bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature and nutrients control the presence and distribution of long-chain diols in Swiss lakes
Authors: Lattaud Julie , Martin Céline , Lloren Ronald , Zborovsky Beata , Dubois Nathalie
Published: June 2024

Long-chain diols are biomarkers commonly used in the marine realm to reconstruct several environmental parameters such as sea surface temperature and salinity. However, they are also produced in lacustrine and slow-flowing river environments, a characteristic that has proved to be useful to trace past riverine inputs in coastal sedimentary records. So far, their use in lacustrine settings is sparse as their controls are not well-known. Previous studies in two lakes have shown that long-chain diol distribution is linked to changes in temperature (in a small Spanish alpine lake), but also to water column stratification (in a large deep Swiss lake). To understand the controls on i) the presence of long-chain diols in lakes, and ii) the distribution of long-chain diol isomers, surface sediments from 52 Swiss lakes were studied. Long-chain diols are present in 57% of the lakes, and machine learning (i.e., random forest model) showed that their presence is mainly controlled by mean annual air temperature, sodium and potassium concentrations and area of the lakes. Long-chain diol isomer relative distribution seems to react to temperature, nutrient (here nitrate) and oxygen concentrations in the lakes. This new insight was tested on a short sedimentary core from Lake Zurich, and compared with other biomarker proxies (based on branched and isoprenoid glycerol dialkyl glycerol tetraethers), as well as with historical record of nutrient contents and temperature. Variations in the long-chain diol index (LDI) mirror measured temperature, but also reacted to changes in nutrients and oxygenation in the lake. This study highlights the potential of long-chain diols as a proxy to trace both nutrients and temperature in lakes, potentially on geological timescales.
eComplexity: validation of a complex thinking instrument from a structural equation model
Authors: Vázquez-Parra José Carlos , Henao-Rodriguez Linda Carolina , Lis-Gutiérrez Jenny Paola , Castillo-Martínez Isolda Margarita , Suarez-Brito Paloma
Published: June 2024

The eComplexity instrument aims to measure the perception of achievement in the complex thinking competency and its sub-competencies. To ensure the reliability of this instrument, validation processes like the one presented in this article are necessary. Methodologically, this study evaluates data from 1,037 university students in Mexico, confirming the statistical validity and reliability of the instrument. As a result, the demonstrated reliability of the eComplexity instrument as a tool for measuring perceived achievements in complex thinking provides a valuable resource for assessing the effectiveness of educational interventions. Consequently, this research contributes to a more informed approach to fostering critical thinking skills, benefiting both theoretical exploration and practical application in educational settings. The study employs the Partial Least Squares Structural Equation Modeling (PLS-SEM) to evaluate students’ self-perceptions of their performance in complex thinking and its sub-competencies, thus advancing the field of educational measurement. Academically, it enriches the discourse on the design and validation of instruments, offering a rigorous model for future efforts in measuring cognitive competencies. Practically, the study’s results inform educational practice by identifying systemic and scientific thinking as key to developing complex thinking skills. This knowledge enables educators to more effectively adapt teaching strategies and curricular designs, aiming to enhance students’ ability to navigate the complexities of the modern world.
Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study
Authors: Guidorizzi Natália Rossin , Valerio Cynthia M. , Viola Luiz F. , Veras Victor Rezende , Fernandes Virgínia Oliveira , Lima Grayce Ellen da Cruz Paiva , Flor Amanda Caboclo , Araújo Jessica Silveira , Gonçalves Muniz Raquel Beatriz , Moreira Rodrigo Oliveira , De Paula Francisco José Albuquerque , Zajdenverg Lenita , Dantas Joana R. , Godoy-Matos Amélio F. , Montenegro Júnior Renan Magalhães , Foss-Freitas Maria Cristina
Published: June 2024

Background

There is a lack of information on the clinical and molecular presentation of familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by partial subcutaneous fat loss.

Objective

This study aimed to provide a comprehensive assessment of the clinical, metabolic, and genetic features of FPLD in the Brazilian population.

Methods

In a multicenter cross-sectional investigation we evaluated patients with FPLD across five Brazilian reference centers for lipodystrophies. Diagnosis of FPLD was made by clinical evaluation and genetic confirmation. Data on genetic, clinical, and metabolic characteristics were captured. Statistical analysis involved the utilization of the Kruskal-Wallis test to identify differences.

Results

The study included 106 patients with genetic confirmation of FPLD. The mean age was 44 ± 15 years, and they were predominantly female (78.3%). LMNA pathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 in 2.8%, and MFN2 in 0.9%. Diabetes mellitus (DM) was highly prevalent (57.5%), affecting 54 females (50.9%). Median triglycerides levels were 199 mg/dL (54–2724 mg/dL), severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%. Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%, and cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due to cardiovascular events.

Conclusion

This study presents an extensive cohort of Brazilian patients with FPLD, predominantly DM with several multisystem complications. A comprehensive characterization of lipodystrophy syndromes is crucial for effective patient management and care.
Nomogram model of serum thymidine kinase 1 combined with ultrasonography for prediction of central lymph node metastasis risk in patients with papillary thyroid carcinoma pre-surgery
Authors: Song Xiaolong , Skog Sven , Wei Long , Qin Jinlv , Yang Ru , Li Jin , Zhou Ji , He Ellen , Zhou Jianping
Published: June 2024

Objective

The aim of this study was to develop a nomogram, using serum thymidine kinase 1 protein (STK1p) combined with ultrasonography parameters, to early predict central lymph node metastasis (CLNM) in patients with papillary thyroid carcinoma (PTC) pre-surgery.

Methods

Patients with PTC pre-surgery in January 2021 to February 2023 were divided into three cohorts: the observation cohort (CLNM, n = 140), the control cohort (NCLNM, n = 128), and the external verification cohort (CLNM, n = 50; NCLNM, n = 50). STK1p was detected by an enzyme immunodot-blot chemiluminescence analyzer and clinical parameters were evaluated by ultrasonography.

Results

A suitable risk threshold value for STK1p of 1.7 pmol/L was selected for predicting CLNM risk by receiver operating characteristic (ROC) curve analysis. Multivariate analysis identified the following six independent risk factors for CLNM: maximum tumor size >1 cm [odds ratio (OR) = 2.406, 95% confidence interval (CI) (1.279–4.526), p = 0.006]; capsule invasion [OR = 2.664, 95% CI (1.324–5.360), p = 0.006]; irregular margin [OR = 2.922; 95% CI (1.397–6.111), p = 0.004]; CLN flow signal [OR = 3.618, 95% CI (1.631–8.027), p = 0.002]; tumor-foci number ≥2 [OR = 4.064, 95% CI (2.102–7.859), p < 0.001]; and STK1p ≥1.7 pmol/L [OR = 7.514, 95% CI (3.852–14.660), p < 0.001]. The constructed nomogram showed that the area under the ROC curve for the main dataset was 0.867 and that for the validation dataset was 0.830, exhibiting effectivity, and was recalculated to a total score of approximately 383. Through monitoring the response post-surgery, all patients were assessed as tumor-free at 12 months post-surgery, which was significantly associated with a reduction in STK1p to disease-free levels.

Conclusion

We demonstrate for the first time that a novel nomogram including STK1p combined with ultrasonography can assist in the clinical prevention of CLNM, by facilitating timely, individualized prophylactic CLNM dissection, thereby reducing the risk of secondary surgery and the probability of recurrence.
Association between elevated homocysteine levels and obstructive sleep apnea hypopnea syndrome: a systematic review and updated meta-analysis
Authors: He Jie , Zhou Haiying , Xiong Juan , Huang Yuanyuan , Huang Na , Jiang Jiaqing
Published: June 2024

Objective

This study aimed to distinguish between healthy controls and patients with OSAHS regarding homocysteine (HCY) levels and investigate how individuals with OSAHS respond to continuous positive airway pressure ventilation (CPAP) in terms of serum and plasma HCY levels.

Methods

To ascertain published articles about OSAHS, an exhaustive search was performed across medical databases, encompassing PubMed, Web of Science, EMBASE, CNKI, and Cochrane Library, until January 2, 2024. This study reviewed the literature regarding HCY levels in individuals with OSAHS and control groups, HCY levels under pre- and post-CPAP treatment, the Pearson/Spearman correlation coefficients between HCY levels and apnea-hypopnea index (AHI), and the hazard ratio (HR) of HCY levels concerning the occurrence of major adverse cerebrocardiovascular events (MACCEs) in patients with OSAHS. Meta-analyses were performed using weighted mean difference (WMD), correlation coefficients, and HR as effect variables. The statistical analysis was conducted using the R 4.1.2 and STATA 11.0 software packages.

Results

In total, 33 articles were selected for the final analysis. The OSAHS group exhibited significantly higher serum/plasma HCY levels than the control group (WMD = 4.25 μmol/L, 95% CI: 2.60–5.91, P< 0.001), particularly among individuals with moderate and severe OSAHS. Additionally, subgroup analysis using mean age, ethnicity, mean body mass index, and study design type unveiled significantly elevated levels of HCY in the serum/plasma of the OSAHS group compared to the control group. CPAP treatment can significantly decrease serum/plasma HCY levels in patients with OSAHS. Moreover, elevated HCY levels in individuals with OSAHS could be one of the risk factors for MACCEs (adjusted HR = 1.68, 95% CI = 1.10–2.58, P = 0.017). AHI scores show a positive correlation with serum/plasma HCY levels.

Conclusion

Patients with OSAHS had elevated serum/plasma HCY levels compared to healthy controls; however, CPAP therapy dramatically decreased HCY levels in patients with OSAHS. In patients with OSAHS, elevated HCY levels were linked with an increased risk of MACCEs, and HCY was positively connected with AHI values. HCY levels may serve as a useful clinical indicator for determining the severity and efficacy of OSAHS treatments.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42024498806.
Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction
Authors: Schill Rebecca L. , Visser Jack , Ashby Mariah L. , Li Ziru , Lewis Kenneth T. , Morales-Hernandez Antonio , Hoose Keegan S. , Maung Jessica N. , Uranga Romina M. , Hariri Hadla , Hermsmeyer Isabel D. K. , Mori Hiroyuki , MacDougald Ormond A.
Published: June 2024

Introduction

Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids.

Methods

In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots.

Results

Mice lacking GR in BMAds (BMAd-Nr3c1-/-) and control mice (BMAd-Nr3c1+/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1-/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle.

Discussion

In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.
Hypothyroidism and metabolic cardiovascular disease
Authors: Patrizio Armando , Ferrari Silvia Martina , Elia Giusy , Ragusa Francesca , Balestri Eugenia , Botrini Chiara , Rugani Licia , Mazzi Valeria , Antonelli Alessandro , Fallahi Poupak , Benvenga Salvatore
Published: June 2024

Cardiovascular disease (CVD) remains the leading cause of death worldwide, representing a major health issue of social and economic relevance. Both hyperthyroidism and hypothyroidism are very common in the adult population, and both disorders may contribute to the onset and progression of CVD. After a brief description of the role of thyroid hormones (THs) on the physiology of the cardiovascular system and the potential mechanism that links THs alterations with changes in cardiac function, blood pressure, endothelial function, and lipid levels, we review updated data about the clinical impact of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) on CV risk, CVD, and mortality. Furthermore, we summarize the current evidence for treating SCH with levothyroxine (L-T4). Several guidelines of distinguished endocrine societies recommend treatment for SCH with TSH higher than 10 mIU/L, where the benefit of L-T4 therapy is more evident for younger people, but still controversial in those aged over 65 years. Based on current knowledge, more research efforts are needed to better address the clinical management of CV risk and CVD in the elderly affected by SCH.
Reduction of nitrogen loss in runoff from sloping farmland by a ridged biochar permeable reactive barrier with vegetated filter strips
Authors: Zhang Yuhe , Gao Jianshuang , Li Qiang , Zhuang Shunyao
Published: June 2024

Introduction

Eutrophication due to nitrogen (N) loss from sloping farmland has a high risk in the Three Gorges Reservoir. Biochar and vegetated filter strips (VFS) are used to control nutrient runoff and increase soil water-holding capacity, soil nutrient retention, and crop yield. However, surface biochar application has limited ability to control N loss, especially from sloping farmland.

Methods

In this study, different widths of ridged biochar permeable reactive barrier (RB-PRB) with VFS were employed to intercept N loss in runoff from sloping farmland. Adsorption characteristics of biochar for nitrate and ammonium N were evaluated using isothermal and kinetic adsorption models before field experiments. N index values for ammonium (NH4+), nitrate (NO3−), dissolved N (DTN), particulate N (PN), and total N (TN) lost through runoff were monitored from April 2019 to January 2020.

Results

NO3− and NH4+ sorption on biochar was predominantly physical adsorption with a maximum capacity of 4.51 and 4.12 mg g-1, respectively. During the research period, the dominant transportation pathway of N loss involved dissolved total N movement through subsurface flow, which accounted for 65.55% of the total loss. TN loss for CK was 1954 g·hm-2, while RB-PRB and VFS decreased N loss from sloping farmland by 36.7%. The interception efficiency of RB-PRB was highest at 0.3 m width. VFS successfully intercepted particulate N and reduced it by 32.75%. In terms of soil nutrients, the RB-PRB and VFS interventions led to a substantial 41.69% increase in the TN content of the soil at a 0.4 m width.

Discussion

The findings suggest that biochar has a favorable adsorption effect on NH4+ and NO3−, an appropriate width of RB-PRB with VFS could effectively reduce nitrogen loss from sloping farmland. Simultaneously, it enhances the water and fertilizer retention capacity of sloping cropland soil; however, the long-term implications necessitate further validation.
Autoimmune uveitis attenuated in diabetic mice through imbalance of Th1/Th17 differentiation via suppression of AP-1 signaling pathway in Th cells
Authors: Takeuchi Masaru , Nishio Yoshiaki , Someya Hideaki , Sato Tomohito , Yoshimura Akihiko , Ito Masataka , Harimoto Kozo
Published: June 2024

Purpose

Inflammation is involved in the pathogenesis of diabetes, however the impact of diabetes on organ-specific autoimmune diseases remains unexplored. Experimental autoimmune uveoretinitis (EAU) is a widely accepted animal model of human endogenous uveitis. In this study, we investigated the effects of diabetic conditions on the development of EAU using a mouse diabetes model.

Methods

EAU was induced in wild-type C57BL/6 (WT) mice and Ins2Akita (Akita) mice with spontaneous diabetes by immunization with IRBP peptide. Clinical and histopathological examinations, and analysis of T cell activation state were conducted. In addition, alternations in the composition of immune cell types and gene expression profiles of relevant immune functions were identified using single-cell RNA sequencing.

Results

The development of EAU was significantly attenuated in immunized Akita (Akita-EAU) mice compared with immunized WT (WT-EAU) mice, although T cells were fully activated in Akita-EAU mice, and the differentiation into Th17 cells and regulatory T (Treg) cells was promoted. However, Th1 cell differentiation was inhibited in Akita-EAU mice, and single-cell analysis indicated that gene expression associated AP-1 signaling pathway (JUN, FOS, and FOSB) was downregulated not only in Th1 cells but also in Th17, and Treg cells in Akita-EAU mice at the onset of EAU.

Conclusions

In diabetic mice, EAU was significantly attenuated. This was related to selective inhibition of Th1 cell differentiation and downregulated AP-1 signaling pathway in both Th1 and Th17 cells.
Establishment of a prognostic model for hypoxia-associated genes in OPSCC and revelation of intercellular crosstalk
Authors: Zhao Yichen , Yu Jintao , Zheng Chang , Zhou Baosen
Published: June 2024

Hypoxia exerts a profound influence on the tumor microenvironment and immune response, shaping treatment outcomes and prognosis. Utilizing consistency clustering, we discerned two hypoxia subtypes in OPSCC bulk sequencing data from GEO. Key modules within OPSCC were identified through weighted gene correlation network analysis (WGCNA). Core modules underwent CIBERSORT immune infiltration analysis and GSEA functional enrichment. Univariate Cox and LASSO analyses were employed to construct prognostic models for seven hypoxia-related genes. Further investigation into clinical characteristics, the immune microenvironment, and TIDE algorithm prediction for immunotherapy response was conducted in high- and low-risk groups. scRNA-seq data were visually represented through TSNE clustering, employing the scissors algorithm to map hypoxia phenotypes. Interactions among cellular subpopulations were explored using the Cellchat package, with additional assessments of metabolic and transcriptional activities. Integration with clinical data unveiled a prevalence of HPV-positive patients in the low hypoxia and low-risk groups. Immunohistochemical validation demonstrated low TDO2 expression in HPV-positive (P16-positive) patients. Our prediction suggested that HPV16 E7 promotes HIF-1α inhibition, leading to reduced glycolytic activity, ultimately contributing to better prognosis and treatment sensitivity. The scissors algorithm effectively segregated epithelial cells and fibroblasts into distinct clusters based on hypoxia characteristics. Cellular communication analysis illuminated significant crosstalk among hypoxia-associated epithelial, fibroblast, and endothelial cells, potentially fostering tumor proliferation and metastasis.
Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer
Authors: Kobayashi Takuro , Nagata Masayoshi , Hachiya Tsuyoshi , Wakita Haruhiko , Ikehata Yoshihiro , Takahashi Keiji , China Toshiyuki , Shimizu Fumitaka , Lu Jun , Jin Yiming , Lu Yan , Ide Hisamitsu , Horie Shigeo
Published: June 2024

Introduction

Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators.

Methods

We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival.

Results

The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10−5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05–11.56, P = 0.042).

Discussion

PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.
Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction
Authors: Li Jiafeng , Vranjkovic Agatha , Read Daniel , Delaney Sean P. , Stanford William L. , Cooper Curtis L. , Crawley Angela M.
Published: June 2024

Background

The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known.

Methods

RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry.

Results

In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance.

Conclusions

This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
Pancreatic islet transplantation: current advances and challenges
Authors: Wang Qi , Huang Yu-xi , Liu Long , Zhao Xiao-hong , Sun Yi , Mao Xinli , Li Shao-wei
Published: June 2024

Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.
Distinct TB-antigen stimulated cytokine profiles as predictive biomarkers for unfavorable treatment outcomes in pulmonary tuberculosis
Authors: Pandiarajan Arul Nancy , Kumar Nathella Pavan , Selvaraj Nandhini , Ahamed Shaik Fayaz , Viswanathan Vijay , Thiruvengadam Kannan , Hissar Syed , Shanmugam Sivakumar , Bethunaickan Ramalingam , Nott Sujatha , Kornfeld Hardy , Babu Subash
Published: June 2024

Introduction

The assessment of tuberculosis (TB) treatment outcomes predominantly relies on sputum culture conversion status. To enhance treatment management, it is crucial to identify non-sputum-based biomarkers that can predict unfavorable outcomes. Cytokines are widely studied as diagnostic biomarkers for active TB. However, their potential as indicators for unfavorable treatment outcomes remains uncertain.

Methodology

This study was conducted within a well-characterized cohort comprising newly diagnosed patients with drug-sensitive pulmonary TB, confirmed through sputum smear and culture positivity. Our objective was to elucidate the TB antigen-stimulated cytokine profile at pre-treatment and at 2 months into anti-TB treatment (ATT) in patients with unfavorable treatment outcomes (cases, n = 27) in comparison to recurrence-free, microbiologically cured controls (n = 31). Whole blood was stimulated with TB antigens using the QuantiFERON In-tube gold method, and plasma supernatants were subjected to a panel of 14 cytokine measurements.

Results

In our study, pre-treatment analysis revealed that eight cytokines (IL-2, IFN-γ, TNF-α, IL-6, IL-10, IL-17A, IL-18, and GM-CSF) were significantly elevated at baseline in cases compared to cured controls, both in unstimulated conditions and following TB antigen (CFP10, ESAT6, and TB7.7) stimulation. A similar pattern was observed at the 2-month mark of ATT, with eight cytokines (IL-2, IL-10, IL-13, IFN-γ, IL-6, IL-12p70, IL-17A, and TNF-α) showing significant differences between the groups. Importantly, no variations were detected following mitogen stimulation, underscoring that these distinctive immune responses are primarily driven by TB-specific antigens.

Conclusion

Our findings indicate that individuals with unfavorable TB treatment outcomes display a characteristic cytokine profile distinct from TB-cured patients, even before commencing ATT. Therefore, the levels of specific cytokine pre-treatment and at the 2-month point in the course of treatment may serve as predictive immune markers for identifying individuals at risk of unfavorable TB treatment outcomes, with these responses being predominantly influenced by TB-specific antigens.
Fully equipped CARs to address tumor heterogeneity, enhance safety, and improve the functionality of cellular immunotherapies
Authors: Alviano Antonio Maria , Biondi Marta , Grassenis Erica , Biondi Andrea , Serafini Marta , Tettamanti Sarah
Published: June 2024

Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.
TM9SF1 offers utility as an efficient predictor of clinical severity and mortality among acute respiratory distress syndrome patients
Authors: Cao Fengsheng , Zhang Lu , Zhao Zhenwang , Shen Xiaofang , Xiong Jinsong , Yang Zean , Gong Baoxian , Liu Mingming , Chen Huabo , Xiao Hong , Huang Min , Liu Yang , Qiu Guangyu , Wang Ke , Zhou Fengqiao , Xiao Juan
Published: June 2024

Introduction

Acute respiratory distress syndrome (ARDS) is a major cause of death among critically ill patients in intensive care settings, underscoring the need to identify biomarkers capable of predicting ARDS patient clinical status and prognosis at an early time point. This study specifically sought to explore the utility and clinical relevance of TM9SF1 as a biomarker for the early prediction of disease severity and prognostic outcomes in patients with ARDS.

Methods

This study enrolled 123 patients with severe ARDS and 116 patients with non-severe ARDS for whom follow-up information was available. The mRNA levels of TM9SF1 and cytokines in peripheral blood mononuclear cells from these patients were evaluated by qPCR. The predictive performance of TM9SF1 and other clinical indicators was evaluated using received operating characteristic (ROC) curves. A predictive nomogram was developed based on TM9SF1 expression and evaluated for its ability in the early prediction of severe disease and mortality in patients with ARDS.

Results

TM9SF1 mRNA expression was found to be significantly increased in patients with severe ARDS relative to those with non-severe disease or healthy controls. ARDS severity increased in correspondence with the level of TM9SF1 expression (odds ratio [OR] = 2.43, 95% confidence interval [CI] = 2.15–3.72, P = 0.005), and high TM9SF1 levels were associated with a greater risk of mortality (hazard ratio [HR] = 2.27, 95% CI = 2.20–4.39, P = 0.001). ROC curves demonstrated that relative to other clinical indicators, TM9SF1 offered superior performance in the prediction of ARDS severity and mortality. A novel nomogram incorporating TM9SF1 expression together with age, D-dimer levels, and C-reactive protein (CRP) levels was developed and was used to predict ARDS severity (AUC = 0.887, 95% CI = 0.715–0.943). A separate model incorporating TM9SF1 expression, age, neutrophil-lymphocyte ratio (NLR), and D-dimer levels (C-index = 0.890, 95% CI = 0.627–0.957) was also developed for predicting mortality.

Conclusion

Increases in ARDS severity and patient mortality were observed with rising levels of TM9SF1 expression. TM9SF1 may thus offer utility as a novel biomarker for the early prediction of ARDS patient disease status and clinical outcomes.
Estimation of chronological age of Risso’s dolphin (Grampus griseus) based on DNA methylation frequency
Authors: Mori Mizuki , Maeda Hikari , Tanabe Atsushi , Sahara Hiroeki , Nozaki Reiko , Kondo Hidehiro , Nakamura Gen , Kanda Naohisa , Murase Hiroto
Published: June 2024

Age of cetaceans is an important data set for their conservation and management. Although the chronological age of a toothed whale has traditionally estimated from the number of annual tooth growth layer groups (GLGs), this method has potential difficulties such as errors due to the subjectivity of the age-readers and time-consuming sample processing, in addition to lethal tooth sampling in many cases. To overcome these difficulties through a non-lethal approach, considerable amount of efforts has been made in recent years to construct chronological age estimation models based on the correlation between chronological and biological age expressed as the frequency of DNA methylation at CpG (cytosine-phosphate-guanine) sites. The present study, by using next-generation sequencing on DNA extracted from the skin tissues of 30 individuals (15 males and 15 females), performed methylation analysis on multiple CpG sites in the three genes previously reported as age-linked in cetaceans (GRIA2, TET2, and CDKN2A) to construct an age estimation model for Risso’s dolphins. Key aspects of this study are: (1) the chronological ages of Risso’s dolphins of wild origins used in this study had been determined by the GLGs of teeth prior to this study, and (2) as Risso’s dolphins are said to have a lifespan of 30 years, samples were collected from individuals aged 1–29 years, covering from young to old ages. Among the 11 CpG sites in GRIA2, 6 CpG sites in TET2, and 7 CpG sites in CDKN2A analyzed, the CpG sites in GRIA2 showed a statistically significant correlation with age, whereas those in TET2 and CDKN2A did not show such a strong correlation. Using multiple regression analysis on the CpG sites in the three genes, the best fitted model was expressed as follows: y=-0.7548 + 5.6164x(GRIA2_CpG3)+2.6187x(TET2_CpG6)-1.5907x(CDKN2A_CpG3) (R²=0.7062, residual mean=2.98, standard deviation=2.3). With the mean error of 2.98 years between the estimated and known chronological ages, the accuracy of this model was found to be comparable to or higher than that of previously reported age estimation models for cetaceans. This study demonstrated for the future that the age of wild Risso’s dolphins can be estimated by using their skin samples collected with minimal invasiveness.
Comparative analysis of risk factors associated with degeneration of adjacent segments: zero-profile anchored spacer vs. anterior cervical plate and cage construct
Authors: Wu Zhikai , Wang Wenhao , Zhou Feng , Xiang Pan , Li Yangfeng , Yang Huilin , Chu Genglei
Published: June 2024

Objective

Anterior cervical discectomy and fusion (ACDF) is an established treatment for cervical degenerative disc disease, but cervical spine surgery may affect sagittal alignment parameters and induce adjacent segment degeneration (ASD). This study aimed to determine the risk factors for developing ASD following anterior cervical plate and cage (ACPC) compared with the use of zero-profile anchored spacer (ROI-C).

Methods

A retrospective contrastive study included 105 patients who underwent ACPC or ROI-C between January 2014 and October 2019 at our treatment centre. There were 50 cases in the ROI-C group and 55 patients in the ACPC group. Clinical and radiological results and the incidence of ASD were assessed after surgery. All patients were further divided into the ASD and non-ASD groups for subgroup analysis.

Results

At each follow-up time, there was no statistically significant in radiographic parameters between the two groups. The overall ASD rate was higher in the ACPC group than in the ROI-C group (65.5% vs. 44.0%, p = 0.027). The low preoperative Cobb angle, low preoperative segment angle (SA), and loss of Cobb (ΔCobb) were significantly correlated with ASD. However, clinical outcomes were not associated with ASD at any postoperative follow-up visit.

Conclusion

Equally good therapeutic effects were achieved with both the ROI-C and ACPC. The occurrence of ASD was considerably higher in the ACPC group than in the ROI-C group. The preoperative Cobb angle, preoperative SA, and ΔCobb were the most associated with an increase in the risk of ASD.
Navigating the challenges of clinical trial professionals in the healthcare sector
Authors: Peralta Galo , Sánchez-Santiago Blanca
Published: June 2024

Clinical trials (CTs) are essential for medical advancements but face significant challenges, particularly in professional training and role clarity. Principal investigators, clinical research coordinators (CRCs), nurses, clinical trial pharmacists, and monitors are key players. Each faces unique challenges, such as maintaining protocol compliance, managing investigational products, and ensuring data integrity. Clinical trials’ complexity and evolving nature demand specialized and ongoing training for these professionals. Addressing these challenges requires clear role delineation, continuous professional development, and supportive workplace environments to improve retention and trial outcomes. Enhanced training programs and a collaborative approach are essential for the successful conduct of clinical trials and the advancement of medical research.
The impact of antibiotic use in gastrointestinal tumors treated with immune checkpoint inhibitors: systematic review and meta-analysis
Authors: Alotaibi Faizah M. , Albalawi Ibrahim Abdullah S. , Anis Amna M. , Alotaibi Hawazin , Khashwayn Seham , Alshammari Kanan , Al-Tawfiq Jaffar A.
Published: June 2024

Background

Immune checkpoint inhibitors (ICI) have improved overall survival in patients with different cancer types. However, treatment efficacy varies between patients depending on several factors. Recent research suggested that antibiotic-induced dysbiosis can impair ICI efficacy. Here we review the impact of antibiotic use in clinical outcome of patients with gastrointestinal cancer treated with ICI.

Methods

This is a systematic review and utilized a thorough search of MEDLINE, Cochrane, Scopus, EB-SCO, Web of Science of studies published till September 2023. The aim of the study is to determine the association between antibiotic use and ICI treatment efficacy in patients with gastrointestinal cancers (GI). We utilized a meta-analysis of the association between the use of antibiotics and overall survival and progression-free survival.

Results

Nine studies met the inclusion criteria with a total of 2,214 patients. The most common type of cancers was hepatocellular carcinoma (HCC). The majority of the studies were retrospective, and one was collective of clinical trials. The use of antibiotics was associated with decreased both overall survival [haz-ard ratio (HR) 1.92, 95% confidence interval (CI) 1.41, 2.63] and progression-free survival [HR 1.81, 95% CI 1.29, 2.54].

Conclusion

The use of antibiotics may affect clinical outcomes in patients with GI cancers treated with ICI. Further prospective studies are needed to improve the understanding of this phenomenon.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023462172.
Regulating bile acids signaling for NAFLD: molecular insights and novel therapeutic interventions
Authors: Wei Meilin , Tu Wei , Huang Genhua
Published: June 2024

Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.
Characterization of Salmonella phage of the genus Kayfunavirus isolated from sewage infecting clinical strains of Salmonella enterica
Authors: Juliet Ramya , Loganathan Archana , Neeravi Ayyanraj , Bakthavatchalam Yamuna Devi , Veeraraghavan Balaji , Manohar Prasanth , Nachimuthu Ramesh
Published: June 2024

The emergence of multi-drug resistance in Salmonella, causing food-borne infections, is a significant issue. With over 2,600 serovars in in Salmonella sp., it is crucial to identify specific solutions for each serovar. Phage therapy serves as an alternate treatment option. In this study, vB_SalP_792 phage was obtained from sewage, forming plaques in eight out of 13 tested clinical S. enterica isolates. Transmission electron microscopy (TEM) examination revealed a T7-like morphotype. The phage was characterized by its stability, life cycle, antibiofilm, and lytic ability in food sources. The phage remains stable throughout a range of temperatures (−20 to 70°C), pH levels (3–11), and in chloroform and ether. It also exhibited lytic activity within a range of MOIs from 0.0001 to 100. The life cycle revealed that 95% of the phages attached to their host within 3 min, followed by a 5-min latent period, resulting in a 50 PFU/cell burst size. The vB_SalP_792 phage genome has a dsDNA with a length of 37,281 bp and a GC content of 51%. There are 42 coding sequences (CDS), with 24 having putative functions and no resistance or virulence-related genes. The vB_SalP_792 phage significantly reduced the bacterial load in the established biofilms and also in egg whites. Thus, vB_SalP_792 phage can serve as an effective biocontrol agent for preventing Salmonella infections in food, and its potent lytic activity against the clinical isolates of S. enterica, sets out vB_SalP_792 phage as a successful candidate for future in vivo studies and therapeutical application against drug-resistant Salmonella infections.
Treatment for non-tuberculous mycobacteria: challenges and prospects
Authors: Conyers Liberty E. , Saunders Bernadette M.
Published: June 2024

Non-Tuberculous mycobacteria (NTM) are opportunistic environmental bacteria. Globally, NTM incidence is increasing and modeling suggests that, without new interventions, numbers will continue to rise. Effective treatments for NTM infections remain suboptimal. Standard therapy for Mycobacterium avium complex, the most commonly isolated NTM, requires a 3-drug regime taken for approximately 18 months, with rates of culture conversion reported between 45 and 70%, and high rates of relapse or reinfection at up to 60%. New therapeutic options for NTM treatment are urgently required. A survey of ongoing clinical trials for new NTM therapy listed on ClinicalTrials.Gov using the terms ‘Mycobacterium avium’, ‘Mycobacterium abscessus’, ‘Mycobacterium intracellulare’, ‘Non tuberculous Mycobacteria’ and ‘Nontuberculous Mycobacteria’ and a selection criterion of interventional studies using antibiotics demonstrates that most trials involve dose and combination therapy of the guideline based therapy or including one or more of; Amikacin, Clofazimine, Azithromycin and the anti-TB drugs Bedaquiline and Linezolid. The propensity of NTMs to form biofilms, their unique cell wall and expression of both acquired and intrinsic resistance, are all hampering the development of new anti-NTM therapy. Increased investment in developing targeted treatments, specifically for NTM infections is urgently required.
Longitudinal molecular analysis of clinical and fecal Escherichia coli isolates at a Veterans Affairs Medical Center in Minnesota, USA, 2012–2019
Authors: Clabots Connie , Thuras Paul , Johnson James R.
Published: June 2024

Introduction

Extraintestinal Escherichia coli infections represent a growing public health threat, However, current studies often overlook important factors such as temporal patterns of infection, phylogenetic and clonal background, or the host gut E. coli population, despite their likely significance.

Methods

In this study, we analyzed >7000 clinical E. coli isolates from patients at the Minneapolis Veterans Affairs Health Care System (2012–2019), and concurrent fecal E. coli from uninfected veterans. We assessed phylogenetic group distribution, membership in selected sequence types (STs), and subsets thereof—including the pandemic, resistance-associated ST131-H30R, and ST1193 lineages—and strain type, as defined by pulsed-field gel electrophoresis. We then analyzed these features alongside the temporal patterns of infection in individual hosts.

Results

The H30R lineage emerged as the leading lineage, both overall and among fluoroquinolone-resistant isolates, with ST1193 following among fluoroquinolone-resistant isolates. Recurrences were common, occurring in 31% of subjects and 41% of episodes, and often multiple and delayed/prolonged (up to 23 episodes per subject; up to 2655d post-index). Remarkably, these recurrences typically involved the subject’s index strain (63% of recurrences), even when affecting extra-urinary sites. ST131, H30R, ST1193, and fluoroquinolone-resistant strains generally caused significantly more recurrences than did other strains, despite similar recurrence intervals. ST131 strain types shifted significantly over the study period. Infection-causing strains were commonly detectable in host feces at times other than during an infection episode; the likelihood of detection varied with surveillance intensity and proximity to the infection. H30R and ST1193 were prominent causes of fecal-clinical clonal overlap.

Discussion

These findings provide novel insights into the temporal and clonal characteristics of E. coli infections in veterans and support efforts to develop anti-colonization interventions.