the diversity of bacteria and fungi in alpine swamps, meadows, steppes, and their degraded and artificially restored ecosystems and analyzed soil environmental conditions.ResultsThe results indicated that moisture content had a greater influence on soil microbial community structure compared to degradation and restoration. Proteobacteria dominated in high moisture alpine swamps and alpine meadows, while Actinobacteria dominated in low moisture alpine steppes and artificial grasslands. A metabolic network analysis of carbon and nitrogen degradation and transformation using metagenomic sequencing revealed that plateau microorganisms lacked comprehensive and efficient enzyme systems to degrade organic carbon, nitrogen, and other biological macromolecules, so that the short-term degradation of alpine vegetation had no effect on the basic composition of soil microbial community. Correlation analysis found that nitrogen fixation was strong in meadows with high moisture content, and their key nitrogen-fixing enzymes were significantly related to Sphingomonas. Denitrification metabolism was enhanced in water-deficient habitats, and the key enzyme, nitrous oxide reductase, was significantly related to Phycicoccus and accelerated the loss of nitrogen. Furthermore, Bacillus contained a large number of amylases (GH13 and GH15) and proteases (S8, S11, S26, and M24) which may promote the efficient degradation of organic carbon and nitrogen in artificially restored grasslands.DiscussionThis study illustrated the irrecoverability of meadow degradation and offered fundamental information for altering microbial communities to restore alpine ecosystems.
Safety and efficacy of lecanemab for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials
Authors: Qiao Yue , Chi Yuewei , Zhang Qingyuan , Ma Ying 
Published: May 2023

ObjectiveWe performed a systematic review and meta-analysis of the cognitive effectiveness and safety of lecanemab on subjects with Alzheimer's disease (AD).MethodsWe screened the literature published before February 2023 in PubMed, Embase, Web of Science, and Cochrane that were searched for randomized controlled trials testing lecanemab for the treatment of cognitive decline in patients with MCI or AD. Outcomes measured were CDR Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), AD Assessment Scale–Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating (CDR), amyloid PET Standardized Uptake Volume Ratio (SUVr), amyloid burden on PET, and risks for adverse events.ResultsA total of four randomized controlled trials were included, involving 3,108 AD patients (1,695 lecanemab groups and 1,413 placebo groups) to synthesize evidence. Baseline characteristics of the two groups were similar in all outcomes except that ApoE 4 status and higher MMSE score were observed in the lecanemab group. It is reported that lecanemab was beneficial to stabilize or slow down the decrease in CDR-SB (WMD: −0.45; 95% CI: −0.64, −0.25;p&lt; 0.00001), ADCOMS (WMD: −0.05; 95% CI: −0.07, −0.03;p&lt; 0.00001), ADAS-cog (WMD: −1.11; 95% CI: −1.64, −0.57;p&lt; 0.0001), amyloid PET SUVr (WMD: −0.15; 95% CI: −0.48, 0.19;p= 0.38), amyloid burden on PET (WMD:−35.44; 95% CI: −65.22,−5.67;p= 0.02), adverse events (subjects with any TEAE) (OR: 0.73; 95% CI: 0.25, 2.15;p= 0.57), ARIA-E (OR:8.95; 95% CI: 5.36, 14.95;p&lt; 0.00001), and ARIA-H (OR:2.00; 95% CI: 1.53, 2.62;p&lt; 0.00001) in early AD patients.ConclusionOur analysis found that lecanemab showed significant positive statistical efficacy with respect to cognition, function, and behavior in patients with early AD though the actual clinical significance is yet to be establishedSystematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD42023393393.