Role In Pathology Research Articles

Recent Neuropathology Concepts.

The last session of the 2024 European Society of Toxicologic Pathology Congress was dedicated to recent neuro concepts, encompassing various topics including artificial intelligence (AI) applied to toxicologic pathology, new technologies for visualization and/or analysis of tissues, as well as specific case reports. Four presentations detailed the role of AI and computational pathology for toxicologic pathologists, usage of cryofluorescent tomography in neuropathology, blood-brain barrier organoids in early drug screening, and spatial transcriptomics in toxicologic pathology. In addition, there were two short presentations about a spontaneous brain lesion in Beagle dogs as well as central nervous system lesions related to adeno-associated virus vectors administration in various preclinical species. This session underscored the current and prospective impact of emerging technologies on drug screening and development.

From Castaways to Discoveries: Unveiling Treasures in Skin RNAseq Using a Novel Multidimensional Data Processing Workflow Including Infection-Host Dynamics.

Defining physiology and methods to measure biological mechanisms is essential. Extensive datasets such as RNA sequencing are used with little analysis of the knowledge gained from the various methodologies. Within this work, we have processed publicly available NCBI RNAseq datasets using a combination of bioinformatics tools for the largest physiological organ, the skin. In many datasets, we identify the quality of the sample, human transcript mapping, the sex of each sample, foreign RNA from bacteria/viruses/protists, and the presence of B/T-cell immune repertoire. Processing 8,274 samples from 132 different experiments for skin samples identifies common flora of skin with elevation of protists (such as Leishmania), bacteria (Staphylococcus, Cutibacterium acnes), and viruses (HSV, HPV) that may be involved in physiological differences. We observed samples with the Heilongjiang tick virus, Human T-cell Leukemia Virus Type I, and Equine Infectious Anemia Virus that likely play pathological roles in physiology. Integrating the various biomarkers identified five ideal datasets for skin pathologies that elucidated a novel correlation between the normal skin flora bacterium Bacillus megaterium with MHC complex regulation and the immune repertoire clonal expansion, particularly in patients with hidradenitis suppurativa. Finally, we show that in multiple independent experiments, biological sex is associated with multiple sex chromosome gene differences, highlighting the importance of future work in studying sex differences in skin. Data integrations and multidimensional data mapping are critical for physiological omics advancements, and this work highlights the exciting ability to apply these tools to skin physiology.

Self-Reported REM Sleep Behavior Disorder in Patients With Progressive Supranuclear Palsy: Clinical and 18F-Florzolotau PET Imaging Findings.

Rapid eye movement sleep behavior disorder (RBD) is increasingly recognized in patients with tauopathies, but its significance and underpinnings remain unclear. To address this gap, we investigated the prevalence of self-reported RBD in patients with progressive supranuclear palsy (PSP) and explored its clinical and imaging correlates using 18F-florzolotau PET imaging. We consecutively enrolled patients meeting the 2017 Movement Disorder Society clinical criteria for PSP at a Chinese tertiary hospital between May 2019 and March 2022. Patients underwent comprehensive clinical assessments and 18F-florzolotau PET to investigate tau deposition patterns. The presence of self-reported RBD was identified using the RBD Single-Question Screen, while its frequency was retrospectively collected from medical history. We examined 148 patients recruited in the ongoing Progressive Supranuclear Palsy Neuroimage Initiative cohort. Self-reported RBD was identified in 18.2% of the participants (27/148). Patients with PSP-Richardson syndrome and PSP-parkinsonism reported the highest frequencies of self-reported RBD (21.7% and 18.5%, respectively), compared with PSP-progressive gait freezing (9.7%). While age and sex were similar in patients with and without self-reported RBD, the former group exhibited greater disease severity, as indicated by higher PSP Rating Scale (PSPrs) scores (38.0 vs 27.0, effect size = 0.256, p = 0.002). Furthermore, patients with RBD had significantly higher 18F-florzolotau binding in the locus coeruleus (LC) (1.50 vs 1.38, effect size = 0.231, p = 0.003), which remained significant after false discovery rate correction (p = 0.042). The frequency of RBD was found to be correlated with tau pathology in the LC (n = 8, r = 0.752, p = 0.002). Notably, the presence of self-reported RBD symptoms mediated the relationship between LC tau pathology and PSPrs total scores (proportion-mediated = 2.09%, 95% CI 0.01%-10.00%, p = 0.044). Approximately one-fifth of patients with PSP reported RBD and exhibited more severe motor and nonmotor symptoms. The elevated 18F-florzolotau binding in the LC and its association with the presence of RBD symptoms underscore the critical role of tau pathology in disrupting sleep-regulating neural circuits. Future studies with larger sample sizes should incorporate polysomnography in patients with PSP with self-reported RBD to further elucidate this relationship.

Targeting the contact-kinin system: A cyclopeptide with anti-thromboinflammatory properties against stroke.

Targeting the contact-kinin system: A cyclopeptide with anti-thromboinflammatory properties against stroke.

LncRNA MIR181A1HG Deficiency Attenuates Vascular Inflammation and Atherosclerosis.

Endothelial cell (EC) dysfunction and vascular inflammation are critical in the initiation and progression of atherosclerosis. Long noncoding RNAs play a critical role in vascular pathology, but relatively little is known about their involvement in controlling vascular inflammation. MIR181A1HG is a conserved long noncoding RNA located in juxtaposition with miR-181a1 and miR-181b1, both involved in vascular inflammation. The study aims to investigate the role of MIR181A1HG in regulating vascular inflammation. We examined the expression of MIR181A1HG in both human and mouse atherosclerotic lesions. Loss-of-function and gain-of-function studies, and multiple RNA-protein interaction assays were used to investigate the role and molecular mechanisms of MIR181A1HG in vascular inflammation and atherosclerosis. The atherosclerotic phenotypes of MIR181A1HG-/-ApoE-/- mice were analyzed in combination with single-cell RNA sequencing. The transcriptional regulation of MIR181A1HG was verified through luciferase reporter and chromatin immunoprecipitation assays. MIR181A1HG expression was abundant in ECs and significantly increased in both human and mouse atherosclerotic lesions. MIR181A1HG-/-ApoE-/- mice had reduced NLRP (NLR family pyrin domain containing) 3 inflammasome signaling, EC activation, monocyte infiltration, and atherosclerotic lesion formation. Genetic deletion of MIR181A1HG in myeloid sells did not alter the progression of atherosclerosis. Single-cell RNA sequencing analysis revealed that MIR181A1HG deficiency reduced the proportion of immune cells and enriched anti-inflammation pathways in EC clusters in atherosclerotic lesions. In contrast, EC-specific MIR181A1HG overexpression promoted NLRP3 inflammasome signaling, EC activation, and atherosclerotic lesion formation, effects that were reversed by pharmacological inhibition of NLRP3 (MCC950). MIR181A1HG was transcriptionally activated via an NF-κB (nuclear factor kappa B)/p65-dependent pathway. Mechanistically, MIR181A1HG mediated these effects on regulating NLRP3 inflammasome and EC activation in part through decoying Foxp1 (forkhead box transcription factor 1) away from the promoters of target genes, which was independent of the miR-181a1/b1 cluster. Finally, EC-specific Foxp1 silencing reversed the antiatherosclerotic effect mediated by MIR181A1HG-deletion in vivo. These findings identify MIR181A1HG as a central driver of vascular inflammation in atherosclerosis by its ability to decoy Foxp1 away from target gene promoters and activate NLRP3 inflammasome in the vascular endothelium. Our study suggests MIR181A1HG as a future therapeutic target for vascular inflammatory disease states.

Serotype and distribution of adhesion genes in Streptococcus mutans isolated from people with Parkinson's disease.

The delicate balance of the oral cavity is disrupted by changes in hygiene and diet, leading to caries. The virulence of Streptococcus mutans, a key caries pathogen, is partly explained by its rhamnose-glucose polysaccharide (RGP) and its sucrose-dependent and -independent adhesion mechanisms. Given their role in comorbidities, this study investigates the diversity of S. mutans through analysis of RGP and sucrose-independent adhesion proteins (SpaP, WapA, Cnm, Cbm) in Parkinson's disease patients. In the PARKIDENT clinical trial, strains were isolated from saliva samples of Parkinson's patients at baseline and during a follow-up visit. Strains were preanalyzed by multiplex PCR for serotype and collagen-binding proteins, followed by high-throughput sequencing and bioinformatics analysis using RAST® and BLAST®. Phylogenetic analyses and protein modeling were also conducted. Of 40 patients in the Parkident clinical trial, only 24 had Streptococcus mutans strains isolable from salivary swabs. Serotyping revealed that over 80% of the 44 strains isolated were serotype c, in line with prevalence data in the literature. Furthermore, only SpaP types A and B were identified in the strains. The low variability observed for the WapA protein underlines its functional importance. Finally, the cbm gene was not found in any strain, and only 5 strains possessed the cnm gene, all of them serotype c. The study of these 44 Streptococcus mutans strains showed characteristics similar to other populations. Serotype c predominates, with minimal peptide sequence variability in adhesion proteins (SpaP, WapA). Collagen-binding proteins Cnm and Cbm are rare or absent. Further research is essential to better characterize strain distribution in the Parkinson's-affected population due to S. mutans' growing role in extra-oral pathologies. Trial registry: ClinicalTrials.gov ID NCT03827551, First submitted: 2019-01-25.

Novel roles of ammonia in physiology and cancer.

Ammonia, traditionally recognized as a toxic nitrogen waste product, has recently emerged as a significant player in diverse physiological processes and implicated in cancer biology. This review article provides an overview of the multifaceted impact of ammonia on cellular signaling pathways, energy metabolism, and tumor microenvironment dynamics, in particular its novel roles in neurotransmission, metabolic homeostasis, cancer cell proliferation, and immune modulation. Notably, ammonia accumulates within the tumor microenvironment, promoting non-essential amino acid synthesis, stimulating mTORC1 activation, promoting lipid synthesis, and impairing various immune cell functions, thereby promoting tumor progression. Furthermore, the potential dual role of ammonia as tumorigenic factor and cancer therapeutic target are discussed, shedding light on its complex regulatory mechanisms and clinical implications. This timely review aims to deepen our understanding of the emerging physiological and pathological roles of ammonia, offering valuable insights into its significance as a potential target for diagnostic and therapeutic interventions in cancer and beyond.

GRK2 and Mitochondrial Dynamics in Cardiovascular Health and Disease

G protein-coupled receptors (GPCRs) represent a family of membrane proteins that regulate several cellular processes. Among the GPCRs, G protein-coupled receptor kinases (GRKs) regulate downstream signaling pathways and receptor desensitization. GRK2 has gained significant interest due to its cardiovascular physiology and pathological involvement. GRK2’s presence in cardiac tissue and its influence on cardiac function, β-adrenergic signaling, and myocardial remodeling underlies its involvement in cardiovascular diseases such as heart failure and ischemia. GRK2’s canonical role is receptor desensitization, but emerging evidence suggests its involvement in mitochondrial dynamics and bioenergetics, influencing processes such as oxidative phosphorylation, reactive oxygen species production, and apoptosis. Moreover, GRK2’s localization within mitochondria suggests a direct role in regulating mitochondrial health and function. Notably, while GRK2 inhibition seems to be a therapeutic approach to heart failure, its precise role in mitochondrial dynamics and pathology needs further investigation. This review explores the complex relationship between mitochondrial function and GRK2 and clarifies the implications for cardiovascular health. Cardiovascular medicine might greatly benefit from future studies that focus on understanding the processes behind GRK2–mitochondrial crosstalk to develop personalized therapies

Thirty years of NRF2: advances and therapeutic challenges.

Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis. Advances in understanding the mechanistic regulation of NRF2 and its roles in human pathology have propelled the investigation of NRF2-targeted therapeutic strategies. This Review dissects the mechanistic intricacies of NRF2 signalling, its cross-talk with biological processes and its far-reaching implications for health and disease, highlighting key discoveries that have shaped innovative therapeutic approaches targeting NRF2.

Placental and Umbilical Cord Anomalies Detected by Ultrasound as Clinical Risk Factors of Adverse Perinatal Outcome: Case Series Review of Selected Conditions. Part 2: Umbilical Cord Abnormalities.

The aim of this second extended review is to describe the pathogenetic mechanisms underlying umbilical cord (UC) anomalies and their relationship with adverse perinatal outcomes. Review of the literature with case presentations to illustrate the relationship between UC pathologies and adverse perinatal outcomes are also reported. Prenatal ultrasound findings and perinatal care in these cases are presented. Our review confirms the ethiopathogenetic role and involvement of UC pathology in a wide variety of obstetric diseases that may jeopardize fetal well-being. Some of these specific pathologies are strongly associated with a high risk of poor perinatal outcomes.

Investigating the expression of anti/pro-inflammatory cytokines in the pathogenesis and treatment of ulcerative colitis and its association with serum level of vitamin D

Ulcerative colitis is an idiopathic gastrointestinal disease described by chronic inflammation of the digestive system. Cytokines may be responsible for immunopathogenesis, mucosal and tissue damage, and even treatment response. In addition to its role in calcium and phosphorus homeostasis and bone health, vitamin D is an immunomodulatory and anti-inflammatory agent. Understanding the role of cytokines may lead to improving the pathogenesis and treatment of this disease, therefore we aimed to investigate the relative gene expression of pro- and anti-inflammatory cytokines in biopsy samples taken from the affected area in the colon of ulcerative colitis patients and its association with serum vitamin D levels. A total of 47 ulcerative colitis patients were enrolled in this case-control study. The case group consisted of 23 patients with treatment-resistant ulcerative colitis, and the control group consisted of 24 ulcerative colitis patients responding to routine treatment. Serum vitamin D levels were measured by ELISA method. Real-time PCR was employed to quantify the relative expression of pro- and anti-inflammatory cytokines in colon biopsy samples from case and control groups. The pro-inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-8, IL-17 A, and IL-33, while the anti-inflammatory cytokines were IL-10, IL-35, and TGF-β. Data are showed as mean ± standard deviation (SD), and p values < 0.05 were considered statistically significant. The mean age of the control group was 45.88 ± 18.51 years, while that of the case group was 41.30 ± 13.01 years. The relative gene expression of TNF-α, IFN-γ, IL-1β, IL-6, IL-8, IL-17 A, IL-33, TGF-β, IL-10, and IL-35, in the case and control groups did not exhibit statistically significant differences (p > 0.05). However, the gene expression levels of the principal pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, were elevated in treatment-resistant patients compared to patients who responded to treatments. No correlation was observed between serum vitamin D levels and the gene expression of pro- and anti-inflammatory cytokines (p > 0.05). The present study did not identify a statistically significant correlation between the expression of pro- or anti-inflammatory cytokines and treatment response. Therefore, routine treatments had no effect on the expression of these cytokines in treatment-resistant patients. Additionally, serum vitamin D levels were not related to the relative expression of pro- and anti-inflammatory cytokines in the affected area of the colon of these patients. Despite the need for further research on the protective and pathological roles of cytokines and vitamin D, regular screening and early and complementary treatment may be beneficial in reducing inflammatory symptoms in these patients.

Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection

Glioblastoma (GBM) is the most aggressive and common type of primary malignant brain cancer in adults. GBM often recurs locally near the resection cavity (RC) following the surgical removal of primary tumors. Recent research has reported that neural stem cells (NSCs) in the subventricular zone (SVZ) harboring cancer-driving mutations serve as the cells of origin for human GBM. However, the pathological role of tumor-initiating NSCs in the SVZ in tumor recurrence remains to be elucidated. Here, we explore the potential contribution of mutation-harboring NSCs in the SVZ to tumor recurrence around the RC following surgical resection. Our hypothesis emerged from performing deep sequencing of longitudinal tissues from 10 patients with GBM, including (i) tumor-free SVZ tissue, (ii) primary tumor tissue, (iii) recurrent tumor tissue, and (iv) blood. As a result of this sequencing, we observed evidence suggesting that recurrent tumors show genetic links to the SVZ in 60% (6/10) of patients, which are distinct from the primary tumors. Using a genome-edited mouse model, we further identified that mutation-harboring NSCs appeared to migrate to the RC through the aberrant growth of oligodendrocyte progenitor cells, potentially contributing to the reconstruction of high-grade malignant gliomas in the RC. This process was associated with the CXCR4/CXCL12 axis, as supported by RNA sequencing data from human recurrent GBM. Taken together, our findings suggest that NSCs in human SVZ tissue may play a role in GBM recurrence, potentially highlighting a novel distant contributor of recurrence.

Do Parkinson's Disease clinical subtypes really exist?

Parkinson's Disease (PD) is a highly heterogeneous entity in terms of clinical manifestations, progression, and treatment response. This variability has given rise to the hypothesis that different clinical subtypes of the disease exist. To date, several clinical subtypes have been described, mostly based on different clinical features, and sometimes with the support of biomarkers, either fluid, neuroimaging, or neurophysiological. The most homogeneous subtypes detected are a 'benign subtype', characterised by younger age at onset, mild non-motor symptoms, and a slower rate of disease progression, and a 'malignant subtype', which features an older age at onset, a higher burden of non-motor symptoms, and faster disease progression. Despite extensive research, none of the subtypes identified so far seem to be biologically supported, so clinical subtyping does not elucidate PD aetiology and does not allow for the prediction of prognosis or treatment response. This study was aimed to review the literature on this topic and to examine the studies on PD subtyping. We also reviewed the proposed biomarkers for a biological classification of PD, and outlined the role of genetics and pathology within this context. In light of the recent proposal of a biological classification of PD, which might overcome the limits of the clinical diagnosis, PD subtyping should hopefully shepherd researchers towards a biological approach, also aided by recent advances in the field of biomarkers.

Role of Meniscal Pathology in the Development of Spontaneous Insufficiency Fractures of the Knee (SIFK): A Radiological Perspective

Introduction: Spontaneous insufficiency fractures of the knee (SIFK) are stress fractures occurring in weight-bearing joints, particularly the knee, due to underlying conditions like osteoporosis. These fractures typically affect elderly, postmenopausal women, individuals with obesity, or those with osteoporosis. Additional risk factors include diseases affecting collagen formation and systemic conditions like systemic lupus erythematosus and prolonged corticosteroid use. The medial femoral condyle is the most affected site, and patients frequently present with acute knee pain without any significant trauma. MRI plays a crucial role in diagnosing these fractures. Materials and Methods: This retrospective review of knee MRI reports from January 2013 to January 2020 was conducted in a tertiary care centre, included 85 cases of SIFK and 85 age and gender matched controls. The analysis included insufficiency fractures of the knee joint and assessment of the associated pathologies like meniscal tears, ACL degeneration and osteoarthritis. The Radiological findings were analyzed using SPSS v27 to evaluate the spectrum of findings. Results: Majority of the study population (59.4%) were females, with the medial femoral condyle being the most frequently affected site. Partial-thickness cartilage loss was the most common finding in both femoral and tibial cartilages, and posterior meniscal tears was observed in 78.8% of cases. ACL degeneration was present in 54.1% of cases, while osteoarthritis was present in 78.8%. The study also introduced a novel scoring system to evaluate the severity and association of insufficiency fractures with meniscal pathology and other related factors. Conclusion: A significant association between SIFK and underlying biomechanical and degenerative factors was well appreciated. A higher incidence of SIFK was observed among females, particularly after sixth decade of life. Meniscal extrusion and cartilage loss were the common associated factors in SIFK, emphasizing the importance of early detection and appropriate management of associated degenerative changes of the knee joint so as to prevent the progression into insufficiency fractures.

Advances in Breast Cancer Care: The Role of Artificial Intelligence and Digital Pathology in Precision Medicine.

Artificial intelligence (AI) and digital pathology are transforming breast cancer management by addressing the limitations inherent in traditional histopathological methods. The application of machine learning algorithms has enhanced the ability of AI systems to classify breast cancer subtypes, grade tumors, and quantify key biomarkers, thereby improving diagnostic accuracy and prognostic precision. Furthermore, AI-powered image analysis has demonstrated superiority in detecting lymph node metastases, contributing to more precise staging, treatment planning, and reduced evaluation time. The ability of AI to predict molecular markers, including human epidermal growth factor receptor 2 status, BRCA mutations and homologus recombination deficiency, offers substantial potential for the development of personalized treatment strategies. A collaborative approach between pathologists and AI systems is essential to fully harness the potential of this technology. Although AI provides automation and objective analysis, human expertise remains indispensable for the interpretation of results and clinical decision-making. This partnership is anticipated to transform breast cancer care by enhancing patient outcomes and optimizing treatment approaches.

MicroRNAs in disease States.

MicroRNAs in disease States.

The application of different biotechnologies in detecting the changes in MAM and their classic discoveries.

The application of different biotechnologies in detecting the changes in MAM and their classic discoveries.

MCNN-glucose: Identifying families of glucose transporters using a deep convolutional neural network based on multiple-scanning windows.

mCNN-glucose: Identifying families of glucose transporters using a deep convolutional neural network based on multiple-scanning windows.

Protocol for the site-specific isolation ofmouseendothelial cells using themodifiedHäutchentechnique.

Protocol for the site-specific isolation ofmouseendothelial cells using themodifiedHäutchentechnique.

Aberrant DNA methylation as a key modulator of cell death pathways: insights into cancer progression and other diseases.

Cell death plays a significant role in the physiology of all living organisms, and its disruption is the underlying cause of various diseases. Previously, it was assumed that apoptosis and necrosis were the only means of cell death. Recent discoveries of alternative cell death pathways highlighted a complicated interplay between cell death regulation and its role in numerous human pathologies. DNA methylation is a universal epigenetic mechanism characterized by the covalent addition of a methyl group to cytosine in CpG dinucleotides. Alterations in DNA methylation patterns lead to the dysregulation of multiple cell death pathways. DNA methylome studies on cell death pathways have improved our understanding of the mechanism of various types of cell death, such as apoptosis, pyroptosis, necroptosis, ferroptosis, anoikis, autophagy, and cuproptosis. The irregular DNA methylation patterns of genes encoding proteins linked to multiple cell death pathways could underlie resistance to cell death. Dysregulation of cell death is linked to ailments in humans, such as cancer. However, unlike genetic alterations, DNA methylation is reversible, making it extremely interesting for therapeutics considering the potential use of DNA methyltransferase inhibitors. Furthermore, tumor microenvironment and genetic heterogeneity of cancers may influence the methylation-dependent regulation of cell death, contributing to tumor progression and therapeutic resistance. Understanding how DNA methylation influences cell death pathways may illuminate the underlying causes of cancer. This review explores the significance of the DNA methylation patterns of key genes involved in cell death pathways, emphasizing their connections and identifying potential gaps that could be exploited for developing epigenetic therapies targeting cancer.