Search

Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound

Hospitals and the concept of a healthcare delivery system are practically synonymous. Surgical services, emergency and disaster services, and inpatient care are the three main services they offer. Outpatient clinics and facilities are also available at some hospitals, where patients can receive specialty consultations and surgical services. What challenges do hospital administrators face when attempting to balance the supply and demand for medical services while preserving service quality and maintaining low prices? In what ways and to what extent has OM literature contributed to the resolution of these issues? What are the current trends in practice? What additional opportunities and challenges do they present to OM students? This study is an attempt by the authors to answer the aforementioned questions. Although service capacity could be measured by the number of physical and human resources employed, we chose to focus on the three primary types of services provided by hospitals.

Patient-derived tumour organoids (PDOs) have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly. Here, we summarise recent advancements in PDOs from the perspective of cancer biology and clinical applications, focusing on the current challenges and opportunities of reconstructing and standardising more sophisticated PDO models. STATEMENT OF SIGNIFICANCE: Patient-derived tumour organoids (PDOs), three-dimensional (3D) self-assembled organotypic structures, have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly.

ObjectivePulmonary cement embolism is a rare but underestimated complication of vertebroplasty due to the relative lack of study and examination. This study aims to investigate the incidence of pulmonary cement embolism in patients with spinal metastasis who undergo PVP with RFA and to analyze the relative risk factors.MethodsA total of 47 patients were retrospectively included and classified into pulmonary cement embolism (PCE) group and non-pulmonary cement embolism (NPCE) group by comparing pre- and postoperative pulmonary CT scan images. The demographic and clinical information of the patients was obtained. Demographic data in the two groups were compared using the chi-square test for qualitative data and the unpaired t test for quantitative data. Multiple logistic regression analysis was used to identify risk factors related to pulmonary cement embolism.ResultsPulmonary cement embolism was detected in 11 patients (23.4%), and all patients were asymptomatic and followed up regularly. Risk analysis showed that multiple segments (≥3, p=0.022), thoracic vertebrae (p=0.0008), and unipedicular puncture approach (p=0.0059) were risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra (pConclusionThe number of involved vertebrae, lesion location, and puncture approach are independent risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra. Surgeons should consider these factors when formulating therapeutic strategies.

Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to “intermediate” risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.

Human complex traits and common diseases show tissue- and cell-type- specificity. Recently, single-cell RNA sequencing (scRNA-seq) technology has successfully depicted cellular heterogeneity in human tissue, providing an unprecedented opportunity to understand the context-specific expression of complex trait-associated genes in human tissue-cell types (TCs). Here, we present the first web-based application to quickly assess the cell-type-specificity of genes, named Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA, available at https://bioinfo.uth.edu/webcsea/). Specifically, we curated a total of 111 scRNA-seq panels of human tissues and 1,355 TCs from 61 different general tissues across 11 human organ systems. We adapted our previous decoding tissue-specificity (deTS) algorithm to measure the enrichment for each tissue-cell type (TC). To overcome the potential bias from the number of signature genes between different TCs, we further developed a permutation-based method that accurately estimates the TC-specificity of a given inquiry gene list. WebCSEA also provides an interactive heatmap that displays the cell-type specificity across 1355 human TCs, and other interactive and static visualizations of cell-type specificity by human organ system, developmental stage, and top-ranked tissues and cell types. In short, WebCSEA is a one-click application that provides a comprehensive exploration of the TC-specificity of genes among human major TC map.

Purpose:The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions.Experimental Design:We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed.Results:A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling.Conclusions:Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Supplementary Figure from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Supplementary Table from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Supplementary Data from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Several factors like cognitive attitude, norms, and behavioral control still influence corruption. Ajzen theory states that social and psychological aspects can be antecedents. This research looks into the variables of the theory of planned behavior (TPB) to anticipate the effect of perceived corruption (PC). Considering the primary entrepreneurial deterrent, the dataset is based on 400 Polish graduate students' entrepreneurial intents and behavior who graduated from higher education programs at eight universities in Poland. These three variables were examined for their influence on corrupt perception and behavior. This study explores the attitude and behavior of corruption/fraud by using Ajzen's TPB. This is accomplished by paying closer attention to the impact of cognition attitude (CA), subjective norm (SN), and perceived behavioral control (PBC), which influence the intention to commit corruption. This provides a solid theoretical basis for this research.

Social participation is a key factor in achieving active aging. This study aimed to explore the trajectories and predictors of social participation changes among older adults in China. The data used in this study are from the ongoing national longitudinal study CLHLS. A total of 2492 older adults from the cohort study were included. Group-based trajectory models (GBTM) were used to identify potential heterogeneity in longitudinal changes over time and investigate associations between baseline predictors and trajectories for different cohort members using logistic regression. Four different trajectories of social participation were reported in older adults, namely, stable (8.9%), slow decline (15.7%), lower score with decline (42.2%), and higher score with decline (9.5%). On multivariate analyses, age, years of schooling, pension, mental health, cognitive function, instrumental activities of daily living, and initial social participation scores significantly impact the rate of change in social participation over time. Four trajectories of social participation were identified in the Chinese elderly population. Management of mental health, physical function, and cognitive function appear to be important in maintaining the long-term social participation of older people in the community. Early identification of factors influencing the rapid decline in social participation and timely interventions can maintain or improve social participation levels in older adults.

To provide evidence-based medicine references for formulating prevention and control policies in plateau areas, we explore the characteristics of anemia patients in Tibet (the plateau areas of China), especially those located at an altitude above 4500 m. We collected clinical data from 379 Tibetan anemia patients over the age of 18 years. We found those female patients accounted for the majority of Tibetan anemia patients. Almost half of the anemia patients aged from 28 to 47 years. The percentage of severe anemia and extremely severe anemia was 45.4% and 2.4%, respectively. 88.7% of patients are engaged in agriculture and animal husbandry, and 81.5% of patients just graduated from primary school or below. The most common causes of anemia were nutritional anemia, especially iron-deficiency anemia. At high-altitude localities, folic acid-deficiency anemia needs more attention. Overall, this study showed that altitude influences the incidence, severity, and cause of anemia. Peasants and herdsmen, low education levels, young and middle-aged women, and nutrition status should be paid attention to in future anemia control.

People often use heuristics as mental shortcuts when making financial decisions. Although the literature typically considers heuristics as behavior biases, we explore how different types of heuristics differ from one another. Through peer-to-peer lending data, we observe that borrowers who use limited attention when applying for loans tend to choose round loan amounts, simplifying the decision-making process but compromising accuracy. This round-number heuristic decreases their funding success rate and increases the probability of default. On the other hand, some borrowers select loan amounts in “lucky numbers” that superstitious lenders favor. This lucky-number heuristic caters to the lenders’ preference, thus increasing the borrowers’ funding success rates and reducing the likelihood of default. Our paper demonstrates that borrowers select heuristics based on their motives, leading to varying consequences. We also show that heuristics are not all the same, and people’s choice of heuristics provides insight into their characteristics and can predict decision outcomes. For instance, factoring in heuristic usage information improves default prediction accuracy in our setting. Our findings can be beneficial to practitioners in refining the underwriting and screening of borrowers and loans.

INTRODUCTION: ChatGPT, a language model developed by OpenAI, uses a 175 billion parameter Transformer architecture for natural language processing tasks. This study aimed to compare the knowledge and interpretation ability of ChatGPT with those of medical students in China by administering the Chinese National Medical Licensing Examination (NMLE) to both ChatGPT and medical students. METHODS We evaluated the performance of ChatGPT in two years' worth of the NMLE, which consists of four units. At the same time, the exam results were compared to those of medical students who had studied for five years at medical colleges. RESULTS ChatGPT’s performance was lower than that of the medical students, and ChatGPT’s correct answer rate was related to the year in which the exam questions were released. CONCLUSION ChatGPT’s knowledge and interpretation ability for the NMLE were not yet comparable to those of medical students in China. It is probable that these abilities will improve through deep learning.

Purpose：Chimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors. Methods： In this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo. Results：Lenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8+ CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment. Conclusion: In summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.

To ensure efficient replication, a virus must hijack or regulate multiple host factors for its own benefit. Understanding virus-host interactions and the molecular mechanisms of host resistance to PRRSV infection is necessary to develop effective strategies to control PRRSV.

This paper studies a road tolling problem in which a road user travels from A to B either via road 1 by paying or via road 2 without charge. The route choice also obeys the user-equilibrium principle. However, the travel time is formulated as a strictly increasing function of the density through the velocity–density relationship or fundamental diagram, which significantly improves the formulation in the classical traffic assignment problem. Accordingly, the influence of toll rate on the road users, the administration department and the road runner is analyzed in detail, by assuming that the user demand is rigid and maximizing the total traffic flow and the runner’s benefits from the collection of toll fees.

Laser quenching is one of the most outstanding gear tooth surface quenching methods due to its high efficiency, environmental friendliness, and performance consistency. Since gear tooth surface laser quenching requires repeated scanning, changing the laser scanning velocity and power by program control can meet the needs of variable depth quenching. The effects of laser scanning velocity and output power on the quenching depth and surface Rockwell hardness after quenching were studied and experimentally analyzed. The result shows that by adjusting the parameters, the surface hardness of the specimen changes slightly with the actual received laser energy. However, the quenching depth can be consistent with the laser scanning velocity. The maximum surface Rockwell hardness that a laser quenched material can achieve depends on the material itself, not on the laser power or scanning velocity. Compared with accelerated laser quenching, decelerated laser quenching is more suitable for tooth surface machining due to the cumulative effect of energy within the quenching depth range of metal materials.

Three-dimensional cancer organoids derived from self-organizing cancer stems are ex vivo miniatures of tumors that faithfully recapitulate their structure, distinctive cancer features, and genetic signatures. As novel tools, current cancer organoids have been well established and rapidly applied in drug testing, genome editing, and transplantation, with the ultimate aim of entering clinical practice for guiding personalized therapy. However, given that the lack of a tumor microenvironment, including immune cells and fibrous cells, is a major limitation of this emerging methodology, co-culture models inspire high hope for further application of this technology in cancer research. Co-culture of cancer organoids and immune cells or fibroblasts is available to investigate the tumor microenvironment, molecular interactions, and chimeric antigen receptor-engineered lymphocytes in cancer treatment. In light of the recent progress in cancer organoid co-culture models, it is only possible to recognize the advantages and drawbacks of this novel model to exploit its full potential. In this review, we summarize the recent advances in the application of cancer organoids and co-culture models and how they could be improved in the future to benefit cancer research, especially precision medicine.