Stages Of Thedisease Research Articles

Tumor Microenvironment and Dermatological Conditions in Prostate Cancer

Tumor initiation, progression, and invasion are closely related to the tumor microenvironment. Inflammation can modulate the activity of the cells in the TME and contribute to all stages of tumor development. The etiopathogenesis of cutaneous manifestations associated with prostate cancer is unclear. The cutaneous phenotype associated with prostate cancer could be supported by intratumoral heterogeneity, the remodeling of interactions in the tumor microenvironment, and the dynamics of the epithelial–mesenchymal transition. Among the urinary system cancers, prostate cancer presents few cutaneous signs and symptoms, most being diagnosed in the advanced stages of the disease. In this review, we analyze the cutaneous events associated with prostate cancer, represented by direct or indirect manifestations of the primary malignancy and the skin toxicities caused by oncological medications.

Serum peroxiredoxin-4, a biomarker of oxidative stress, associates with new-onset chronic kidney disease: A population-based cohort study

BackgroundChronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population. MethodsThis study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, or both. ResultsBaseline median Prx4 level was 0.65 [interquartile range (IQR): 0.42–1.04] U/L, median eGFR was 98 [IQR: 87–108] mL/min/1.73 m2, and median UAE was 8.1 [IQR: 6.0–12.1] mg/L. During a median follow-up of 10.4 [IQR: 6.3–11.4] years, 867 (16.2 %) patients developed new-onset CKD. Higher Prx4 levels were significantly associated with an increased risk of CKD (hazard ratio (HR) per doubling: 1.29 [95 % confidence interval (CI): 1.21–1.37], p < 0.001), also after adjustment for risk factors including sex, smoking status, systolic blood pressure, high-sensitive C-reactive protein, chronic heart failure, diabetes mellitus and dyslipidemia (HR per doubling: 1.16 [1.06–1.24], p < 0.001). Sensitivity analyses confirmed the robustness of these findings. ConclusionsThis study supports the hypothesis that systemic oxidative stress, reflected by higher serum Prx4 levels, is significantly associated with the risk of developing CKD in the general population. These findings suggest that Prx4 could be a valuable biomarker for early risk stratification and prevention strategies in CKD management.

Sialoadenosis caused by spirocercosis in two dogs from Sri Lanka

AbstractSpirocercosis is a common parasitic disease in dogs in tropical and mediterranean regions of the world caused by the nematode Spirocerca lupi. Some dogs with spirocercosis develop sialoadenosis, a condition identified by non‐inflammatory, painless, bilateral enlargement of the mandibular salivary glands. Development of sialoadenosis in dogs infected with S. lupi occurs as a consequence of neurological stimulation caused by larval migration and oesophageal parasitic nodule formation. This report describes the clinical signs, diagnosis, treatment and the treatment outcome of two dogs diagnosed with sialoadenosis caused by spirocercosis. Phenobarbital therapy is useful to control clinical signs shown by the dogs with sialoadenosis secondary to spirocercosis presented at an early stage of the disease. A more favourable disease outcome is possible when phenobarbital therapy is combined with anti‐parasitic medication effective against S. lupi.

Assessing clinical progression measures in Alzheimer's disease trials: A systematic review and meta-analysis.

Assessing treatments for Alzheimer's disease (AD) relies on reliable tools for measuring AD progression. In this analysis, we evaluate the sensitivity of clinical progression measures in AD within randomized controlled trials (RCTs) with confirmed positive amyloid (Aβ+) status prior to trial enrollment. Excluding trials targeting non-cognitive symptoms, we conducted meta-analyses on progression measures from 25 selected RCTs using R version 4.2.0, along with the metafor and emmeans libraries. The Functional Activities Questionnaire (FAQ) demonstrated the greatest sensitivity over 12weeks. Other cognitive measures demonstrated lower sensitivity. The integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) seemed more effective than their individual cognitive components. Neuropsychiatric measures were the least sensitive in measuring progression. Functional measures generally outperformed other measure categories. Purely cognitive domain-based measures were suboptimal for tracking early AD progression. Ideally, future measures should incorporate both cognitive and functional components to enhance sensitivity. Concerns remain regarding the limitations of current outcome measures used in AD clinical trials, particularly their sensitivity in the early and preclinical stages of the disease, which hampers their reliability as indicators of AD progression. The Functional Activities Questionnaire (FAQ) demonstrated the most substantial weighted mean change over 12weeks, followed by the Mini-Mental State Examination (MMSE). Functional measures outperformed other measure categories. Composite scores of integrated Alzheimer's Disease Rating Scale and Clinical Dementia Rating-Sum of Boxes are more sensitive to change than their individual cognitive components, possibly driven by the functional components of the score. Neuropsychiatric measures analyzed in this study appeared to be the least sensitive in measuring progression.

Pathomorphological changes in the lung tissues of Syrian hamsters during experimental infection with SARS‐COV‐2

The new coronavirus infection caused by SARS‐CoV‐2 is a dangerous respiratory disease. The aim of the investigation was to study the pathomorphological changes in lungs of Syrian hamsters infected with SARS‐CoV‐2 as is necessary for adequate therapy and prevention of the disease.Syrian hamsters of the SPF category were infected intranasally with a dose of 5×105TCID50 SARS‐CoV‐2/human/RUS/Nsk‐FRCFTM‐1/2020). Animals were euthanised on days 3, 6, 10, 14 and 21 after infection and the lungs were collected. To determine virus replication real‐time RT‐PCR was used. The lungs was used for histological examination. Statistics was performed using Statistics for Windows 10 software.Specific pathological lesions characterising the inflammatory process were detected in all groups of animals. The severity of pathological changes and the volume of lung tissue lesions varied depending on the stage of the disease. The most severe lesions were observed on days 6–10. By day 21, the process of organ structure restoration was noticed.The study showed that pathological changes in the Syrian hamster’s lungs caused by experimental infection with the SARS‐CoV‐2 were multifaceted and complex. In mild cases, congestion and infiltration are observed, and in severe cases, atelectasis and pulmonary edema were life‐threatening. The most severe lesions in lungs were noted on days 6–10. By day 21, the process of restoration was observed.

Can molecular patterns help to classify overlapping entities in myeloid neoplasms?

Myeloid neoplasms include myeloproliferative and myelodysplastic neoplasms and acute myeloid leukaemia. Historically, these diseases have been diagnosed based on clinicopathological features with sometimes arbitrary thresholds that have persisted even as molecular features were gradually incorporated into their classification. As such, although current diagnostic approaches can classify the majority of myeloid neoplasms accurately using a combination of molecular and clinicopathological features, some areas of overlap persist and occasionally pose diagnostic challenges. These include overlap across BCR::ABL1-negative myeloproliferative neoplasms; between clonal cytopenia of undetermined significance and myelodysplastic neoplasms; myelodysplastic/myeloproliferative neoplasms; and, detection of KIT mutations in myeloid neoplasms other than mastocytosis, raising the prospect of systemic mastocytosis. Molecular testing has become state of the art in the diagnostic work-up of myeloid neoplasms, and molecular patterns can inherently help to classify overlapping entities if considered within a framework of haematological presentations. For future development, molecular testing will likely include whole genome and transcriptome sequencing, and primarily molecular classifications of myeloid neoplasms have already been suggested. As such, genetically defined groups should still constitute the basis for our understanding of disease development from early onset to progression, while clinicopathological features could then be used to describe the stage of the disease rather than the specific type of myeloid neoplasm.

Case report: Advanced breast cancer with scalp metastases: a report of two cases

BackgroundBreast cancer, identified as the most prevalent cancer worldwide, presents considerable difficulties in advanced stages, especially when involving metastatic spread. Scalp metastasis from breast cancer represents a rare and insufficiently explored occurrence. This paper seeks to illuminate this uncommon manifestation by presenting two cases of scalp metastatic breast cancer in Chinese women.Case reportCase 1: A 45-year-old Chinese woman with a history of invasive ductal carcinoma presented with a scalp lesion indicative of recurrence. Concurrently, she was diagnosed with bone metastases and recurrence at the original site. Despite undergoing various treatments, including chemotherapy and hormonal therapy, her condition worsened, ultimately leading to her passing. Case 2: A 40-year-old Chinese woman was initially diagnosed with bilateral breast invasive mucinous carcinoma presenting with bilateral breast masses and a scalp lesion. She also had multiple bone metastases. Following chemotherapy and hormonal therapy, her disease stabilized.ConclusionThese cases of scalp metastatic breast cancer underscore the complexities involved in managing advanced stages of the disease, especially with rare metastatic manifestations. They highlight the importance of comprehensive diagnostic methods, encompassing full-body skin evaluations, and draw attention to the socioeconomic challenges faced in cancer treatment. These findings point to the necessity for more targeted research on uncommon metastatic forms in breast cancer aiming to enhance patient outcomes and refine management approaches.

Resolution of the Expert Council on the problem of early diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disease and the most common cause of dementia. In daily practice, AD is often diagnosed late, while the early stages of the disease are overlooked or mistaken for cerebrovascular pathology. However, the efficacy of existing and newly developed (disease-modifying) AD therapies is the greatest in the early stages of the disease. An accurate diagnosis of AD is possible when biological markers of the main pathological process (cerebral amyloidosis, tauopathy) are detected using positron emission tomography or neurochemical examination of cerebrospinal fluid, which are gradually being introduced into practice in Russia. The experts discussed the clinical aspects of the use of biological markers, obtained in the leading specialized centers of our country for the diagnosis and treatment of cognitive impairment (CI). First and foremost, biomarker testing is indicated in patients with mild CI and mild dementia possibly associated with AD, so that disease-modifying (pathogenetic) therapy can be initiated as early as possible upon on its availability (currently, drugs for anti-amyloid disease-modifying therapy are not registered in the Russian Federation). Patients with a non-classical (non-amnestic) or atypical AD phenotype are another group of patients in whom it is also advisable to analyze biomarkers for differential diagnostic purposes.

Fasting and Diet: Overview in Chronic Lymphocytic Leukemia

Background: This review aims to provide an overview of the potential impact of fasting and diet on cancer, and in particular, on chronic lymphocytic leukemia (CLL), which is the most frequent form of leukemia in the Western world. Methods: Experimental and clinical studies have provided evidence of the crucial role of fasting in enhancing cancer treatment and improving outcomes for oncological patients, particularly at the early stages of the disease. Results: Emerging evidence highlights that fasting creates a differential stress response under critical conditions by fostering the survival of normal cells while limiting the survival and growth of cancer cells. Pivotal studies on CLL have highlighted the potential of fasting and dietary components to influence the stromal microenvironment and certain metabolic pathways, thereby affecting cancer cell apoptosis and immune response. In addition, explorative and initial clinical studies suggest that fasting and specific diets can mitigate the toxicity of chemotherapy. Conclusions: Clinical trials are needed to evaluate the efficacy and safety of nutritional and fasting approaches in cancer and CLL. Future investigations could provide new insights into the potential role of diet and fasting in the prevention and treatment of cancer, potentially leading to more effective and personalized therapeutic strategies.

Mesenchymal tumors of the mediastinum: analysis of the clinical case

Mediastinal tumors include a wide range of benign and malignant neoplasms. The latter in the early stages are characterized by a long latent course and carry a significant threat of com pression and / or invasion of vital organs of the mediastinum. The complexity of their diagnosis is complemented by a mixed clinical picture, similar to other somatic diseases. Considering all of the above, mediastinal tumors are an urgent problem for the modem oncological community, they require improving knowledge and gaining experience in their surgical and conservative treatment. Mesenchym al tumors of the mediastinum make up a small part of tumors of the mediastinal space, and the low incidence of neoplasm s of this anatomical localization dictates the need for an interdisciplinary approach to the diagnosis and treatment of mesenchym al tumors of the mediastinal space. A clinical case of the disease is considered, an effective and radical surgical treatment method is demonstrated. The asymptomatic course of the early stages of the disease, as w ell as the relatively low effectiveness of surgical intervention in the late period of oncogenesis, dictates the need to search for new approaches in the diagnosis and treatment of mediastinal tumors.

Integrated temporal transcriptional and epigenetic single-cell analysis reveals the intrarenal immune characteristics in an early-stage model of IgA nephropathy during its acute injury

RationaleKidney inflammation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), yet the specific phenotypes of immune cells involved in disease progression remain incompletely understood. Utilizing joint profiling through longitudinal single-cell RNA-sequencing (scRNAseq) and single-cell assay for transposase-accessible chromatin sequencing (scATACseq) can provide a comprehensive framework for elucidating the development of cell subset diversity and how chromatin accessibility regulates transcription.ObjectiveWe aimed to characterize the dynamic immune cellular landscape at a high resolution in an early IgAN mouse model with acute kidney injury (AKI).Methods and resultsA murine model was utilized to mimic 3 immunological states –”immune stability (IS), immune activation (IA) and immune remission (IR)” in early human IgAN-associated glomerulopathy during AKI, achieved through lipopolysaccharide (LPS) injection. Urinary albumin to creatinine ratio (UACR) was measured to further validate the exacerbation and resolution of kidney inflammation during this course. Paired scRNAseq and scATACseq analysis was performed on CD45+ immune cells isolated from kidney tissues obtained from CTRL (healthy vehicle), IS, IA and IR (4 or 5 mice each). The analyses revealed 7 major cell types and 24 clusters based on 72304 single-cell transcriptomes, allowing for the identification and characterization of various immune cell types within each cluster. Our data offer an impartial depiction of the immunological characteristics, as the proportions of immune cell types fluctuated throughout different stages of the disease. Specifically, these analyses also revealed novel subpopulations, such as a macrophage subset (Nlrp1b Mac) with distinct epigenetic features and a unique transcription factor motif profile, potentially exerting immunoregulatory effects, as well as an early subset of Tex distinguished by their effector and cytolytic potential (CX3CR1-transTeff). Furthermore, in order to investigate the potential interaction between immune cells and renal resident cells, we conducted single-cell RNA sequencing on kidney cells obtained from a separate cohort of IS and IA mice without isolating immune cells. These findings underscored the diverse roles played by macrophages and CD8+ T cells in maintaining homeostasis of endothelial cells (ECs) under stress.ConclusionsThis study presents a comprehensive analysis of the dynamic changes in immune cell profiles in a model of IgAN, identifying key cell types and their roles and interactions. These findings significantly contribute to the understanding of the pathogenesis of IgAN and may provide potential targets for therapeutic intervention.

The Role of 18F-FDG PET in the Diagnosis of Aortitis and Large Vessel Vasculitis

Background: 18F-FDG PET metabolic imaging provides significant help in the early diagnosis of inflammation of large and medium arteries, even before the appearance of structural vascular alterations. This retrospective study aims to evaluate the role of 18F-FDG PET in the diagnosis and management of large vessel vasculitis (LVV), including aortitis. Methodology: Fifty patients with clinical and/or biological suspicion of large vessel vasculitis but without a definitive diagnosis underwent 18F-FDG PET scanning. A qualitative visual scoring system and an average total vascular score (TVS) were used to compare 18F-FDG uptake in the vascular walls with that in the liver. Patients who had been on corticosteroids for more than 8 days were excluded from the study. Results: The study included 50 patients, 27 women and 23 men, with an average age of 65.8 ± 14.5 years. The analysis of 18F-FDG PET images allowed for the classification of subjects into two distinct groups. Among the 50 subjects, 16 (32%) showed higher 18F-FDG uptake in the vascular walls compared to hepatic uptake (PET-positive group), while 34 (68%) showed lower uptake (PET-negative group). In the positive group, 75% were diagnosed with Horton’s disease, and the remaining 25% with other inflammatory diseases such as Takayasu arteritis or polyarteritis nodosa. None of the subjects in the positive group had an aortic aneurysm. All patients with a positive 18F-FDG PET had elevated levels of C-reactive protein. The TVS obtained for aortitis alone was 5.9 ± 4.7, while the score for more global vasculitis was obviously higher, at 10.4 ± 6.3. Conclusion: 18F-FDG PET has become a valuable tool in the diagnosis of large vessel vasculitis, particularly in the early stages of the disease. It also allows for mapping of arterial involvement and estimation of disease severity using the TVS.

A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients

Abstract Early detection of Alzheimer’s disease is vital for timely treatment. Existing biomarkers for Alzheimer’s disease reflect amyloid- and tau-related pathology, but it is unknown whether the disease can be detected before cerebral amyloidosis is observed. N-glycosylation has been suggested as an upstream regulator of both amyloid and tau pathology, and levels of the N-glycan structure bisecting N-acetylglucosamine (GlcNAc) correlate with tau in blood and CSF already at preclinical stages of the disease. Therefore, we aimed to evaluate if bisecting GlcNAc could predict future cognitive decline in patients from a memory clinic cohort, stratified by amyloid/tau status. We included 251 patients (mean age: 65.6 ± 10.6 years, 60.6% female) in the GEDOC cohort, from the Memory Clinic at Karolinska University Hospital, Stockholm, Sweden. Patients were classified as amyloid/tau positive or negative based on CSF biomarkers. Cognitive decline, measured by longitudinal Mini-Mental State Examination scores, was followed for an average of 10.7 ± 4.1 years, and modelled using non-linear mixed effects models. Additionally, bisecting N-acetylglucosamine levels were measured in hippocampus and cortex with lectin-based immunohistochemistry in ten Alzheimer’s disease and control brains. We found that CSF bisecting GlcNAc levels were elevated in tau positive individuals compared to tau negative individuals, but not in amyloid positive individuals compared to amyloid negative individuals. In the whole sample, high levels of CSF bisecting GlcNAc predicted earlier cognitive decline. Strikingly, amyloid/tau stratification showed that high CSF bisecting GlcNAc levels predicted earlier cognitive decline in amyloid negative patients (β = 2.53 ± 0.85 years, p = 0.003) and tau negative patients (β = 2.43 ± 1.01 years, p = 0.017), but not in amyloid- or tau-positive patients. Finally, histochemical analysis of bisecting GlcNAc showed increased levels in neurons in hippocampus and cortex of Alzheimer’s disease compared to control brain (fold change = 1.44–1.49, p &amp;lt; 0.001). In conclusion, high CSF levels of bisecting GlcNAc reflected neuronal pathology and predicted cognitive decline in amyloid- and tau-negative individuals, suggesting that abnormal glycosylation precedes cerebral amyloidosis and tau hyperphosphorylation in Alzheimer’s disease. Bisecting N-acetylglucosamine is a promising novel early biomarker for Alzheimer’s disease.

Greater humoral EBV response may be associated with choroid plexus inflammation in progressive MS.

Choroid plexus (CP) inflammation can be quantified in vivo with MRI in people with multiple sclerosis (pwMS). It remains unknown whether Epstein Barr Virus (EBV) is related to CP changes. Total of 170 pwMS (116 relapsing-remitting; RRMS and 54 progressive MS; PMS) underwent MRI examination and measurement of humoral anti-EBV response. CP volume and CP pseudo-T2 (pT2), a relaxation time indicative of edema and neuroinflammation, were measured. Moreover, anti-EBV nuclear antigen-1 (EBNA-1) IgG and anti-EBV capsid antigen (VCA) IgG antibodies were measured. The PMS group had greater CP pT2 value when compared to RRMS (1120ms vs. 954ms, p = 0.037). After adjusting for age and therapy effects, higher CP pT2 values were associated with higher anti-EBNA-1 IgG levels only in PMS (r = 0.352, p = 0.015). Higher Anti-EBV humoral response in pwMS may be associated with increased CP neuroinflammatory changes and may be more relevant for the later chronic stage of the disease. Large-scale studies should investigate whether these findings are generalizable to all types of progressive MS.

Pathogenesis and Systemic treatment of Hepatocellular Carcinoma: Current Status and Prospects.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options have greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Semisynthetic Ecdysteroid Cinnamate Esters and tert-Butyl Oxime Ether Derivatives with Trypanocidal Activity.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects the lives of millions of indigenous people in Latin America. As medications to treat Chagas disease are limited to the application of benznidazole and nifurtimox, which are not ideal treatments for the chronic stage of the disease, the search for new antichagasic drug candidates is an important need. Ecdysone has previously been shown to interfere with the life cycle of T. cruzi. Here, we report the biological profiling and subsequent semisynthetic structure optimization of 47 ecdysteroids against T. cruzi with the aim of identifying selective trypanocidal ecdysteroids. Two moderately trypanocidal pharmacophores were identified: ecdysteroids containing a 6-tert-butyl oxime ether and a cinnamic ester moiety. These functional groups were combined into the structures of four new semisynthetic ecdysteroids (44-47), among which 44 exerted potent and selective trypanocidal activity (IC50 < 2 μM). Cellular infection assays showed that ecdysteroid 44 potently and efficiently inhibited amastigote replication as determined by trypomastigote release after cellular infection with an IC50 of 2.7 ± 0.1 μM. The compound was similarly potent to benznidazole (IC50 = 3.8 ± 0.7 μM) and more than 5-fold more cytotoxic toward T. cruzi over RAW264.7 host macrophages. Overall, the ecdysteroid cinnamate ester 44 is a novel trypanocidal lead structure that needs to be further characterized in follow-up studies.

Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson's Disease Rat Model.

The detection of early molecular mechanisms and potential biomarkers in Parkinson's disease (PD) remains a challenge. Recent research has pointed to novel roles for post-translational citrullination/deimination caused by peptidylarginine deiminases (PADs), a family of calcium-activated enzymes, in the early stages of the disease. The current study assessed brain-region-specific citrullinated protein targets and their associated protein-protein interaction networks alongside PAD isozymes in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb) were compared between controls/shams and the pre-motor PD model. For all brain regions, there was a significant difference in citrullinated protein IDs between the PD model and the controls. Citrullinated protein hits were most abundant in cortex and hippocampus, followed by cerebellum, midbrain, olfactory bulb and striatum. Citrullinome-associated pathway enrichment analysis showed correspondingly considerable differences between the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in PD brains only were associated with neurological, metabolic, immune and hormonal functions and included the following: "Axon guidance"; "Spinocerebellar ataxia"; "Hippo signalling pathway"; "NOD-like receptor signalling pathway"; "Phosphatidylinositol signalling system"; "Rap1 signalling pathway"; "Platelet activation"; "Yersinia infection"; "Fc gamma R-mediated phagocytosis"; "Human cytomegalovirus infection"; "Inositol phosphate metabolism"; "Thyroid hormone signalling pathway"; "Progesterone-mediated oocyte maturation"; "Oocyte meiosis"; and "Choline metabolism in cancer". Some brain-region-specific differences were furthermore observed for the five PAD isozymes (PADs 1, 2, 3, 4 and 6), with most changes in PAD 2, 3 and 4 when comparing control and PD brain regions. Our findings indicate that PAD-mediated protein citrullination plays roles in metabolic, immune, cell signalling and neurodegenerative disease-related pathways across brain regions in early pre-motor stages of PD, highlighting PADs as targets for future therapeutic avenues.

Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer

Background and aimsHistomorphology is a powerful and cost-efficient tool for evaluating inflammatory and neoplastic conditions. Inflammatory bowel disease (IBD) is a widespread condition with globally rising incidences, and a lot of research is done to better understand the pathogenesis of IBD and to identify potential therapeutic approaches. However, standardized and reproducible scores for the histomorphological evaluation of murine IBD models are lacking. Therefore, we aimed to develop an easy-to-use and reproducible score for standardized assessment of colitis and associated cancer models. MethodsIn this study, samples from three different colitis models with and without associated cancer formation were analyzed to develop a universal, robust, and reproducible score for the grading of murine colitis models using the following three parameters: 1. Extent of leucocyte infiltration, 2. Tissue damage, 3. Architectural disruption of the mucosa. ResultsA scoring system was established for different kinds of colitis models (genetically induced enterocolitis, genetically induced metabolic injury, and chemically induced colitis-associated cancer) and all stages of the disease, from mild inflammatory changes to severe inflammation with neoplastic changes as the extreme extent of IBD. The scoring scheme is easy to use, can easily be learned, and proves to have a high interrater reliability. ConclusionsWe propose a robust histological scoring system for the assessment of murine colitis and colitis-associated cancer models, giving more researchers access to conclusive and reliable histological assessment.

A Map of Transcriptomic Signatures of Different Brain Areas in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches.

Correlations among quality of life, spinal mobility, and disease activity in early-treated axial spondyloarthritis: a single-center cross-sectional study

BackgroundAxial spondyloarthritis (axSpA) significantly impacts patients’ lives. The ASAS-OMERACT guideline was formulated for the multidimensional evaluation of axSpA patients, employing a specific set of tools. Given the pivotal role of patient perception, comprehensive correlation among these tools, especially concerning quality of life, may provide a clinically relevant perspective and enhance treatment efficacy in the early stages of the disease. This study aims to investigate the correlation among disease activity, functional ability, and quality of life in early-treated axSpA patients. In addition, the association between high disease activity and clinical characteristics was explored.MethodsThis cross-sectional study was conducted in a tertiary hospital in Thailand. Patients diagnosed with axSpA according to ASAS classification criteria and receiving treatment from rheumatologists within three years of onset of symptoms were included. Clinical and laboratory data were retrieved from a hospital database. Disease activity was assessed using the Ankylosing Spondylitis Disease Activity Score with ESR or CRP (ASDAS-ESR/CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Spinal mobility was measured using the Bath Ankylosing Spondylitis Metrology Index (BASMI), while quality of life and function were evaluated using the ASAS Health Index (ASAS-HI) and Bath Ankylosing Spondylitis Functional Index (BASFI), respectively. The correlation between these measurements was analyzed using the Pearson correlation coefficient (r). Additionally, factors associated with high disease activity (ASDAS/CRP > 2.1) were explored using multivariate regression analysis.ResultsSixty-six patients (41 males; mean age 49.3 ± 13.3 years) were enrolled between April to December 2022. Disease activity (ASDAS-CRP) was significantly inversely correlated with spinal mobility (BASMI), function (BASFI), and quality of life (ASAS-HI). High disease activity was associated with obesity (BMI ≥ 30 kg/m^2) and a longer duration of symptoms before treatment (≥ 2 years).ConclusionIn early-treated axSpA patients, ASDAS-CRP showed significant correlations with functional ability, quality of life, and spinal mobility. High disease activity was associated with obesity and a longer pre-treatment symptom duration in our study. Early treatment may enhance patients’ function, mobility, and quality of life, with weight reduction being possibly beneficial for obese axSpA patients.Clinical trial numberNot applicable.