bluuebunny/crossref_metadata_2025_split huggingface dataset:
U-shaped association between triglyceride-glucose index and all-cause mortality among critically ill pediatrics: a population-based retrospective cohort study
Authors: Gao Qi , Luo Fan , Yu Hongxue , Lin Yuxin , Xu Ruqi , Li Pingping , Zhang Yuping , Liu Jiao , Su Licong , Li Yanqin 
Published: June 2024

Abstract
Background
Previous studies have shown that an elevated triglyceride-glucose (TyG) index was associated with all-cause mortality in both general adult individuals and critically ill adult patients. However, the relationship between the TyG index and clinical prognosis in pediatric patients admitted to the intensive care unit (ICU) remains unknown. We aimed to investigate the association of the TyG index with in-hospital all-cause mortality in critically ill pediatric patients.

Methods
A total of 5706 patients in the Pediatric Intensive Care database were enrolled in this study. The primary outcome was 30-day in-hospital all-cause mortality, and secondary outcome was 30-day in-ICU all-cause mortality. The restricted cubic spline (RCS) curves and two-piecewise multivariate Cox hazard regression models were performed to explore the relationship between the TyG index and outcomes.

Results
The median age of the study population was 20.5 [interquartile range (IQR): 4.8, 63.0] months, and 3269 (57.3%) of the patients were male. The mean TyG index level was 8.6 ± 0.7. A total of 244 (4.3%) patients died within 30 days of hospitalization during a median follow-up of 11 [7, 18] days, and 236 (4.1%) patients died in ICU within 30 days of hospitalization during a median follow-up of 6 [3, 11] days. The RCS curves indicated a U-shape association between the TyG index and 30-day in-hospital and in-ICU all-cause mortality (both P values for non-linear < 0.001). The risk of 30-day in-hospital all-cause mortality was negatively correlated with the TyG index until it bottoms out at 8.6 (adjusted hazard ratio [HR], 0.72, 95% confidence interval [CI] 0.55–0.93). However, when the TyG index was higher than 8.6, the risk of primary outcome increased significantly (adjusted HR, 1.51, 95% CI 1.16–1.96]). For 30-day in-ICU all-cause mortality, we also found a similar relationship (TyG < 8.6: adjusted HR, 0.75, 95% CI 0.57–0.98; TyG ≥ 8.6: adjusted HR, 1.42, 95% CI 1.08–1.85). Those results were consistent in subgroups and various sensitivity analysis.

Conclusions
Our study showed that the association between the TyG index and 30-day in-hospital and in-ICU all-cause mortality was nonlinear U-shaped, with a cutoff point at the TyG index of 8.6 in critically ill pediatric patients. Our findings suggest that the TyG index may be a novel and important factor for the short-term clinical prognosis in pediatric patients.
Challenges and opportunities in the management of type 2 diabetes in patients with lower extremity peripheral artery disease: a tailored diagnosis and treatment review
Authors: Mahé Guillaume , Aboyans Victor , Cosson Emmanuel , Mohammedi Kamel , Sarlon-Bartoli Gabrielle , Lanéelle Damien , Mirault Tristan , Darmon Patrice 
Published: June 2024

AbstractLower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i.
Antiproliferative effect of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues on IL-6 mediated STAT3 and role of the apoptotic pathway in albino Wistar rats of ethyl carbamate-induced lung carcinoma: In-silico, In-vitro, and In-vivo study
Authors: Sonkar Archana Bharti , Verma Abhishek , Yadav Sneha , Kumar Rohit , Singh Jyoti , Keshari Amit K. , Rani Soniya , Kumar Anurag , Kumar Dharmendra , Shrivastava Neeraj Kumar , Rastogi Shubham , Alamoudi Mariam K. , Ansari Mohd Nazam , Saeedan Abdulaziz S. , Kaithwas Gaurav , Saha Sudipta 
Published: June 2024

AbstractLung cancer (LC) ranks second most prevalent cancer in females after breast cancer and second in males after prostate cancer. Based on the GLOBOCAN 2020 report, India represented 5.9% of LC cases and 8.1% of deaths caused by the disease. Several clinical studies have shown that LC occurs because of biological and morphological abnormalities and the involvement of altered level of antioxidants, cytokines, and apoptotic markers. In the present study, we explored the antiproliferative activity of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues against LC using in-vitro, in-silico, and in-vivo models. In-vitro screening against A549 cells revealed compounds 9B (8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) and 12B (5-(4-chlorophenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) as potential pyrimidine analogues against LC. Compounds 9B and 12B were docked with different molecular targets IL-6, Cyt-C, Caspase9, and Caspase3 using AutoDock Vina 4.1 to evaluate the binding affinity. Subsequently, in-vivo studies were conducted in albino Wistar rats through ethyl-carbamate (EC)- induced LC. 9B and 12B imparted significant effects on physiological (weight variation), and biochemical (anti-oxidant [TBAR’s, SOD, ProC, and GSH), lipid (TC, TG, LDL, VLDL, and HDL)], and cytokine (IL-2, IL-6, IL-10, and IL-1β) markers in EC-induced LC in albino Wistar rats. Morphological examination (SEM and H&E) and western blotting (IL-6, STAT3, Cyt-C, BAX, Bcl-2, Caspase3, and caspase9) showed that compounds 9B and 12B had antiproliferative effects. Accordingly, from the in-vitro, in-silico, and in-vivo experimental findings, we concluded that 9B and 12B have significant antiproliferative potential and are potential candidates for further evaluation to meet the requirements of investigation of new drug application.
Investigation of antimicrobial susceptibility patterns, risk factors and their impact on mortality in cancer patients at a tertiary care cancer hospital- A prospective study
Authors: Shelke Akshay , Priya Pallavi , Mishra Shiwani , Chauhan Richa , Murti Krishna , Ravichandiran V. , Dhingra Sameer 
Published: June 2024

Abstract
Background
Cancer patients are vulnerable to infections due to immunosuppression caused by cancer itself and its treatment. The emergence of antimicrobial-resistant bacteria further complicates the treatment of infections and increases the mortality and hospital stays. This study aimed to investigate the microbial spectrum, antimicrobial resistance patterns, risk factors, and their impact on clinical outcomes in these patients.

Methods
A prospective study was conducted at a tertiary care cancer hospital in Patna, Bihar, India, which included cancer patients aged 18 years and older with positive microbial cultures.

Results
This study analysed 440 patients, 53% (234) of whom were females, with an average age of 49.27 (± 14.73) years. A total of 541 isolates were identified, among which 48.01% (242) were multidrug resistant (MDR), 29.76% (150) were extensively drug resistant (XDR), and 19.84% (112) were sensitive. This study revealed that patients who underwent surgery, chemotherapy, were hospitalized, had a history of antibiotic exposure, and had severe neutropenia were more susceptible to MDR and XDR infections. The average hospital stays were 16.90 (± 10.23), 18.30 (± 11.14), and 22.83 (± 13.22) days for patients with sensitive, MDR, and XDR infections, respectively. The study also revealed overall 30-day mortality rate of 31.81% (140), whereas the MDR and XDR group exhibited 38.92% and 50.29% rates of 30-day mortality respectively (P < 0.001). Possible risk factors identified that could lead to mortality, were cancer recurrence, sepsis, chemotherapy, indwelling invasive devices such as foley catheter, Central venous catheter and ryles tube, MASCC score (< 21) and pneumonia.

Conclusions
This study emphasizes the necessity for personalized interventions among cancer patients, such as identifying patients at risk of infection, judicious antibiotic use, infection control measures, and the implementation of antimicrobial stewardship programs to reduce the rate of antimicrobial-resistant infection and associated mortality and hospital length of stay.
Deciphering the tumor immune microenvironment from a multidimensional omics perspective: insight into next-generation CAR-T cell immunotherapy and beyond
Authors: Zhou Zhaokai , Wang Jiahui , Wang Jiaojiao , Yang Shuai , Wang Ruizhi , Zhang Ge , Li Zhengrui , Shi Run , Wang Zhan , Lu Qiong 
Published: June 2024

AbstractTumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches.
Advanced gene nanocarriers/scaffolds in nonviral-mediated delivery system for tissue regeneration and repair
Authors: Zhang Wanheng , Hou Yan , Yin Shiyi , Miao Qi , Lee Kyubae , Zhou Xiaojian , Wang Yongtao 
Published: June 2024

AbstractTissue regeneration technology has been rapidly developed and widely applied in tissue engineering and repair. Compared with traditional approaches like surgical treatment, the rising gene therapy is able to have a durable effect on tissue regeneration, such as impaired bone regeneration, articular cartilage repair and cancer-resected tissue repair. Gene therapy can also facilitate the production of in situ therapeutic factors, thus minimizing the diffusion or loss of gene complexes and enabling spatiotemporally controlled release of gene products for tissue regeneration. Among different gene delivery vectors and supportive gene-activated matrices, advanced gene/drug nanocarriers attract exceptional attraction due to their tunable physiochemical properties, as well as excellent adaptive performance in gene therapy for tissue regeneration, such as bone, cartilage, blood vessel, nerve and cancer-resected tissue repair. This paper reviews the recent advances on nonviral-mediated gene delivery systems with an emphasis on the important role of advanced nanocarriers in gene therapy and tissue regeneration.
9-cis-retinoic acid signaling in Sertoli cells regulates their immunomodulatory function to control lymphocyte physiology and Treg differentiation
Authors: Kamińska Alicja , Pardyak Laura , Lustofin Sylwia , Gielata Karolina , Arent Zbigniew , Pietsch-Fulbiszewska Agnieszka , Hejmej Anna 
Published: June 2024

Abstract
Background
Testis is an immune privileged organ, which prevents the immune response against sperm antigens and inflammation. Testicular cells responsible for immune tolerance are mainly Sertoli cells, which form the blood-testis barrier and produce immunosuppressive factors. Sertoli cells prevent inflammation in the testis and maintain immune tolerance by inhibiting proliferation and inducing lymphocyte apoptosis. It has been shown that 9-cis-retinoic acid (9cRA) blocks ex vivo apoptosis of peripheral blood lymphocytes and promotes the differentiation of Treg cells in the gut. However, the role of retinoid signaling in regulating the immune privilege of the testes remains unknown.

Objective
The aim of this study was to determine whether 9cRA, acting via the retinoic acid receptors (RAR) and the retinoic X receptors (RXR), controls the immunomodulatory functions of Sertoli cells by influencing the secretion of anti-inflammatory/pro-inflammatory factors, lymphocyte physiology and Treg cell differentiation.

Methods
Experiments were performed using in vitro model of co-cultures of murine Sertoli cells and T lymphocytes. Agonists and antagonists of retinoic acid receptors were used to inhibit/stimulate retinoid signaling in Sertoli cells.

Results
Our results have demonstrated that 9cRA inhibits the expression of immunosuppressive genes and enhances the expression of pro-inflammatory factors in Sertoli cells and lymphocytes, increases lymphocyte viability and decreases apoptosis rate. Moreover, we have found that 9cRA blocks lymphocyte apoptosis acting through both RAR and RXR and inhibiting FasL/Fas/Caspase 8 and Bax/Bcl-2/Caspase 9 pathways. Finally, we have shown that 9cRA signaling in Sertoli cells inhibits Treg differentiation.

Conclusion
Collectively, our results indicate that retinoid signaling negatively regulates immunologically privileged functions of Sertoli cells, crucial for ensuring male fertility. 9cRA inhibits lymphocyte apoptosis, which can be related to the development of autoimmunity, inflammation, and, in consequence, infertility.
TGF-β signaling: critical nexus of fibrogenesis and cancer
Authors: Giarratana Anna O. , Prendergast Conor M. , Salvatore Mary M. , Capaccione Kathleen M. 
Published: June 2024

AbstractThe transforming growth factor-beta (TGF-β) signaling pathway is a vital regulator of cell proliferation, differentiation, apoptosis, and extracellular matrix production. It functions through canonical SMAD-mediated processes and noncanonical pathways involving MAPK cascades, PI3K/AKT, Rho-like GTPases, and NF-κB signaling. This intricate signaling system is finely tuned by interactions between canonical and noncanonical pathways and plays key roles in both physiologic and pathologic conditions including tissue homeostasis, fibrosis, and cancer progression. TGF-β signaling is known to have paradoxical actions. Under normal physiologic conditions, TGF-β signaling promotes cell quiescence and apoptosis, acting as a tumor suppressor. In contrast, in pathological states such as inflammation and cancer, it triggers processes that facilitate cancer progression and tissue remodeling, thus promoting tumor development and fibrosis. Here, we detail the role that TGF-β plays in cancer and fibrosis and highlight the potential for future theranostics targeting this pathway.
Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation
Authors: Li Qing , Huang Zicheng , Yang Hongsheng , Tang Jian , Zuo Tao , Yang Qingfan , Huang Zhaopeng , Guo Qin , Li Miao , Gao Xiang , Chao Kang 
Published: June 2024

Abstract
Background
Variations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD.

Methods
The GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset.

Results
A total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers.

Conclusions
Th1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients.
Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov.
Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics
Authors: Deng Xuewen , Terunuma Hiroshi 
Published: June 2024

AbstractThe aging process intricately involves immune system dynamics, with a crucial role in managing senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Unfortunately, immunosenescence, a progressively dysregulated immunity with age, hampers effective SNC elimination, leading to accumulation, coupled with the release of SASPs, which, in turn, inhibits immunity and heightened susceptibility to aging-associated diseases (AADs). Natural killer (NK) cells, integral to the innate immune system, play a pivotal role in addressing SNCs swiftly. These cells also coordinate with other components of both innate and adaptive immunity to surveil and eliminate these cells. Accordingly, preserving NK cell function during aging is crucial for evading AADs and promoting healthy aging. Alternatively, NK-cell-based therapies present promising avenues for addressing the challenges associated with aging. Notable, recent studies in adoptive NK cell therapy have shown promise in rejuvenating immunosenescence, eliminating SNCs, and alleviating SASPs. This progress provides the proof-concept of adoptive NK cell therapy for senotherapy and holds promise as an emerging revolution in longevity therapeutics.
Knowledge, attitude and practice of healthcare workers on isoniazid preventive treatment in Tanzania; a health facility-based cross-sectional study
Authors: Mshiu Johnson Jeremia , Alexander Felix Christopher , Rushaigo Anelisa Martin , Nyigo Vitus Alberto , Majaha Melkisedeck Lolakeha , Maokola Werner Meinrad , Ngowi Bernard James , Wiketye Victor Enock , Kimbute Omari Abdallah , Mgina Erick Josephat , Makasi Charles Elias , Range Nyagosya Segere , Kilale Andrew Martin 
Published: June 2024

Abstract
Background
Tuberculosis (TB) remains a significant public health concern globally, particularly in regions with a high prevalence of HIV/AIDS. In Tanzania, the co-occurrence of TB and HIV poses a substantial challenge to healthcare systems. Isoniazid Preventive Therapy (IPT) has become an important intervention to mitigate the risk of TB infection among individuals living with HIV. Despite its proven efficacy, the extent of knowledge, attitude, and practice of healthcare workers (HCWs) in Tanzania is not well-documented. This study aimed to evaluate the levels of knowledge, attitude, and practice regarding IPT among healthcare workers.

Methods
A cross-sectional study was carried out among healthcare workers working at TB/HIV clinics in 12 regions of Tanzania mainland. A semi-structured questionnaire was administered to the respondents consisting of social demographic characteristics, knowledge, attitude, and practice questions. Data were analyzed using Stata version 14.0.

Results
A total of 464 respondents were interviewed, with 282 (60.8%) being female. The mean age was 36.4 years (SD = 11.0). Among the interviewed, 255 (55.0%) were nurses. Regarding knowledge, attitude, and practice on IPT, 217 (46.8%), 220 (47.0%), and 422 (90.9%) respondents respectively demonstrated adequacy in these domains. Factors such as gender, university education, professional role in healthcare practice, cumulative work experience of one year or more, tenure at a TB/HIV clinic of one year or longer, and attendance at IPT-related training emerged as significant determinants. These factors influence respondents' knowledge, attitude, and practice towards IPT.

Conclusion
The findings underscored a notable knowledge gap and a less favourable attitude towards IPT among HCWs, despite commendable practices. Addressing this disparity through targeted training interventions for healthcare workers holds promise for enhancing their understanding and attitude toward IPT, thereby fostering increased acceptance and utilization of this preventive therapy.