Clinical Therapeutic Strategies Research Articles

Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke.

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema.

Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy

Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.

A bibliometric analysis of the application of the PI3K-AKT-mTOR signaling pathway in cancer.

PI3K-AKT-mTOR plays as important role in the growth, metabolism, proliferation, and migration of cancer cells, and in apoptosis, autophagy, inflammation, and angiogenesis in cancer. In this study, the aim was to comprehensively review the current research landscape regarding the PI3K-AKT-mTOR pathway in cancer, using bibliometrics to analyze research hotspots, and provide ideas for future research directions. Literature published on the topic between January 2006 and May 2023 was retrieved from the Web of Science core database, and key information and a visualization map were analyzed using CiteSpace and VOSviewer. A total of 5800 articles from 95 countries/regions were collected, including from China and the USA. The number of publications on the topic increased year on year. The major research institution was the University of Texas MD Anderson Cancer Center. Oncotarget and Clinical Cancer Research were the most prevalent journals in the field. Of 26,621 authors, R Kurzrock published the most articles, and J Engelman was cited most frequently. "A549 cell," "first line treatment," "first in human phase I," and "inhibitor" were the keywords of emerging research hotspots. Inhibitors of the PI3K-AKT-mTOR pathway and their use in clinical therapeutic strategies for cancer were the main topics in the field, and future research should also focus on PI3K-AKT-mTOR pathway inhibitors. This study is the first to comprehensively summarize trends and development s in research into the PI3K-AKT-mTOR pathway in cancer. The information that was obtained clarified recent research frontiers and directions, providing references for scholars of cancer management.

Albumin Oxidation and Albumin Glycation Discordance During Type 2 Diabetes Therapy: Biological and Clinical Implications.

Aims: Cys34 albumin redox modifications (reversible "cysteinylation" and irreversible "di/trioxidation"), besides being just oxidative stress biomarkers, may have primary pathogenetic roles to initiate and/or aggravate cell, tissue, and vascular damage in diabetes. In an exploratory "proof-of-concept" pilot study, we examined longitudinal changes in albumin oxidation during diabetes therapy. Methods: Mass spectrometric analysis was utilized to monitor changes in human serum albumin (HSA) post-translational modifications {glycation [glycated albumin (GA)], cysteinylation [cysteinylated albumin (CA) or human non-mercaptalbumin-1; reversible], di/trioxidation (di/trioxidized albumin or human non-mercaptalbumin-2; irreversible), and truncation (truncated albumin)} during ongoing therapy. Four informative groups of subjects were evaluated [type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity, and healthy controls] at baseline, and subjects with diabetes were followed for a period up to 280 days. Results: At baseline, T2DM was associated with relatively enhanced albumin cysteinylation (CA% total) compared with T1DM (P = 0.004), despite comparable mean hyperglycemia (P values: hemoglobin A1c = 0.09; GA = 0.09). T2DM, compared with T1DM, exhibited selectively and significantly higher elevations of all the "individual" glycated cum cysteinylated ("multimodified") albumin isoforms (P values: CysHSA+1G = 0.003; CysHSA+2G = 0.007; and CysHSA+3G = 0.001). Improvements in glycemic control and decreases in albumin glycation during diabetes therapy in T2DM were not always associated with concurrent reductions of albumin cysteinylation, and in some therapeutic situations, albumin cysteinylation worsened (glycation-cysteinylation discordance). Important differences were observed between the effects of sulfonylureas and metformin on albumin molecular modifications. Conclusions: T2DM was associated with higher oxidative (cysteinylation) and combined (cysteinylation plus glycation) albumin molecular modifications, which are not ameliorated by improved glucose control alone. Further studies are required to establish the clinical significance and optimal therapeutic strategies to address oxidative protein damage and resulting consequences in diabetes.

The Immunomodulatory effect of exosomes in diabetes: a novel and attractive therapeutic tool in diabetes therapy.

Exosomes carry proteins, metabolites, nucleic acids and lipids from their parent cell of origin. They are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Therefore, exosomes are often modified in reaction to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, all of which involve a significant inflammatory aspect. Here, we discuss how immune cell-derived exosomes origin from neutrophils, T lymphocytes, macrophages impact on the immune reprogramming of diabetes and the associated complications. Besides, exosomes derived from stem cells and their immunomodulatory properties and anti-inflammation effect in diabetes are also reviewed. Moreover, As an important addition to previous reviews, we describes promising directions involving engineered exosomes as well as current challenges of clinical applications in diabetic therapy. Further research on exosomes will explore their potential in translational medicine and provide new avenues for the development of effective clinical diagnostics and therapeutic strategies for immunoregulation of diabetes.

Pituitary Apoplexy: An Updated Review.

Pituitary apoplexy (PA) is an acute, life-threatening clinical syndrome caused by hemorrhage and/or infarction of the pituitary gland. It is clinically characterized by the sudden onset of headache. Depending on the severity, it may also be accompanied by nausea, vomiting, visual disturbances, varying degrees of adenohypophyseal hormone deficiency, and decreased level of consciousness. Corticotropic axis involvement may result in severe hypotension and contribute to impaired level of consciousness. Precipitating factors are present in up to 30% of cases. PA may occur at any age and sometimes develops during pregnancy or the immediate postpartum period. PA occurs more frequently in men aged 50-60, being rare in children and adolescents. It can develop in healthy pituitary glands or those affected by inflammation, infection, or tumor. The main cause of PA is usually spontaneous hemorrhage or infarction of a pituitary adenoma (pituitary neuroendocrine tumor, PitNET). It is a medical emergency requiring immediate attention and, in many cases, urgent surgical intervention and long-term follow-up. Although the majority of patients (70%) require surgery, about one-third can be treated conservatively, mainly by monitoring fluid and electrolyte levels and using intravenous glucocorticoids. There are scoring systems for PA with implications for management and therapeutic outcomes that can help guide therapeutic decisions. Management of PA requires proper evaluation and long-term follow-up by a multidisciplinary team with expertise in pituitary pathology. The aim of the review is to summarize and update the most relevant aspects of the epidemiology, etiopathogenesis, pathophysiology, clinical presentation and clinical forms, diagnosis, therapeutic strategies, and prognosis of PA.

Stress in childhood: clinical implications and therapeutic strategies

Stress is a universal evolutionarily determined physiological mechanism that allows to mobilize of organism reserves in life-threatening situations. However, like any mobilisation process, it is possible only for a short period of time. Then, the reserves are depleted and, according to Hans Sellier’s theory, distress occurs. In the context of the human organism, in our case, the child’s organism, stress-induced pathology debuts, which often has a systemic character, affecting many organs and systems. In addition, stress, acting as an epigenetic factor, can provoke the debut of diseases to which a particular individual has a predisposition. The literature review presents the modern concept of stress, its influence on the growing organism of a child and describes a number of stress-associated pathological conditions.

Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Abstract 6741: Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer

Abstract Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy. Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6741.

The role of PI3K/Akt signaling pathway in chronic kidney disease.

Chronic kidney disease (CKD), including chronic glomerulonephritis, IgA nephropathy and diabetic nephropathy, are common chronic diseases characterized by structural damage and functional decline of the kidneys. The current treatment of CKD is symptom relief. Several studies have reported that the phosphatidylinositol 3 kinases (PI3K)/protein kinase B (Akt) signaling pathway is a pathway closely related to the pathological process of CKD. It can ameliorate kidney damage by inhibiting this signal pathway which is involved with inflammation, oxidative stress, cell apoptosis, epithelial mesenchymal transformation (EMT) and autophagy. This review highlights the role of activating or inhibiting the PI3K/Akt signaling pathway in CKD-induced inflammatory response, apoptosis, autophagy and EMT. We also summarize the latest evidence on treating CKD by targeting the PI3K/Akt pathway, discuss the shortcomings and deficiencies of PI3K/Akt research in the field of CKD, and identify potential challenges in developing these clinical therapeutic CKD strategies, and provide appropriate solutions.

OFF episode quality of life impact scale (OFFELIA): A new measure of quality of life for off episodes in Parkinson's disease

IntroductionOFF Episodes occur in people with Parkinson's disease when their medication wears off, and motor and/or non-motor symptoms emerge. Existing measures used to assess OFF Episodes focus on the time spent in OFF Episodes through diaries or by identifying symptoms, but they are limited in their ability to capture the severity and functional impact of OFF episodes. The aim of this study was to develop and validate a new instrument, called “OFFELIA,” that measures the impact of OFF episodes on the quality of life of individuals with Parkinson's disease. MethodsParticipants completed a cross-sectional questionnaire, “Impact and Communication on OFF Periods,” while enrolled in the online clinical study Fox Insights. The data collected was used to develop OFFELIA. Psychometric testing was performed on 18 candidate items using classical, exploratory factor analysis, and item response theory methods. Results569 individuals with Parkinson's disease completed the questionnaire. All items were retained for the final measure, with 17 items aggregated into two multi-item scales (functioning and psychological well-being) and one item reported separately as it did not function well with the other items (employment). Known group comparisons based on average duration, frequency and unpredictability of OFF episodes indicated that OFFELIA subscales were more sensitive than existing generic and condition-specific measures. ConclusionInitial evidence supports the validity of OFFELIA, a new instrument that assesses the impact of OFF periods on daily life. This instrument can be used in assessing clinical therapeutic strategies targeting OFF episodes in Parkinson's disease.

Summary of the clinical characteristics of tuberculous otitis media

Objective:The purpose of this study was to analyze and summarize the clinical characteristics and diagnostic methods of tuberculous otitis media（TOM）, to enrich clinical experience in diagnosis and treatment of tuberculous otitis media, so as to reduce missed diagnosis and misdiagnosis, and facilitate timely and effective therapy for better prognosis. Methods:This study retrospectively analyzed the clinical data of patients with tuberculous otitis media who were hospitalized in the Ear ward of our hospital and received surgical treatment from 2008 to 2022. The data of patients' clinical characteristics, radiological examination, intraoperative findings and therapeutic strategies were recorded and summarized. Results:A total of 23 cases （26 ears） of tuberculous otitis media were included in this retrospective study. The most common clinical symptoms were otorrhea（thin odorless fluid）（100%） and conductive hearing loss（100%）, with a high incidence of facial paralysis（23.1%）. It was not sensitive to traditional antibiotic treatment, eg. Levofloxacin （50% effective rate only）, and relapsed soon after drug withdrawal. It was revealed that all the surgical views had gray and white tough granulation tissue hyperplasia（100%）, and 23.1% with caseous necrosis. The purpose of surgery was to clear the lesion, reduce the recurrence rate of suppurative infection, and repair the function （hearing reconstruction or facial nerve decompression） as appropriate. The paraffin pathology of granulation tissue were reported as typical granulomatous inflammation and caseous necrosis with positive acid-fast staining, which was consistent with tuberculosis. Conclusion:It was easily confused by the clinical manifestations of tuberculous otitis media and common chronic suppurative otitis media. When met with the following conditions, we should pay highly attention to suspect tuberculous otitis media: The severity of local manifestations did not match with the length of the disease; with poor tympanic membrane at the early stage with no obvious cholesteatomas, with facial paralysis or hearing loss early onset; insensitive to traditional antibiotic treatment; with extensive granulation appeared in the tympanum and or mastoid cavity, with or without caseous necrosis or dead bone in the early days. The diagnosis should be confirmed based on the acid-fast staining of the histopathological section to detect positive acid-fast bacilli. Meanwhile, multiple laboratory examination methods（such as T-spot and PCR） should be integrated synchronously to help support the diagnosis.

Therapeutic Potential of Spesolimab-Sbzo in the Management of Generalized Pustular Psoriasis Flares in Adults: Evidence to Date.

Generalized pustular psoriasis (GPP) is a rare, chronic, and severe skin disorder characterized by the eruption of non-infectious pustules on an erythematous background often associated with systemic symptoms. It may appear in association with plaque psoriasis or occur in previously healthy individuals. It differs from psoriasis vulgaris in clinical presentation, immunopathogenesis, histology, and therapeutic strategies. Overexpression of interleukin 36 (IL-36) or a loss-of-function mutation of IL-36 receptor antagonist (IL-36RA) are thought to play a pivotal role in the pathogenesis of this disease. There are currently no globally approved guidelines for the treatment of GPP, and the therapies used so far, with variable results, have given unsatisfactory results. Spesolimab, a selective humanized antibody against the IL-36 receptor that blocks its activation, is the first biologic drug approved in Europe in December 2022 for the treatment of GPP flares. It represents a promising therapy, demonstrating efficacy in reducing disease severity and improving patient outcomes. In our review, we have analyzed the latest advancements and findings regarding the efficacy and safety of spesolimab in the context of GPP management.

Exploration of the prognostic prediction value of the PANoptosis-based risk score and its correlation with tumor immunity in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common cancer with high mortality worldwide. PANoptosis is a novel inflammatory programmed cell death modality with the characteristics of pyroptosis, apoptosis and necroptosis. It is necessary to explore PANoptosis-related genes in LUAD patients and offer evidence for prognosis prediction and therapeutic strategies. Single-cell RNA sequencing data and RNA expression profiles of LUAD patients from The Cancer Genome Atlas and Gene Expression Omnibus databases are used to screen PANoptosis-related differential genes for the construction of a risk model. Fifteen PANoptosis-related markers with prognostic value were identified byLeast Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. Kaplan-Meier analysis and receiver operating characteristic curve analysis further demonstrated the significant predictive capability. Immune infiltration, Single Nucleotide Variants (SNV) mutations, and clinical drug susceptibility were analyzed. In conclusion, a risk model of 15 PANoptosis-related genes has significant value in prognostic prediction for LUAD and has potential to direct clinical therapeutic strategies during the treatment.

LncRNA MACC1-AS1 induces gemcitabine resistance in pancreatic cancer cells through suppressing ferroptosis.

Pancreatic ductal adenocarcinoma (PDA) mortality is primarily attributed to metastasis and chemotherapy resistance. In this research, the long non-coding RNA MACC1-AS1 was studied, playing a significant role in regulating lipid oxidation processes. This regulation could further lead to the inhibition of ferroptosis induced by chemotherapeutic drugs, making it a contributing factor to gemcitabine resistance in PDA. In both gemcitabine-resistant PDA patients and mouse models, the elevated expression level of MACC1-AS1 in the tumors was noted. Additionally, overexpression of MACC1-AS1 in pancreatic cancer cells was found to enhance tolerance to gemcitabine and suppress ferroptosis. Proteomic analysis of drug-resistant pancreatic cells revealed that overexpressed MACC1-AS1 inhibited the ubiquitination degradation of residues in the protein kinase STK33 by MDM4. Furthermore, its accumulation in the cytoplasm activated STK33, further activating the ferroptosis-suppressing proteins GPX4, thereby counteracting gemcitabine-induced cellular oxidative damage. These findings suggested that the long non-coding RNA MACC1-AS1 could play a significant role in the ability of pancreatic cancer cells to evade iron-mediated ferroptosis induced by gemcitabine. This discovery holds promise for developing clinical therapeutic strategies to combat chemotherapy resistance in pancreatic cancer.

ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing intracellular glycine biosynthesis

BackgroundZinc finger SWIM-type containing 4 (ZSWIM4) induces drug resistance in breast cancer cells. However, its role in epithelial ovarian cancer (EOC) remains unknown. In this study, we aimed to investigate the clinical significance of ZSWIM4 expression in EOC and develop new clinical therapeutic strategies for EOC.MethodsZSWIM4 expression in control and EOC tumor tissues was examined using immunohistochemistry. Lentiviral transduction, Cell Counting Kit-8 assay, tumorsphere formation assay, flow cytometry, western blotting, and animal xenograft model were used to assess the role of ZSWIM4 in chemotherapy. Cleavage Under Targets and Tagmentation (CUT&Tag) assays, chromatin immunoprecipitation assays, and luciferase reporter assays were used to confirm FOXK1-mediated upregulation of ZSWIM4 expression. The mechanism by which ZSWIM4 inhibition improves chemosensitivity was evaluated using RNA-sequencing. A ZSWIM4-targeting inhibitor was explored by virtual screening and surface plasmon resonance analysis. Patient-derived organoid (PDO) models were constructed from EOC tumor tissues with ZSWIM4 expression.ResultsZSWIM4 was overexpressed in EOC tumor tissues and impaired patient prognoses. Its expression correlated positively with EOC recurrence. ZSWIM4 expression was upregulated following carboplatin treatment, which, in turn, contributed to chemoresistance. Silencing ZSWIM4 expression sensitized EOC cells to carboplatin treatment in vitro and in vivo. FOXK1 could bind to the GTAAACA sequence of the ZSWIM4 promoter region to upregulate ZSWIM4 transcriptional activity and FOXK1 expression increased following carboplatin treatment, leading to an increase in ZSWIM4 expression. Mechanistically, ZSWIM4 knockdown downregulated the expression of several rate-limiting enzymes involved in glycine synthesis, causing a decrease in intracellular glycine levels, thus enhancing intracellular reactive oxygen species production induced by carboplatin treatment. Compound IPN60090 directly bound to ZSWIM4 protein and exerted a significant chemosensitizing effect in both EOC cells and PDO models.ConclusionsZSWIM4 inhibition enhanced EOC cell chemosensitivity by ameliorating intracellular glycine metabolism reprogramming, thus providing a new potential therapeutic strategy for EOC.

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis.

Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.

Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes.

The purpose of this article was to provide an overview of syndromic gliomas. The authors conducted a nonsystematic literature review. Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited. In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.

Diosgenin as a substitute for cholesterol alleviates NAFLD by affecting CYP7A1 and NPC1L1-related pathway

BackgroundNonalcoholic fatty liver disease (NAFLD) rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NAFLD treatment. Diosgenin as the structural analogue of cholesterol attenuates hypercholesterolemia by inhibiting cholesterol metabolism, which is an important pathogenesis in NAFLD progression. However, there has been no few report concerning its effects on NAFLD so far. MethodsUsing a high-fat diet & 10% fructose-feeding mice, we evaluated the anti-NAFLD effects of diosgenin. Transcriptome sequencing, LC/MS analysis, molecular docking simulation, molecular dynamics simulations and Luci fluorescent reporter gene analysis were used to evaluate pathways related to cholesterol metabolism. ResultsDiosgenin treatment ameliorated hepatic dysfunction and inhibited NAFLD formation including lipid accumulation, inflammation aggregation and fibrosis formation through regulating cholesterol metabolism. For the first time, diosgenin was structurally similar to cholesterol, down-regulated expression of CYP7A1 and regulated cholesterol metabolism in the liver (p < 0.01) and further affecting bile acids like CDCA, CA and TCA in the liver and feces. Besides, diosgenin decreased expression of NPC1L1 and suppressed cholesterol transport (p < 0.05). Molecular docking and molecular dynamics further proved that diosgenin was more strongly bound to CYP7A1. Luci fluorescent reporter gene analysis revealed that diosgenin concentration-dependently inhibited the enzymes activity of CYP7A1. ConclusionOur findings demonstrated that diosgenin was identified as a specific regulator of cholesterol metabolism, which pave way for the design of novel clinical therapeutic strategies.

Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d′Étude des Tumeurs Uro-Génitales) study

BackgroundAmong patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. ObjectivesTo report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC. MethodsWe retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. ResultsWe identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC95%=[4.2–7.1]) and 1.9 years (IC95%=[1.2–3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. ConclusionWe report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic.