Current Perspectives in Giant Cell Arteritis: Can We Better Connect Pathogenesis and Treatment?

Giant cell arteritis (GCA) is a large-vessel vasculitis affecting elderly patients and targeting the aorta and its main branches, leading to cranial and extracranial manifestations. The mechanism behind the ischemia is a granulomatous-type inflammation with potentially critical lesions, including visual loss involving the ophthalmic artery. Despite significant progress in unraveling the pathophysiology of this disease, treatment options still rely on glucocorticoids (GCs) to overcome active vascular lesions and disease flares. However, uncertainty still revolves around the optimal dose and tapering rhythm. Few corticosteroid-sparing agents have proven useful in GCA, namely, methotrexate and tocilizumab, benefiting cumulative GC dose and relapse-free intervals. The future looks promising with regard to using other agents like abatacept and Janus-kinase inhibitors or blocking the granulocyte-macrophage colony-stimulating factor receptor.

The impact of coal mine dust characteristics on pathways to respiratory harm: investigating the pneumoconiotic potency of coals.

Exposure to dust from the mining environment has historically resulted in epidemic levels of mortality and morbidity from pneumoconiotic diseases such as silicosis, coal workers' pneumoconiosis (CWP), and asbestosis. Studies have shown that CWP remains a critical issue at collieries across the globe, with some countries facing resurgent patterns of the disease and additional pathologies from long-term exposure. Compliance measures to reduce dust exposure rely primarily on the assumption that all "fine" particles are equally toxic irrespective of source or chemical composition. For several ore types, but more specifically coal, such an assumption is not practical due to the complex and highly variable nature of the material. Additionally, several studies have identified possible mechanisms of pathogenesis from the minerals and deleterious metals in coal. The purpose of this review was to provide a reassessment of the perspectives and strategies used to evaluate the pneumoconiotic potency of coal mine dust. Emphasis is on the physicochemical characteristics of coal mine dust such as mineralogy/mineral chemistry, particle shape, size, specific surface area, and free surface area-all of which have been highlighted as contributing factors to the expression of pro-inflammatory responses in the lung. The review also highlights the potential opportunity for more holistic risk characterisation strategies for coal mine dust, which consider the mineralogical and physicochemical aspects of the dust as variables relevant to the current proposed mechanisms for CWP pathogenesis.

Modern Concepts in Melanocytic Tumors. / Conceptos modernos en tumores melanocíticos.

The advent of molecular pathology has fueled unprecedented advances in the diagnosis and understanding of melanocytic tumors. These advances, however, have also generated concepts that may be difficult to grasp for clinical practitioners, who are not always conversant with the array of genetic techniques employed in the laboratory. These same practitioners, however, are being increasingly called on to provide treatments that are often based on the latest molecular findings for melanocytic tumors. We review the most recent concepts in the pathway classification of melanocytic tumors, including intermediate lesions known as melanocytomas. We examine the genetic and molecular techniques used to study these tumors, look at where they overlap, and discuss their limitations and some of the most difficult-to-interpret results.

Substrate reduction therapy using Genz-667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease.

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood-brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B-epoxide (CBE), an irreversible inhibitor of acid beta-glucosidase (GCase), the enzyme defective in nGD, with or without co-injection with Genz-667161, a prototype for SRT which crosses the BBB. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co-injection with Genz-667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that Genz-667161 largely reversed the changes in genes and pathways that were differentially expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain.

Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population.

BACKGROUND: Ischemic stroke (IS) is a multifactorial disease that displays a strong genetic predisposition. However, the genetic architecture of IS has yet to be fully elucidated. It was hypothesized that epistasis between genes in multiple atherothrombotic pathways may play a vital role in determining the susceptibility to IS. The aim of the present study was to investigate the contributions of the hypothesized genetic factors to IS and the interactions between these genetic factors in a Chinese population. METHODS: In this study, 351 cases with IS and 417 control subjects from a Chinese population were genotyped for single-nucleotide polymorphisms (SNPs) in 12 genes hypothesized to be involved in atherosclerosis, coagulation, and related pathways. We examined SNP main effects and epistatic interactions between these polymorphic loci. RESULTS: rs710446 of the KNG1 gene was associated with IS susceptibility based on an additive genetic model (rs710446: P = .012; odds ratio [OR], 1.247; 95% confidence interval [CI], 1.050-1.481) after adjusting for covariates. Furthermore, an epistatic interaction between the ALOX5AP, THBD, and KNG1 gene was also identified in association with stroke susceptibility (P < .001 after 1000 permutations). Based on the chi-squared test, the OR of the high-risk combination of the three-locus model increased the risk of IS by 2.53-fold (95% CI, 1.60-4.01; P < .0001). CONCLUSIONS: Our findings support the association of the epistatic interactions of ALOX5AP, THBD, and KNG1 and present novel evidence for the main effect of KNG1 gene on IS susceptibility, suggesting a modulation of stroke risk by a genetic main effect and gene-gene interactions.

Inflammatory Cytokines in Rheumatoid Arthritis: Diagnostic Challenges, Pathogenic Mechanisms and their Role in Depression and Management.

Depression being a common comorbidity of rheumatoid arthritis (RA) is found to be responsible for the reduction in the lifespan of the sufferer along with the compromised quality of life. The study quoted below highlights the pathogenic pathways, the frequency of RA along with its impact on patients, thus, raising awareness about the concerned topic. It is found that the chances and frequency of developing depression are 2-3 times higher in patients with RA in comparison to the general population. For such studies, self-reported questionnaires along with proper screening of inclusion and exclusion criteria have been employed which helped in a better comparative study of the topic. As per a report from a meta-analysis, 16.8% of patients with RA have been observed to develop severe depression. According to recent research in the related field, the hypothesis of the role of immune-mediated processes and their role in brain networks and inflammation has been found to be engaged in the progression and pathophysiology of depression in patients with RA. Autoimmune mechanisms and cytokines are found to play an essential role in coordination for initiating and sustaining the disorder. Involvement of IL-1, IL-6 and TNF-α has been studied and analysed widely. A number of studies have shown a connection between depression and RA-related physical impairment, fatigue, and increased pain. Higher mortality, reduced treatment compliance, and more comorbidities effects increased suicide risk. It is also found that depression along with RA leads to hospitalizations, which in turn increase the cost of care for the patient. Hence, it could be stated that the study of depression in RA can be an important marker for the progression of RA and its prognosis. The latest treatment strategies for RA include management of symptoms and early disorder treatment The current review aims to investigate and bring the links between RA and its symptoms into the limelight, including the psycho-social, physiological, and neurological aspects along with their molecular mechanism, for a better discernment of the topic for the readers.

The Plasma DIA-Based Quantitative Proteomics Reveals the Pathogenic Pathways and New Biomarkers in Cervical Cancer and High Grade Squamous Intraepithelial Lesion.

OBJECTIVE: The process of normal cervix changing into high grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer is long and the mechanisms are still not completely clear. This study aimed to reveal the protein profiles related to HSIL and cervical cancer and find the diagnostic and prognostic molecular changes. METHODS: Data-independent acquisition (DIA) analysis was performed to identify 20 healthy female volunteers, 20 HSIL and 20 cervical patients in a cohort to screen differentially expressed proteins (DEPs) for the HSIL and cervical cancer. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional annotation of DEPs; the protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) were performed for detection of key molecular modules and hub proteins. They were validated using the Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: A total of 243 DEPs were identified in the study groups. GO and KEGG analysis showed that DEPs were mainly enriched in the complement and coagulation pathway, cholesterol metabolism pathway, the IL-17 signaling pathway as well as the viral protein interaction with cytokine and cytokine receptor pathway. Subsequently, the WGCNA analysis showed that the green module was highly correlated with the cervical cancer stage. Additionally, six interesting core DEPs were verified by ELISA, APOF and ORM1, showing nearly the same expression pattern with DIA. The area under the curve (AUC) of 0.978 was obtained by using ORM1 combined with APOF to predict CK and HSIL+CC, and in the diagnosis of HSIL and CC, the AUC can reach to 0.982. The high expression of ORM1 is related to lymph node metastasis and the clinical stage of cervical cancer patients as well as the poor prognosis. CONCLUSION: DIA-ELSIA combined analysis screened and validated two previously unexplored but potentially useful biomarkers for early diagnosis of HSIL and cervical cancer, as well as possible new pathogenic pathways and therapeutic targets.

Attention-deficit/hyperactive disorder updates.

Background: Attention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management. Objectives: We aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors. Methods: References for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022. Results: Several genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway. Conclusion: The dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

Conceptos modernos en tumores melanocíticos / Modern Concepts in Melanocytic Tumors

Con el desarrollo de la enfermedad molecular, el diagnóstico y la comprensión de los tumores melanocíticos ha experimentado un avance descomunal en los últimos años. Esto ha significado la aparición de conceptos de difícil asimilación en el mundo clínico, el cual no está siempre en contacto directo con las técnicas genéticas de laboratorio. Al mismo tiempo, sin embargo, al clínico se le está exigiendo una terapéutica basada en muchas ocasiones en los hallazgos moleculares más recientes de un tumor melanocítico. El presente artículo explora los conceptos moleculares más recientes de la clasificación en rutas patogénicas de los tumores melanocíticos, incluidas las formas intermedias conocidas como melanocitomas, y repasa las técnicas auxiliares usadas en el estudio de estos tumores, discutiendo los resultados más complejos, sus limitaciones, y sus solapamientos (AU)

The advent of molecular pathology has fueled unprecedented advances in the diagnosis and understanding of melanocytic tumors. These advances, however, have also generated concepts that may be difficult to grasp for clinical practitioners, who are not always conversant with the array of genetic techniques employed in the laboratory. These same practitioners, however, are being increasingly called on to provide treatments that are often based on the latest molecular findings for melanocytic tumors. We review the most recent concepts in the pathway classification of melanocytic tumors, including intermediate lesions known as melanocytomas. We examine the genetic and molecular techniques used to study these tumors, look at where they overlap, and discuss their limitations and some of the most difficult-to-interpret results (AU)

[Translated article] Modern Concepts in Melanocytic Tumors / Conceptos modernos en tumores melanocíticos

The advent of molecular pathology has fueled unprecedented advances in the diagnosis and understanding of melanocytic tumors. These advances, however, have also generated concepts that may be difficult to grasp for clinical practitioners, who are not always conversant with the array of genetic techniques employed in the laboratory. These same practitioners, however, are being increasingly called on to provide treatments that are often based on the latest molecular findings for melanocytic tumors. We review the most recent concepts in the pathway classification of melanocytic tumors, including intermediate lesions known as melanocytomas. We examine the genetic and molecular techniques used to study these tumors, look at where they overlap, and discuss their limitations and some of the most difficult-to-interpret results (AU)

Con el desarrollo de la enfermedad molecular, el diagnóstico y la comprensión de los tumores melanocíticos ha experimentado un avance descomunal en los últimos años. Esto ha significado la aparición de conceptos de difícil asimilación en el mundo clínico, el cual no está siempre en contacto directo con las técnicas genéticas de laboratorio. Al mismo tiempo, sin embargo, al clínico se le está exigiendo una terapéutica basada en muchas ocasiones en los hallazgos moleculares más recientes de un tumor melanocítico. El presente artículo explora los conceptos moleculares más recientes de la clasificación en rutas patogénicas de los tumores melanocíticos, incluidas las formas intermedias conocidas como melanocitomas, y repasa las técnicas auxiliares usadas en el estudio de estos tumores, discutiendo los resultados más complejos, sus limitaciones, y sus solapamientos (AU)

Evolving paradigm of treatment for autoimmune hepatitis.

INTRODUCTION: Current medications for autoimmune hepatitis have broad anti-inflammatory and immunosuppressive actions, and their effects are short-lived and inconsistent. The goals of this review were to describe the actions and shortcomings of these medications, indicate the key pathogenic mechanisms that might be targeted by site-directed interventions, and present the pivotal studies supporting development of these alternative agents. Areas covered: Abstracts cited in PubMed from April 1964 to February 2017 were identified using the search words 'treatment of autoimmune hepatitis'. A secondary bibliography was developed from the references cited in selected articles, and additional searches were performed to expand the concepts developed in these articles. The number of abstracts reviewed exceeded 1000, and the number of full-length articles reviewed exceeded 100. Expert commentary: Molecular, cellular, and pharmacological interventions that target key pathogenic pathways promise to change the current paradigm of treatment for autoimmune hepatitis. Interventions affecting lymphocyte activation, lymphocyte differentiation, effector cell migration, hepatocyte apoptosis, oxidative-nitrosative stress, fibrogenesis, and intestinal dysbiosis promise to emerge as supplemental or replacement therapies. The intestinal microbiome constitutes the next investigational frontier that may influence future management strategies. Unwanted and unexpected consequences of manipulating these homeostatic pathways constitute the major unmeasured risks of these evolving regimens.