bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of fetuin-A on predicting aortic arch calcification: secondary analysis of a community-based survey
Authors: Lin Yi-Hung , Lin Meng-Hung , Shi Chung-Sheng , Lin Yu-Sheng , Lin Chun-Liang , Yang Yao-Hsu , Liao Yu-San , Chen Mei-Yen , Tsai Ming-Horng , Lin Ming-Shyan
Published: July 2024

Introduction

Atherosclerotic cardiovascular disease is associated with a high mortality rate due to vascular calcification. The role of fetuin-A in aortic arch calcification (AAC) is less well understood.

Methods

An analysis of secondary biomarkers was performed on 800 individuals from the biobank using the community database. AAC was defined by radiologists based on imaging. Multiple variables logical analysis was used for risk analysis.

Results

A total of 736 individual samples were collected based on age and gender. The average age is 65 ± 10 years, and half the population comprises men. In spite of similar body weight, renal function, and hepatic function, the AAC group had higher blood pressure and fetuin-A levels independently: systolic blood pressure (SBP) index ≥130 mmHg [adjusted odds ratio (aOR) 1.85, 95% confidence interval (CI) 1.34–2.57, p = 0.002] and fetuin-A (aOR 0.62, 95% CI 0.50–0.76, p < 0.001). Moreover, it is evident that AAC can be predicted more accurately when combined with SBP ≥130 mmHg and a low fetuin-A level (<358 μg/ml: aOR 5.39, 95% CI 3.21–9.08) compared with the reference.

Conclusion

Low fetuin-A levels are significantly correlated with AAC while there is an increased association between vascular calcification and coexisting hypertension.
The potential therapeutic value of the natural plant compounds matrine and oxymatrine in cardiovascular diseases
Authors: Chen Shanjiang , Wu Shu , Lin Bin
Published: July 2024

Matrine (MT) and Oxymatrine (OMT) are two natural alkaloids derived from plants. These bioactive compounds are notable for their diverse pharmacological effects and have been extensively studied and recognized in the treatment of cardiovascular diseases in recent years. The cardioprotective effects of MT and OMT involve multiple aspects, primarily including antioxidative stress, anti-inflammatory actions, anti-atherosclerosis, restoration of vascular function, and inhibition of cardiac remodeling and failure. Clinical pharmacology research has identified numerous novel molecular mechanisms of OMT and MT, such as JAK/STAT, Nrf2/HO-1, PI3 K/AKT, TGF-β1/Smad, and Notch pathways, providing new evidence supporting their promising therapeutic potential against cardiovascular diseases. Thus, this review aims to investigate the potential applications of MT and OMT in treating cardiovascular diseases, encompassing their mechanisms, efficacy, and safety, confirming their promise as lead compounds in anti-cardiovascular disease drug development.
Diabetic retinopathy incidence, predictors and its association with longitudinal fasting blood sugar level changes among diabetes mellitus patients in Ethiopia: joint model
Authors: Abuhay Habtamu Wagnew , Lakew Ayenew Molla , Wolde Haileab Fekadu , Mengistu Berhanu , Legesse Mandefro Tadesse , Yenit Melaku Kindie
Published: July 2024

Background

Diabetes mellitus (DM) is a global public health problem characterized by an elevated blood glucose level. Monitoring blood sugar levels is vital for effective diabetes management and preventing complications. However, the association between longitudinal biomarkers and the incidence of diabetic complications is often overlooked. Therefore, this study aimed to assess the incidence of diabetic retinopathy, predictors, and association with longitudinal fasting blood sugar level changes among diabetes mellitus patients in Ethiopia.

Methods

A multicenter retrospective follow-up study was carried out in referral hospitals in Amhara region, Ethiopia. A random sample of 462 newly diagnosed DM patients was selected. The proportional hazard assumption was checked for the survival sub-model, and for the longitudinal sub-model, the normality assumption was checked. Then the joint modeling with time-dependent lagged parameterizations was fitted. Model assumptions and comparisons were checked. Finally, the hazard ratio with a 95% confidence interval (CI) with a corresponding P-value<0.05 was used to identify predictors.

Results

In this study, Overall, 54 patients developed DR, and the incidence rate was 2.33 per 1000 person-months over the follow-up period, with a 95% CI of [1.78, 3.05]. Rural residence (AHR = 2.21, 95% CI: [1.21, 4.05]), hypertension co-morbidity (AHR = 3.01, 95% CI: [1.85, 6.53]), and longer duration of DM (>5 years) (AHR = 2.28, 95% CI: [1.91, 5.15]) were important predictors for the incidence of DR. In addition, the incidence of DR was substantially correlated with the time-dependent lagged value of FBS change (AHR = 4.20, 95% CI [1.62, 10.85]).

Conclusions

In this study, the incidence of diabetic retinopathy was somewhat high when compared to prior similar studies in Ethiopia. A joint model of longitudinal fasting blood sugar level changes was significantly associated with an increased risk of DR. Besides, being rural residence, hypertension co-morbidity, and a longer duration of DM were significant predictors for the incidence of DR. Therefore, public awareness, an integrated care approach, and prioritizing glycemic control are highly recommended.
Intra- and postoperative relative angiotensin II deficiency in patients undergoing elective major abdominal surgery
Authors: Krenn Katharina , Höbart Petra , Adam Lukas , Riemann Gregor , Christiansen Finn , Domenig Oliver , Ullrich Roman
Published: July 2024

Introduction

The classical axis of the renin–angiotensin system (RAS) makes an important contribution to blood pressure regulation under general anesthesia via the vasopressor angiotensin II (Ang II). As part of the alternative RAS, angiotensin-converting enzyme 2 (ACE2) modulates the pro-inflammatory and fibrotic effects of Ang II by processing it into the organ-protective Ang 1–7, which is cleaved to Ang 1–5 by ACE. Although the levels of ACE2 may be associated with postoperative complications, alternative RAS metabolites have never been studied perioperatively. This study was designed to investigate the perioperative kinetics and balance of both RAS axes around major abdominal surgery.

Methods

In this observational cohort study, 35 patients undergoing elective major abdominal surgery were included. Blood sampling was performed before and after induction of anesthesia, at 1 h after skin incision, at the end of surgery, and on postoperative days (POD) 1, 3, and 7. The equilibrium concentrations of Ang I–IV, Ang 1–7, and Ang 1–5 in plasma were quantified using mass spectrometry. The plasma protein levels of ACE and ACE2 were measured with ELISA.

Results

Surgery caused a rapid, transient, and primarily renin-dependent activation of both RAS axes that returned to baseline on POD 1, followed by suppression. After induction, the Ang II/Ang I ratio persistently decreased, while the ACE levels started to increase on POD 1 (all p < 0.01 versus before anesthesia). Conversely, the ACE2 levels increased on POD 3 and 7 (both p < 0.001 versus before anesthesia), when the median Ang 1–7 concentrations were unquantifiably low.

Discussion

The postoperative elevation of ACE2 may prolong the decrease of the Ang II/Ang I ratio through the increased processing of Ang II. Further clarification of the intraoperative factors leading to relative Ang II deficiency and the sources of postoperatively elevated ACE2 is warranted.
Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods
Authors: Ozcagli Eren , Kubickova Barbara , Jacobs Miriam N.
Published: July 2024

Whilst western diet and sedentary lifestyles heavily contribute to the global obesity epidemic, it is likely that chemical exposure may also contribute. A substantial body of literature implicates a variety of suspected environmental chemicals in metabolic disruption and obesogenic mechanisms. Chemically induced obesogenic metabolic disruption is not yet considered in regulatory testing paradigms or regulations, but this is an internationally recognised human health regulatory development need. An early step in the development of relevant regulatory test methods is to derive appropriate minimum chemical selection lists for the target endpoint and its key mechanisms, such that the test method can be suitably optimised and validated. Independently collated and reviewed reference and proficiency chemicals relevant for the regulatory chemical universe that they are intended to serve, assist regulatory test method development and validation, particularly in relation to the OECD Test Guidelines Programme. To address obesogenic mechanisms and modes of action for chemical hazard assessment, key initiating mechanisms include molecular-level Peroxisome Proliferator-Activated Receptor (PPAR) α and γ agonism and the tissue/organ-level key event of perturbation of the adipogenesis process that may lead to excess white adipose tissue. Here we present a critical literature review, analysis and evaluation of chemicals suitable for the development, optimisation and validation of human PPARα and PPARγ agonism and human white adipose tissue adipogenesis test methods. The chemical lists have been derived with consideration of essential criteria needed for understanding the strengths and limitations of the test methods. With a weight of evidence approach, this has been combined with practical and applied aspects required for the integration and combination of relevant candidate test methods into test batteries, as part of an Integrated Approach to Testing and Assessment for metabolic disruption. The proposed proficiency and reference chemical list includes a long list of negatives and positives (20 chemicals for PPARα, 21 for PPARγ, and 11 for adipogenesis) from which a (pre-)validation proficiency chemicals list has been derived.
Computational mining of B cell receptor repertoires reveals antigen-specific and convergent responses to Ebola vaccination
Authors: Richardson Eve , Bibi Sagida , McLean Florence , Schimanski Lisa , Rijal Pramila , Ghraichy Marie , von Niederhäusern Valentin , Trück Johannes , Clutterbuck Elizabeth A. , O’Connor Daniel , Luhn Kerstin , Townsend Alain , Peters Bjoern , Pollard Andrew J. , Deane Charlotte M. , Kelly Dominic F.
Published: July 2024

Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3–15 and IGHV3–13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires.
LncRNA Nostrill promotes interferon-γ-stimulated gene transcription and facilitates intestinal epithelial cell-intrinsic anti-Cryptosporidium defense
Authors: Sharmin Zinat , Jin Kehua , Gong Ai-Yu , Deng Silu , Pok Chansorena , Graham Marion L. , Wang Shuhong , Mathy Nicholas W. , Shibata Annemarie , Chen Xian-Ming
Published: July 2024

Intestinal epithelial cells possess the requisite molecular machinery to initiate cell-intrinsic defensive responses against intracellular pathogens, including intracellular parasites. Interferons(IFNs) have been identified as cornerstones of epithelial cell-intrinsic defense against such pathogens in the gastrointestinal tract. Long non-coding RNAs (lncRNAs) are RNA transcripts (>200 nt) not translated into protein and represent a critical regulatory component of mucosal defense. We report here that lncRNA Nostrill facilitates IFN-γ-stimulated intestinal epithelial cell-intrinsic defense against infection by Cryptosporidium, an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children. Nostrill promotes transcription of a panel of genes controlled by IFN-γ through facilitating Stat1 chromatin recruitment and thus, enhances expression of several genes associated with cell-intrinsic defense in intestinal epithelial cells in response to IFN-γ stimulation, including Igtp, iNos, and Gadd45g. Induction of Nostrill enhances IFN-γ-stimulated intestinal epithelial defense against Cryptosporidium infection, which is associated with an enhanced autophagy in intestinal epithelial cells. Our findings reveal that Nostrill enhances the transcription of a set of genes regulated by IFN-γ in intestinal epithelial cells. Moreover, induction of Nostrill facilitates the IFN-γ-mediated epithelial cell-intrinsic defense against cryptosporidial infections.
The efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of hemophagocytic lymphohistiocytosis in adult patients: an open-label, single-center study
Authors: Hu Junxia , Wang Jingshi , Wang Zhao
Published: July 2024

Background

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH.

Methods

An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators.

Results

A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment.

Conclusion

The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.
Anti-inflammatory mechanism of Apolipoprotein A-I
Authors: Tao Xia , Tao Ran , Wang Kaiyang , Wu Lidong
Published: July 2024

Apolipoprotein A-I(ApoA-I) is a member of blood apolipoproteins, it is the main component of High density lipoprotein(HDL). ApoA-I undergoes a series of complex processes from its generation to its composition as spherical HDL. It not only has a cholesterol reversal transport function, but also has a function in modulating the inflammatory response. ApoA-I exerts its anti-inflammatory effects mainly by regulating the functions of immune cells, such as monocytes/macrophages, dendritic cells, neutrophils, and T lymphocytes. It also modulates the function of vascular endothelial cells and adipocytes. Additionally, ApoA-I directly exerts anti-inflammatory effects against pathogenic microorganisms or their products. Intensive research on ApoA-I will hopefully lead to better diagnosis and treatment of inflammatory diseases.
A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency
Authors: Lullo Vincenzo , Cecere Francesco , Batti Saveria , Allegretti Sara , Morone Barbara , Fioriniello Salvatore , Pisapia Laura , Genesio Rita , Della Ragione Floriana , Giardino Giuliana , Pignata Claudio , Riccio Andrea , Matarazzo Maria R. , Strazzullo Maria
Published: July 2024

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.
The therapeutic potential of exosomes in immunotherapy
Authors: Li Guangyao , Zhang Shuyi , Zou Yitan , Ai Hongru , Zheng Xinya , Qian Kewen , Lei Changhai , Fu Wenyan
Published: July 2024

Exosomes are found in various tissues of the body and carry abundant contents including nucleic acids, proteins, and metabolites, which continuously flow between cells of various tissues and mediate important intercellular communication. In addition, exosomes from different cellular sources possess different physiopathological immunomodulatory effects, which are closely related to the immune regeneration of normal or abnormal organs and tissues. Here, we focus on the mechanistic interactions between exosomes and the human immune system, introduce the immuno-regenerative therapeutic potential of exosomes in common clinical immune-related diseases, such as infectious diseases, autoimmune diseases, and tumors, and reveal the safety and efficacy of exosomes as a novel cell-free immune regenerative therapy.
Immunomodulatory effect of PLGA-encapsulated mesenchymal stem cells-derived exosomes for the treatment of allergic rhinitis
Authors: Shahzad Khawar Ali , Wang Zhao , Li Xuran , Li Jiaojiao , Xu Maoxiang , Tan Fei
Published: July 2024

Introduction

Allergic rhinitis (AR) is an upper airway inflammatory disease of the nasal mucosa. Conventional treatments such as symptomatic pharmacotherapy and allergen-specific immunotherapy have considerable limitations and drawbacks. As an emerging therapy with regenerative potential and immunomodulatory effect, mesenchymal stem cell-derived exosomes (MSC-Exos) have recently been trialed for the treatment of various inflammatory and autoimmune diseases.

Methods

In order to achieve sustained and protected release of MSC-Exos for intranasal administration, we fabricated Poly(lactic-co-glycolic acid) (PLGA) micro and nanoparticles-encapsulated MSC-Exos (PLGA-Exos) using mechanical double emulsion for local treatment of AR. Preclinical in vivo imaging, ELISA, qPCR, flow cytometry, immunohistochemical staining, and multiomics sequencing were used for phenotypic and mechanistic evaluation of the therapeutic effect of PLGA-Exos in vitro and in vivo.

Results

The results showed that our PLGA platform could efficiently encapsulate and release the exosomes in a sustained manner. At protein level, PLGA-Exos treatment upregulated IL-2, IL-10 and IFN-γ, and downregulated IL-4, IL-17 and antigen-specific IgE in ovalbumin (OVA)-induced AR mice. At cellular level, exosomes treatment reduced Th2 cells, increased Tregs, and reestablished Th1/Th2 balance. At tissue level, PLGA-Exos significantly attenuated the infiltration of immune cells (e.g., eosinophils and goblet cells) in nasal mucosa. Finally, multiomics analysis discovered several signaling cascades, e.g., peroxisome proliferator-activated receptor (PPAR) pathway and glycolysis pathway, that might mechanistically support the immunomodulatory effect of PLGA-Exos.

Discussion

For the first time, we present a biomaterial-facilitated local delivery system for stem cell-derived exosomes as a novel and promising strategy for AR treatment.
Triglyceride glucose index as a predictor for non-alcoholic fatty liver disease: insights from a longitudinal analysis in non-obese individuals
Authors: Ning Qi , Zheng Keyang , Yan Jiafu , Zhu Chao
Published: July 2024

Background

A substantial portion of non-obese population is afflicted with Non-alcoholic Fatty Liver Disease (NAFLD). The Triglyceride Glucose (TyG) index, a quantifier of insulin resistance magnitude, is determined by the product of fasting plasma glucose and triglyceride concentrations. The relationship between the TyG index and NAFLD within this cohort remains ambiguous.

Methods

We conducted a retrospective analysis utilizing datasets acquired from the Dryad digital repository. Non-obese participants (BMI < 25 kg/m2) were enrolled at the Wenzhou Medical Center of Wenzhou People’s Hospital between January 2010 and December 2014. Demographic information and biochemical parameters were systematically compiled, and the diagnosis of NAFLD was established through ultrasonographic evidence.

Results

This study cohort included 16,172 non-obese participants with a 5-year follow-up, among whom 2,322 (14.36%) developed NAFLD. The disparity between TyG index quartiles in the accumulative incidence of new-onset NAFLD was distinct, with an increasing risk of new-onset NAFLD as the TyG index increased. Participants in highest quartile exhibited the maximum risk of NAFLD. In the fully adjusted model 3, the hazard ratios for NAFLD in Q2, Q3, and Q4 were 2.15 (1.62, 2.87), 2.89 (2.20, 3.80) and 4.58 (3.48, 6.02), respectively. Meanwhile, the TyG index and NAFLD risk showed a highly significant overall correlation (p < 0.0001) and nonlinearity (p < 0.0001) according to the limited cubic splines. In subgroup analysis, a significant interaction was noted between new-onset NAFLD and SBP (<140 mmHg vs. ≥140 mmHg; P for interaction = 0.0114). The SBP < 140 mmHg subgroup demonstrated an enhanced TyG index influence on NAFLD risk (HR = 2.83, 95% CI: 2.48–3.23, p < 0.0001).

Conclusion

The TyG index serves as a straightforward instrument for assessing NAFLD risk in non-obese individuals, enabling prompt identification and management in this population segment.
Codon usage bias in yeasts and its correlation with gene expression, growth temperature, and protein structure
Authors: Baeza Marcelo , Sepulveda Dionisia , Cifuentes Víctor , Alcaíno Jennifer
Published: July 2024

Codon usage bias (CUB) has been described in viruses, prokaryotes, and eukaryotes and has been linked to several cellular and environmental factors, such as the organism's growth temperature, gene expression levels, and regulation of protein synthesis and folding. Most of the studies in this area have been conducted in bacteria and higher eukaryotes, in some cases with different results. In this study, a comparative analysis of CUB in yeasts isolated from cold and template environments was performed in order to evaluate the correlation of CUB with yeast optimal temperature of growth (OTG), gene expression levels, cellular function, and structure of encoded proteins. Among the main findings, highly expressed ORFs tend to have a more similar CUB within and between yeasts, and a direct correlation between codons ending in C and expression level was generally found. A low correspondence between CUB and OTG was observed, with an inverse correlation for some codons ending in C. The clustering of yeasts based on their CUB partially aligns with their OTG, being more consistent for yeasts with lower OTG. In most yeasts, the abundance of preferred codons was generally lower at the 5′ end of ORFs, higher in segments encoding beta strand, lower in segments encoding extracellular and transmembrane regions, and higher in “translation” and “energy metabolism” pathways, especially in highly expressed ORFs. Based on our findings, it is suggested that the abundance and distribution of preferred and non-preferred codons along mRNAs contribute to proper protein folding and functionality by regulating protein synthesis rates, becoming a more important factor under conditions that require faster protein synthesis in yeasts.
Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models
Authors: Rentsch Peggy , Ganesan Kiruthika , Langdon Alexander , Konen Lyndsey M. , Vissel Bryce
Published: July 2024

Background

Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance.

Methods

In the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice.

Results

At the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology.

Conclusion

The study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.
A three-step, “brute-force” approach toward optimized affine spatial normalization
Authors: Wilke Marko
Published: July 2024

The first step in spatial normalization of magnetic resonance (MR) images commonly is an affine transformation, which may be vulnerable to image imperfections (such as inhomogeneities or “unusual” heads). Additionally, common software solutions use internal starting estimates to allow for a more efficient computation, which may pose a problem in datasets not conforming to these assumptions (such as those from children). In this technical note, three main questions were addressed: one, does the affine spatial normalization step implemented in SPM12 benefit from an initial inhomogeneity correction. Two, does using a complexity-reduced image version improve robustness when matching “unusual” images. And three, can a blind “brute-force” application of a wide range of parameter combinations improve the affine fit for unusual datasets in particular. A large database of 2081 image datasets was used, covering the full age range from birth to old age. All analyses were performed in Matlab. Results demonstrate that an initial removal of image inhomogeneities improved the affine fit particularly when more inhomogeneity was present. Further, using a complexity-reduced input image also improved the affine fit and was beneficial in younger children in particular. Finally, blindly exploring a very wide parameter space resulted in a better fit for the vast majority of subjects, but again particularly so in infants and young children. In summary, the suggested modifications were shown to improve the affine transformation in the large majority of datasets in general, and in children in particular. The changes can easily be implemented into SPM12.
Risk factors for postoperative late deterioration in patients with spinal dural arteriovenous fistulas
Authors: Ge Yuanhong , Lai Qingjia , Guo Wei , Xu Xuejun
Published: July 2024

Background

Approximately 86% of patients with spinal dural arteriovenous fistulas (SDVAFs) exhibit clinical improvement after surgery. However, 12%-55.8% of these patients experience late deterioration (LD) after an initial period of improvement. The risk factors for LD remain unclear. The aim of this study was to explore the risk factors for LD in SDVAF patients.

Methods

The clinical data of patients who were admitted to two tertiary hospitals between June 2014 and May 2022 were reviewed. Patients were divided into two groups: the LD group and the no LD group. The severity of neurological dysfunction (NDF) was evaluated using the Modified Aminoff and Logue Scale. Univariable and multivariable Cox regression analyses were performed.

Results

A total of 105 eligible patients were enrolled, with a mean age of 57.55 ± 9.42 years. The LD group comprised 37 individuals, while the no LD group consisted of 68 individuals. According to the univariable analysis, preoperative NDF severity and treatment strategy were associated with the risk of LD. According to the multivariable analysis, patients who underwent microsurgery (MS) had a lower risk of LD than did those who underwent endovascular treatment (EVT; HR 0.197, 95% CI 0.085-0.457), and patients with severe NDF had a higher risk of LD than did those with mild NDF (HR 3.604, 95% CI 1.226-10.588), whereas the risk of LD in patients with moderate NDF was similar to that of patients with mild NDF (HR 1.352, 95% CI 0.519-3.524).

Conclusion

EVT and severe preoperative NDF are independent risk factors for LD.
Research progress of neuron-specific enolase in cognitive disorder: a mini review
Authors: Liu Fang , Li Haiyan , Hong Xiaqing , Liu Ying , Yu Ze
Published: July 2024

Numerous studies have demonstrated that neuron-specific enolase (NSE) serves as a distinctive indicator of neuronal injury, with its concentration in blood reflecting the extent and magnitude of nervous system damage, and the expression of serum NSE is correlated with cognitive dysfunction. The assessment of NSE holds significant importance in diagnosing cognitive dysfunction, assessing disease severity, predicting prognosis, and guiding treatment. In this review, the research progress of NSE in cognitive dysfunction was reviewed, and the value of serum NSE level in predicting disease severity and prognosis of patients with cognitive dysfunction was discussed.
Development of a nomogram for predicting malnutrition in elderly hospitalized cancer patients: a cross-sectional study in China
Authors: Duan Ran , Luo Yan , Feng Tong , Ren Tao
Published: July 2024

Objectives

The Patient-Generated Subjective Global Assessment (PG-SGA) serves as a specialized nutritional assessment instrument designed for cancer patients. Despite its specificity, the complexity and time requirements of this tool, along with the necessity for administration by trained professionals, limit its practicality in clinical settings. Our objective is to identify a straightforward, efficient, and dependable nutritional assessment tool to promote broader adoption in clinical practice.

Methods

This study encompassed a total of 450 patients diagnosed with cancer. Of these, 315 individuals constituted the training set, and the remaining 135 were allocated to the external validation set. The model variables were identified through the Least Absolute Shrinkage and Selection Operator (LASSO) regression method. Binary logistic regression outcomes facilitated the development of a nomogram, offering a visual depiction of the predicted probabilities. The predictive accuracy of the nomogram model was evaluated by calculating the area under the Receiver Operating Characteristic (ROC) curve.

Results

The LASSO method detected four variables that were included in the final prediction model: age, serum albumin levels (ALB), body mass index (BMI), and activities of daily living (ADL). The area under the curve (AUC) for this prediction model was 0.905. Both the internal and external calibration curves for malnutrition showed that the predictive nomogram model was highly accurate.

Conclusion

The study has developed a prediction model that demonstrates remarkable accuracy in forecasting malnutrition. Furthermore, it presents a streamlined nutritional assessment tool aimed at swiftly identifying cancer patients at nutritional risk, thereby facilitating oncologists in delivering targeted nutritional support to these individuals.
Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer
Authors: Beaussire-Trouvay Ludivine , Duhamel Orianne , Perdrix Anne , Lévêque Emilie , Vion Roman , Rovelet-Lecrux Anne , Sarafan-Vasseur Nasrin , Di Fiore Frédéric , Crouzet Agathe , Leheurteur Marianne , Clatot Florian
Published: July 2024

Background

Cervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients.

Objective

We investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A).

Methods

This single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes.

Results

Among the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed.

Conclusion

HPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.
Genetic predisposition to milder forms of COVID-19 may provide some resilience to head and neck cancers
Authors: Han Boxuan , Sun Minghong , Zhao Yanming , Baranova Ancha , Cao Hongbao , Liu Shaokun , Shen Xixi , Hou Lizhen , Fang Jugao , Lian Meng
Published: July 2024

Introduction

The impact of the COVID-19 pandemic on head and neck cancer (HNC) has been suggested, but the causal relationship remains unclear.

Methods

We explore this connection by utilizing the Mendelian randomization (MR) approach applied to publicly available genome-wide association study (GWAS) summary datasets for COVID-19 and HNC. The datasets included critical COVID-19 (13,769 cases, 1,072,442 controls), hospitalized COVID-19 (32,519 cases, 2,062,805 controls), SARS-CoV-2 infection (122,616 cases, 2,475,240 controls), and HNC (2,131 cases, 287,137 controls). Mechanistic underpinnings of the causal relationships identified by MR analysis were explored through functional annotation augmented by AI-based literature data mining.

Results

Surprisingly, a genetic predisposition to contracting a milder form of COVID-19 substantially reduced the risks of developing HNC (OR: 0.52, 95% CI: 0.35–0.78, p = 1.42E-03), with no significant association between genetic liability to severe COVID-19 and the risk of HNC detected. Additionally, our findings highlighted 14 genes linked to SARS-CoV-2 infection, potentially playing a protective role in the context of HNC. These genes include OAS1, LOC107985887, BCL11A, DPP9, LOC107984685, LINC02326, MUC4, NXPE3, IFNAR2, LZTFL1, LOC105372437, NAPSA, LOC105376622, LOC107986082, and SLC6A20.

Conclusion

Our study emphasizes the protective role of the genetic liability to milder COVID-19 in reducing the risk of HNC while refuting a causal relationship between severe COVID-19 and HNC.
Multimodal diagnostic strategies and precision medicine in mucinous ovarian carcinoma: a comprehensive approach
Authors: Wang Yue , Peng Lina , Ye Wanlu , Lu Yanming
Published: July 2024

Mucinous ovarian carcinoma (MOC) represents a distinct entity within ovarian malignancies, characterized by diagnostic challenges due to its rarity and the potential overlap with other tumor types. The determination of tumor origin is important for precise postsurgical treatment. This article highlights the accurate diagnosis and management of MOC, including the use of imaging modalities, serological tumor markers, immunohistochemistry, and genomic analyses. Transabdominal and transvaginal ultrasonography, complemented by MRI and CT, plays a pivotal role in differentiating MOC from other mucinous tumors and in surgical planning, particularly for fertility preservation. Serological markers like CA19-9, CA-125, and CEA, though not definitive, provide valuable preoperative insights. Immunohistochemistry aids in distinguishing primary MOC from metastatic mucinous carcinomas, while genomic profiling offers the potential for precision medicine through the identification of specific molecular signatures and treatment susceptibilities. Despite advancements in diagnostic techniques, no single method conclusively differentiates between primary and metastatic tumors intraoperatively. The paper reviews the origins, diagnosis, and differential diagnosis of primary mucinous ovarian carcinoma highlights the need for a multimodal diagnostic approach and advocates for the inclusion of MOC patients in clinical trials for personalized therapies, recognizing the heterogeneity of the disease at the molecular level.
The incidence of periungual desquamation and thrombocytosis in Kawasaki disease and the importance of systematic observation in the subacute phase
Authors: Kim Beom Joon , Choi Arum , Kim Sukil , Han Ji-Whan
Published: July 2024

Background

Periungual desquamation and thrombocytosis are characteristic of the subacute phase of Kawasaki disease (KD). However, accurate observations of periungual desquamation and thrombocytosis are lacking.

Methods

This retrospective study included patients with acute-phase KD who received treatment at seven affiliated university hospitals in Korea between 2015 and 2017. Data were extracted from an anonymized registry established by the Korean Society of Kawasaki Disease. We investigated whether the findings of patients observed according to a set protocol until the subacute stage (group I) were different from those of patients observed without the use of a protocol (group II).

Results

A total of 879 patients with KD were included in the analysis. Periungual desquamation was observed in 85% and 12.7% of patients in groups I and II, respectively. Thrombocytosis was observed in 76.7% and 44.7% of patients in groups I and II, respectively. Furthermore, compared to the initial test, the platelet counts of patients increased 100% and 67.9% in group I and II, respectively. When incomplete KD was defined only by the main symptoms during the acute stage and the diagnostic criterion of periungual desquamation during the subacute stage was excluded, the significant difference in the incidence of incomplete KD between groups I and II was no longer apparent.

Conclusion

Performing regular and detailed observations has resulted in a higher incidence of periungual desquamation and thrombocytosis during the subacute phase of KD than those reported in recent studies. This indicates that until now, we have been neglecting the observation of symptoms and signs during the subacute phase. Regular monitoring during this period can also aid in differentiating suspected cases of KD and facilitate appropriate follow-up of complications.
Toxicological evaluation of porcine bile powder in Kunming mice and Sprague–Dawley rats
Authors: Wu Lirong , Wang Jieyi , Lei Jing , Ge Kun , Qu Chun , Liu Jiajian , Huang Fengjie , Sun Dongnan , Chao Xiaowen , Chen Tianlu , Zhao Aihua , Jia Wei , Zheng Xiaojiao , Xie Guoxiang
Published: July 2024

Background: Porcine bile powder (PBP) is a traditional Chinese medicine that has been used for centuries in various therapeutic applications. However, PBP has not previously undergone comprehensive component analysis and not been evaluated for safety through standard in vivo toxicological studies.

Methods: In our study, we characterized the component of PBP by liquid chromatography-mass spectrometry. The acute and subchronic oral toxicity, genotoxicity, and teratogenicity studies of PBP were designed and conducted in Kunming mice and Sprague-Dawley (SD) rats.

Results: The chemical analysis of PBP showed that the main components of PBP were bile acids (BAs), especially glycochenodeoxycholic acid. There were no signs of toxicity observed in the acute oral test and the subchronic test. In the genotoxicity tests, no positive results were observed in the bacterial reverse mutation test. Additionally, in the mammalian micronucleus test and mouse spermatocyte chromosomal aberration test, no abnormal chromosomes were observed. In the teratogenicity test, no abnormal fetal development was observed.

Conclusion: Our findings demonstrate that PBP, composed mainly of BAs, is non-toxic and safe based on the conditions tested in this study.
Intestinal barrier permeability: the influence of gut microbiota, nutrition, and exercise
Authors: Dmytriv Tetiana R. , Storey Kenneth B. , Lushchak Volodymyr I.
Published: July 2024

The intestinal wall is a selectively permeable barrier between the content of the intestinal lumen and the internal environment of the body. Disturbances of intestinal wall permeability can potentially lead to unwanted activation of the enteric immune system due to excessive contact with gut microbiota and its components, and the development of endotoxemia, when the level of bacterial lipopolysaccharides increases in the blood, causing chronic low-intensity inflammation. In this review, the following aspects are covered: the structure of the intestinal wall barrier; the influence of the gut microbiota on the permeability of the intestinal wall via the regulation of functioning of tight junction proteins, synthesis/degradation of mucus and antioxidant effects; the molecular mechanisms of activation of the pro-inflammatory response caused by bacterial invasion through the TLR4-induced TIRAP/MyD88 and TRAM/TRIF signaling cascades; the influence of nutrition on intestinal permeability, and the influence of exercise with an emphasis on exercise-induced heat stress and hypoxia. Overall, this review provides some insight into how to prevent excessive intestinal barrier permeability and the associated inflammatory processes involved in many if not most pathologies. Some diets and physical exercise are supposed to be non-pharmacological approaches to maintain the integrity of intestinal barrier function and provide its efficient operation. However, at an early age, the increased intestinal permeability has a hormetic effect and contributes to the development of the immune system.
Wheat yield and grain-filling characteristics due to cultivar replacement in the Haihe Plain in China
Authors: Zhang Xuecheng , Liu Xiaoli , Wang Li , Zhao Qiancheng , Yu Yang , Du Ruirui , Xu Yadong , Zhen Wenchao , Wang Yandong
Published: July 2024

Background

The Haihe Plain plays an important role in wheat production and food security in China and has experienced continuous cultivar replacement since the 1950s.This study assessed the evolution of the yield and grain-filling characteristics of the main winter wheat cultivars in the Haihe Plain over the last seven decades (1950s to date).

Methods

Cultivar characterization indicated that the increase in yield was negatively affected by spike number and positively affected by the number of kernels per spike before the 2000s and kernel weight after the 2000s. Field trials were conducted across two ecological zones over two consecutive wheatgrowing seasons. The results showed that genetic gains in grain yield, spike number, and kernel weight during 1955 to 2021 were 0.629%, 0.574%, and 0.332% year–1 on a relative basis or 39.12 kg ha–1, 24,350 hm–2, and 0.15 g year–1 on an absolute basis, respectively. However, the increase in the kernel number per spike was not significant. Moreover, cultivar replacement explained 25.6%, 12.8%, and 37.5% of the total variance in grain yield, spike number, and kernel weight, respectively. In summary, during the initial grain-filling stage, wheat cultivar replacement led to the shortening of grain-filling duration and rapid grain-filling rate. However, a longer active grain-filling duration was produced by prolonged durations of rapid and late grain-filling. Additionally, the experimental year had a greater effect on the kernel number, which explained 53.2% of the total variance. Ultimately, modern wheat cultivars had a greater kernel weight.

Results

Although the increase in kernel weight has affected grain yield during cultivar replacements in the Haihe Plain, the potential for further yield increase through kernel weight enhancement alone is limited. Consequently, future breeding efforts and cultivation practices should focus on improving spike traits and canopy architecture to enhance productivity.