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ObjectivesWe aim to assess the pooled incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in clinical trials and real-world studies of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancy and compare the incidences among different agents.MethodsThe PubMed, Embase, and Web of Science databases were searched for clinical trials and real-world studies. An inverse-variance weighting model was used to calculate pooled incidences and subgroup analyses. Multivariable analysis was conducted using binomial-normal modeling.ResultsSeventy-five trials comprising 3,184 patients were included. The overall pooled incidence was 26.9% (95% CI, 21.7–32.7%) for all-grade and 10.5% (95% CI, 8.1–13.6%) for high-grade ICANS. In subgroup analysis, cohorts with anti-CD19 drugs had significantly higher ICANS incidences than cohorts with other agents. The multivariable analysis demonstrated higher odds of ICANS in anti-CD19 drug studies for high-grade (OR, 4.6) compared to anti-BCMA drug studies. In 12 real-world studies, studies used axicabtagene ciloleucel with CD28 (54.0% all-grade, 26.4% high-grade) exhibited significantly higher rates of all-grade and high-grade ICANS than studies using tisagenlecleucel with 4-1BB (17.2% all-grade, 6.1% high-grade).ConclusionsThe overall incidences of ICANS with CAR T-cell therapy were 26.9% for all-grade and 10.5% for high-grade. Compared with other agents, patients with anti-CD19 drugs had a significantly increased risk of developing high-grade ICANS. Therefore, careful monitoring of ICANS should be considered for patients undergoing CAR T-cell therapy.

While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population. We retrospectively identified 128 patients with grade 1–3A FL who had an interim PET after 2–4 cycles of frontline CIT at 2 academic centers. PET scans were analyzed using Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Interim PET DS was a significant predictor of PFS (P < 0.003). Patients with a DS of 3 had outcomes similar to those of patients with a DS of 4, so were categorized as PET-positive for additional analyses. Interim PET remained a strong predictor of PFS (DS 3-5, hazard ratio [HR] 2.4, P = 0.006) in a multivariable analysis and was also an early predictor of both a positive end-of-treatment PET (P < 0.001) and progression of disease within 24 months (POD24) (P = 0.006). An optimal ΔSUVmax cutoff of 75% was selected using the bootstrap method. ΔSUVmax

Category: Ankle; Ankle Arthritis Introduction/Purpose: Recently, talofibular bony impingement has been postulated to be a source of ankle pain. This study aimed to evaluate the relationship between talofibular impingement and increased talar tilt in incongruent varus ankle OA patients using bilateral weightbearing CT. Methods: Incongruent varus ankle osteoarthritis was defined as a talar tilt of more than 4° on standard ankle anteroposterior radiographs. We retrospectively reviewed 30 patients with unilateral incongruent varus ankle osteoarthritis with normal alignment of the contralateral ankle. All patients underwent bilateral weightbearing computed tomography and standing plain radiographs. The talar tilt and the distance between the talar lateral process and lateral malleolar tip were measured from a standing ankle anteroposterior radiograph of both sides. Talar and fibular spurs were assessed on the coronal and axial views of weightbearing computed tomography. After simulating the correction of the talar tilt in varus ankle osteoarthritis, talofibular bony impingement was reassessed. Results: On the varus side, the distance between the talar lateral process and the lateral malleolar tip was significantly shorter than that on the contralateral side (p < .001). Talar spur was present in the varus side of all 30 patients on the axial view of weightbearing computed tomography and in the control side of 10 patients. After the simulation of talar tilt correction, talofibular impingement (overlap) occurred in all 30 patients with a larger extent in the severe talar tilt subgroup (p < .001). Conclusion: Talofibular impingement by lateral gutter osteophytes is closely related to increased talar tilt in patients with incongruent varus ankle osteoarthritis. Therefore, lateral gutter osteophytes should be resected to stabilize mortise and improve clinical outcomes.

PET/CT is a commonly used modality in cancer imaging, as it can help in diagnosis, staging and assessment of treatment response in many cancer types. A better understanding of the tumor microenvironment and identification of multiple selective targets are promoting further investigation into different radiotracers for diagnosis and therapy. In the past few decades many radiopharmaceuticals have emerged for specific oncologic indications providing superior detection rate than some morphologic modalities. The purpose of this review is to provide an update on the most current radiopharmaceuticals used in cancer imaging including the mechanism of action, indications and pitfalls.

The objective of this study was to compare the effects of supplementation with two methionine isoforms, L-methionine (L-Met) or D-methionine (D-Met), on transcriptome expression in broiler chickens under acute heat stress. A total of 240 one-day-old chicks were randomly assigned to one of four treatments in a 2 × 2 factorial arrangement: thermo-neutral vs. acute heat-stress and L-Met vs. D-Met supplementation. On day 14, the heat-stressed group was exposed to 32°C for 5 h, while the others remained at 25°C. Six chicks were randomly selected per treatment and total RNA was isolated from whole blood, ileum, and liver tissues. Two RNA samples from each tissue of each treatment group were randomly selected and pooled in equal amounts. A total of 1.87 billion raw reads obtained from 36 samples (four treatments × three tissues × three composited replicates) were mapped to the reference genome build (Gallus_gallus-5.0) and used to identify differentially expressed genes (DEGs) using DESeq2. Functional enrichment of DEGs was tested using DAVID. Comparing the two isoforms of supplemented methionine, two, three, and ten genes were differentially expressed (> 1 or < -1 log2 fold change) in whole blood, ileum, and liver, respectively. A total of 38, 71, and 16 genes were differentially expressed in response to the interaction between heat stress and Met isoforms in the blood, ileum, and liver, respectively. Three-tissue-specific DEGs were functionally enriched for regulation of cholesterol homeostasis and metabolism, glucose metabolism, and vascular patterning. Chicks fed with L-Met had lower immune (e.g., IL4I1 and SERPINI1) and intestinal angiogenic responses (e.g., FLT1 and FGD5), and stable glucose and lipid metabolism (e.g., PCK1 and LDLR) under heat stress conditions. In conclusion, unlike D-Met, L-Met supplementation seems to help maintain physiological homeostasis and enhances cellular defense systems against external stresses like high environmental temperature.

Heavy metal is one of the most frequent soil contaminants and contaminated soils generally include numerous metals. Although exposure to multiple metals may increase the toxicity to humans and ecosystems, only additive effects are considered in the risk assessment. In this study, the synergistic effect of heavy metals (Cu and Zn) on a model plant, Arabidopsis thaliana, was quantified by the isobolographic method. The plant was cultured via the growth assay method on a plant agar containing individual heavy metals or combinations of Cu + Zn in a growth chamber. The concentration of Cu varied by eight levels from 0 to 200 μM and the concentration of Zn also varied by eight levels from 0 to 400 μM. In the combination of metals, each of the three levels of Cu (25–75 μM) and Zn (20–100 μM) were applied. After 8 days, plants were harvested for root/shoot weight and measured for leaf chlorophyll and carotenoid content. The primary and secondary root elongation of A. thaliana was estimated using image analysis to calculate total root length. The EC50 values of Cu and Zn on A. thaliana, based on the total root length, were 40.0 and 76.4 μM, respectively. When two heavy metals were administered in combination, the EC values decreased less than those of the individual metals. The average value of the combination index was 0.6, proving the synergistic toxic effect on the root growth of A. Thaliana. As a result, the isobolograhic method is a useful tool for estimating the quantitative toxic effect of chemicals on plants.

Objective DNA methylation plays a major role in regulating the expression of genes related to traits of economic interest (e.g., weight gain) in livestock animals. This study characterized and investigated the functional inferences of genome-wide DNA methylome in the loin (longissimus dorsi) muscle (LDM) of swine. Methods A total of 8.99 Gb methylated DNA immunoprecipitation sequence data were obtained from LDM samples of eight Duroc pigs (four pairs of littermates). The reference pig genome was annotated with 78.5% of the raw reads. A total of 33,506 putative methylated regions (PMR) were identified from methylated regions that overlapped at least two samples. Results Of these, only 3.1% were commonly observed in all eight samples. DNA methylation patterns between two littermates were as diverse as between unrelated individuals (p = 0.47), indicating that maternal genetic effects have little influence on the variation in DNA methylation of porcine LDM. The highest density of PMR was observed on chromosome 10. A major proportion (47.7%) of PMR was present in the repeat regions, followed by introns (21.5%). The highest conservation of PMR was found in CpG islands (12.1%). These results show an important role for DNA methylation in species- and tissue-specific regulation of gene expression. PMR were also significantly related to muscular cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism. Conclusion This study indicated the biased distribution and functional role of DNA methylation in gene expression of porcine LDM. DNA methylation was related to cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism (e.g., insulin signaling pathways). Nutritional and environmental management may have a significant impact on the variation in DNA methylation of porcine LDM.

The sequence of cattle genome provided a valuable opportunity to systematically link genetic and metabolic traits of cattle. The objectives of this study were 1) to reconstruct genome-scale cattle-specific metabolic pathways based on the most recent and updated cattle genome build and 2) to identify duplicated metabolic genes in the cattle genome for better understanding of metabolic adaptations in cattle. A bioinformatic pipeline of an organism for amalgamating genomic annotations from multiple sources was updated. Using this, an amalgamated cattle genome database based on UMD_3.1, was created. The amalgamated cattle genome database is composed of a total of 33,292 genes: 19,123 consensus genes between NCBI and Ensembl databases, 8,410 and 5,493 genes only found in NCBI or Ensembl, respectively, and 266 genes from NCBI scaffolds. A metabolic reconstruction of the cattle genome and cattle pathway genome database (PGDB) was also developed using Pathway Tools, followed by an intensive manual curation. The manual curation filled or revised 68 pathway holes, deleted 36 metabolic pathways, and added 23 metabolic pathways. Consequently, the curated cattle PGDB contains 304 metabolic pathways, 2,460 reactions including 2,371 enzymatic reactions, and 4,012 enzymes. Furthermore, this study identified eight duplicated genes in 12 metabolic pathways in the cattle genome compared to human and mouse. Some of these duplicated genes are related with specific hormone biosynthesis and detoxifications. The updated genome-scale metabolic reconstruction is a useful tool for understanding biology and metabolic characteristics in cattle. There has been significant improvements in the quality of cattle genome annotations and the MetaCyc database. The duplicated metabolic genes in the cattle genome compared to human and mouse implies evolutionary changes in the cattle genome and provides a useful information for further research on understanding metabolic adaptations of cattle.

Marbling from intramuscular fat is an important trait of meat quality and has an economic benefit for the beef industry. Quantitative trait loci (QTL) fine mapping was performed to identify the marbling trait in 266 Hanwoo steers using a 10K single nucleotide polymorphism panel with the combined linkage and linkage disequilibrium method. As a result, we found nine putative QTL regions for marbling: three on BTA6, two on BTA17, two on BTA22, and two on BTA29. We detected candidate genes for marbling within 1 cM of either side of the putative QTL regions. Additionally, to understand the functions of these candidate genes at the molecular level, we conducted a functional categorization using gene ontology and pathway analyses for those genes involved in lipid metabolism or fat deposition. In these putative QTL regions, we found 95 candidate genes for marbling. Using these candidate genes, we found five genes that had a direct interaction with the candidate genes. We also found SCARB1 as a putative candidate gene for marbling that involves fat deposition related to cholesterol transport.

Gastric cancer remains a significant global health concern, coercing the need for advancements in imaging techniques for ensuring accurate diagnosis and effective treatment planning. Artificial intelligence (AI) has emerged as a potent tool for gastric-cancer imaging, particularly for diagnostic imaging and body morphometry. This review article offers a comprehensive overview of the recent developments and applications of AI in gastric cancer imaging. We investigated the role of AI imaging in gastric cancer diagnosis and staging, showcasing its potential to enhance the accuracy and efficiency of these crucial aspects of patient management. Additionally, we explored the application of AI body morphometry specifically for assessing the clinical impact of gastrectomy. This aspect of AI utilization holds significant promise for understanding postoperative changes and optimizing patient outcomes. Furthermore, we examine the current state of AI techniques for the prognosis of patients with gastric cancer. These prognostic models leverage AI algorithms to predict long-term survival outcomes and assist clinicians in making informed treatment decisions. However, the implementation of AI techniques for gastric cancer imaging has several limitations. As AI continues to evolve, we hope to witness the translation of cutting-edge technologies into routine clinical practice, ultimately improving patient care and outcomes in the fight against gastric cancer. [ABSTRACT FROM AUTHOR]

Objective: DNA methylation plays a major role in regulating the expression of genes related to traits of economic interest (e.g., weight gain) in livestock animals. This study characterized and investigated the functional inferences of genome-wide DNA methylome in the loin (longissimus dorsi) muscle (LDM) of swine. Methods: A total of 8.99 Gb methylated DNA immunoprecipitation sequence data were obtained from LDM samples of eight Duroc pigs (four pairs of littermates). The reference pig genome was annotated with 78.5% of the raw reads. A total of 33,506 putative methylated regions (PMR) were identified from methylated regions that overlapped at least two samples. Results: Of these, only 3.1% were commonly observed in all eight samples. DNA methylation patterns between two littermates were as diverse as between unrelated individuals (p = 0.47), indicating that maternal genetic effects have little influence on the variation in DNA methylation of porcine LDM. The highest density of PMR was observed on chromosome 10. A major proportion (47.7%) of PMR was present in the repeat regions, followed by introns (21.5%). The highest conservation of PMR was found in CpG islands (12.1%). These results show an important role for DNA methylation in species- and tissue-specific regulation of gene expression. PMR were also significantly related to muscular cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism. Conclusion: This study indicated the biased distribution and functional role of DNA methylation in gene expression of porcine LDM. DNA methylation was related to cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism (e.g., insulin signaling pathways). Nutritional and environmental management may have a significant impact on the variation in DNA methylation of porcine LDM. [ABSTRACT FROM AUTHOR]

This study developed a multi-criteria approach to spatially assess the robust water resource vulnerability in sub-basins and applied it to the Han River basin. The Intergovernmental Panel on Climate Change (IPCC) suggested three factors of vulnerability; namely, exposure, sensitivity and adaptive capacity were used in this study with respect to water quantity and quality. In this study, 16 water quantity indicators and 13 water quality indicators were selected to identify the vulnerability using the Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) method. Environmental and socioeconomic data were obtained from the national statistics database, and hydrological data were simulated using the calibrated Soil andWater Assessment Tool (SWAT) model. Expert surveys and Shannon entropy method were used to determine subjective and objective weights for all indicators, individually. As a result, water quantity-vulnerable sub-basins were associated with high water use and water leakage ratios. Water quality-vulnerable sub-basins were associated with relatively high values of maximum consecutive dry days and heatwave days. The water quantity indices of both weighting methods showed relatively similar spatial distributions, while the distribution of water quality indices was distinct. These results suggest that considering different weighting methods is important for assessing the robust water resource vulnerability of sub-basins. [ABSTRACT FROM AUTHOR]

Although real-time cell electronic sensing (RT-CES) system-based natural killer (NK) cytotoxicity has been introduced, it has not been evaluated using human blood samples. In present study, we measured flowcytometry based assay (FCA) and RT-CES based NK cytotoxicity and analyzed degranulation activity (CD107a) and cytokine production. In 98 healthy individuals, FCA with peripheral blood mononuclear cells (PBMCs) at effectorto target (E/T) ratio of 32 revealed 46.5 ± 2.6% cytolysis of K562 cells, and 23.5 ± 1.1% of NK cells showed increased degranulation. In RT-CES system, adherent NIH3T3 target cells were resistant to basal killing by PBMC or NK cells. NK cell activation by adding IL-2 demonstrated real-time dynamic killing activity, and lymphokineactivated PBMC (E/T ratio of 32) from 15 individuals showed 59.1 ± 6.2% cytotoxicity results after 4 hours incubation in RT-CES system. However, there was no significant correlation between FCA and RT-CES cytotoxicity. After K562 target cell stimulation, PBMC produced profound proinflammatory and immunoregulatory cytokines/chemokines including IL-2, IL-8, IL-10, MIP-1αβ, IFN-γ, and TNF-α, and cytokine/chemokine secretion was related to flowcytometry-based NK cytotoxicity. These data suggest that RT-CES and FCA differ in sensitivity, applicability and providing information, and further investigations are necessary in variable clinical conditions. [ABSTRACT FROM AUTHOR]