Stages Of Disease Progression Research Articles

Durable Clinical Impacts and Mechanisms of Action and Resistance in EZH1/2-Targeting Epigenetic Therapy

Background: Epigenomes allow the rectification of disordered gene expressions, thereby providing new targets for pharmacological interventions in cancer therapy. The clinical utility of targeting histone H3 lysine tri-methylation (H3K27me3) as an epigenetic hallmark has been demonstrated. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumor cells remain unclear. Results and Discussion: We conducted intensive molecular monitoring of three patients enrolled in the valemetostat first-in-human phase 1 clinical trial (NCT02732275) for adult T-cell leukemia/lymphoma (ATL). Valemetostat was administered orally once daily (200 mg/day) until a sign of disease progression could be observed. The number of abnormal lymphocytes (Ably) in these three patients drastically decreased after one week of treatment. All patients could stay on valemetostat single agent for more than 2 years with acceptable safety and durable response. PBMC samples (n = 55) were collected from these three patients immediately before (Pre) and during treatment, as well as during the progressive disease (PD) stage. Flow cytometry-based histone methylation assay demonstrated that tumor H3K27me3 level was generally high in the Pre-samples, but the valemetostat treatment reduced it to a normal level in all patients. In addition, ChIP sequencing (ChIP-seq) could directly assess how valemetostat affects the tumor epigenome. The pre-treatment tumor cells showed an overall increasing trend in H3K27me3. For all H3K27me3 peaks (51,683 peaks), 85.9% of the peak signals decreased at the average fold-change of 0.742 after the valemetostat treatment. Focusing on the gene loci, an overall decrease could be observed around the TSS and across the gene body. The characteristic H3K27me3 clusters initially observed in the tumor cells were demethylated. We also conducted integrative multilayered single-cell analyses (scATAC-seq and scRNA-seq) and showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, such as tumor suppressor genes (TSGs), in all patients. These results demonstrated that valemetostat sufficiently restored the epigenome of the tumor cells close to the healthy state, leading to clinical improvements. Although all tested cases showed a durable response for more than 2 years, these responses were eventually interrupted due to the recurrence of ATL. We identified characteristic somatic mutations of EZH2 during clonal repopulation at PD. The identified amino acid substitutions were all located at the interface between EZH2 and valemetostat. Direct evaluation of the H3K27me3 level in the PD sample harboring the acquired EZH2 mutation showed that tumor cells in a hypermethylated state were repopulating. The scATAC-seq analysis also showed strong chromatin compaction of the same gene set occurred in the rapidly propagating resistant clone, indicating that the clonally selected mutations should be responsible for resistance. In patients free of the EZH2 resistant mutations, we detected TET2 mutation or elevated DNMT3A expression in the propagated resistant clones. Genome-wide DNA methylation analysis revealed increased DNA methylation near the TSS in the resistant clones. The genes characterized by the H3K27me3-related chromatin condensation were restored by valemetostat treatment but were again strongly re-condensed by mCpG gain at PD. Consequently, the gene regulation of several important TSGs restored by valemetostat was repressed again. Furthermore, in the single-cell platform, we successfully identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Conclusion: This study illustrates, for the first time, the molecular and cellular dynamics in patients in response to a molecular-targeting inhibitor designed for histone methyltransferases. Eliminating H3K27me3 leads to the reprogramming of the cancer epigenome, thereby exerting a sustained benefit on tumors. Targeting chromatin homeostasis might provide opportunities for further sustained epigenetic therapies.

Visualization of clonal expansion after massive depletion of cells carrying the bovine leukemia virus (BLV) integration sites during the course of disease progression in a BLV naturally-infected cow: a case report

Bovine leukemia virus (BLV) infects cattle, integrates into host DNA as a provirus, and induces malignant B-cell lymphoma. Previous studies have addressed the impact of proviral integration of BLV on BLV-induced leukemogenesis. However, no studies have monitored sequential changes in integration sites in which naturally infected BLV individuals progress from the premalignant stage to the terminal disease. Here, we collected blood samples from a single, naturally infected Holstein cow at three disease progression stages (Stage I: polyclonal stage, Stage II: polyclonal toward oligoclonal stage, Stage III: oligoclonal stage) and successfully visualized the kinetics of clonal expansion of cells carrying BLV integration sites using our BLV proviral DNA-capture sequencing method. Although 24 integration sites were detected in Stages I and II, 92% of these sites experienced massive depletion in Stage III. Of these sites, 46%, 37%, and 17% were located within introns of Refseq genes, intergenic regions, and repetitive sequences, respectively. At Stage III cattle with lymphoma, only two integration sites were generated de novo in the intergenic region of Chr1, and the intron of the CHEK2 gene on Chr17 was significantly increased. Our results are the first to demonstrate clonal expansion after the massive depletion of cells carrying BLV integration sites in a naturally infected cow.

Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods.

We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p < 0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q < 0.01). These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn's Disease.

Crohn's disease is a lifelong disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohn's. Ileal biopsies were obtained from (1) control subjects (n = 6), (2) treatment-naïve patients (n = 7), and (3) established (n = 14) Crohn's patients along with remission (n = 3) and refractory (n = 11) treatment groups. The biopsies processed using 10x Genomics single cell 5' yielded 139 906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis, and gene ontology enrichment were carried out for each cell type. We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between control, treatment-naïve, and established groups, with the significant changes in the epithelial subtypes of the treatment-naïve patients, including microfold, tuft, goblet, enterocyte,s and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed; however, gene expression in the epithelial and immune compartment was different between Crohn's phenotypes, indicating changes in cellular activity. Our study identified cellular and transcriptional signatures associated with treatment-naïve Crohn's disease that collectively point to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity among patients within the same disease phenotype, shining a new light on personalized treatment responses and strategies.

Analysis of Palliative Care Utilization and Medical Expenses among Patients with Chronic Diseases in Taiwan: A Population-Based Cohort Study.

Palliative care (PC) is an important alternative treatment for patients with chronic diseases, particularly for those in the later stages of disease progression. This is because these diseases are often irreversible, with progressive worsening of symptoms. By encouraging the use of tranquility resources for good death and spiritual relief, PC can reduce the physical and psychological burden on patients at the end of their lives. Currently, most discussions on PC have focused on patients with cancers, and few have further discussed the differences in medical expenses between PC and emergency treatment in patients with chronic diseases at the end of their lives. This study analyzed the top three chronic diseases in patients who used PC resources in the past decade and identified the impact of emergency treatment on mean survival time and medical expenses based on the medical records from the National Health Insurance Research Database. In total, 4061 patients with chronic diseases who were admitted to hospice wards were included in this study; of them, 85 patients still received emergency treatment, including urinary catheterization, nasogastric intubation, and respirator use, at the end of their lives. The mean survival time of patients aged 50–64 years who received emergency treatment was longer than that of the same age group who did not receive emergency treatment. Different comparisons of the mean survival time and medical expenses using real-world data provides important insights regarding PC management that may assist in establishing health policies in the future.

Staging heart failure patients with secondary mitral regurgitation undergoing transcatheter edge-to-edge repair

Abstract Background Heart failure with reduced ejection fraction (HFrEF) and secondary mitral regurgitation (SMR) are closely related. Progression of HFrEF-SMR is associated with characteristic pathophysiological changes. Recently, staging of HFrEF-SMR patients showed prognostic value in a SMR cohort on medical therapy. Whether these stages are prognostic for SMR patients undergoing transcatheter edge-to-edge mitral valve repair (M-TEER) in addition to drug therapy is unknown. Purpose The present study aimed at classifying HFrEF-SMR patients undergoing M-TEER into progressive disease stages based on cardiac and extracardiac involvement. We sought to evaluate the impact of the disease stages on survival outcome and symptomatic improvement after M-TEER Methods Based on echocardiographic transthoracic evaluation, patients were assigned into one of the following subsequent HFrEF-SMR stages representing disease progression (Figure 1): left ventricular (LV) dysfunction alone (Stage 1, LV end diastolic volume ≥159 ml and/or LV ejection fraction <50%); left atrial (LA) involvement (Stage 2, history of atrial fibrillation and/or indexed LA volume >34 ml/m2); right ventricular (RV) pressure/volume overload (Stage 3, tricuspid regurgitation ≥3+ and/or systolic pulmonary artery pressure >65 mmHg); biventricular failure (Stage 4, RV to pulmonary artery coupling <0.274 mm/mmHg). A Cox regression model was implemented to investigate the impact of HFrEF-SMR stages on two-year all-cause mortality and symptomatic outcome was assessed with New York Heart Association (NYHA) functional class at follow-up. Results Among a total of 849 included patients who underwent M-TEER for symptomatic MR from 2008 until 2019, 9.5% (n=81) presented with LV dysfunction alone, 46% (n=393) with LA involvement, 15% (n=129) with pressure/volume overload and 29% (n=246) with biventricular failure. At baseline and follow-up, successive HFrEF-SMR stages were associated with more severe heart failure symptoms as expressed by NYHA functional class. An increase in HFrEF-SMR stage was associated with increased two-year all-cause mortality rates after M-TEER (Hazard ratio 1.39, confidence interval 1.23–1.58, p<0.01, Figure 2). Conclusions Classifying HFrEF-SMR patients undergoing M-TEER into subsequent disease stages provides prognostic value regarding heart failure symptoms and survival. Funding Acknowledgement Type of funding sources: None.

P.129 One-year data from ENDEAVOR, a phase 1b trial of delandistrogene moxeparvovec in boys with DMD

Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy developed for targeted skeletal and cardiac muscle expression of a micro-dystrophin that is being studied in patients with Duchenne muscular dystrophy (DMD). Findings from ongoing Phase 1 and 2 trials demonstrate micro-dystrophin expression in patients treated with delandistrogene moxeparvovec clinical process material. ENDEAVOR (NCT04626674) is a two-part, open-label, Phase 1b study assessing the expression and safety of commercially representative delandistrogene moxeparvovec material in boys with DMD who represent different stages of disease progression. Four cohorts will be evaluated: Cohort 1: ≥4- to <8-year-old ambulatory boys; Cohort 2: ≥8- to <18-year-old ambulatory boys; Cohort 3: non-ambulatory boys; and cohort 4: ≥3- to <4-year-old ambulatory boys. Inclusion criteria include a genetic DMD diagnosis and stable steroid dosing (Cohorts 1 3 only, ≥12 weeks prior to screening). Participants received a single intravenous dose of commercially representative delandistrogene moxeparvovec material. The follow-up period consists of: Part 1, from post-infusion through to week 12, and Part 2, from week 12 through to week 260. The primary outcome measure is the change in micro-dystrophin protein expression from baseline to Week 12 (Part 1). Secondary outcome measures include change in micro-dystrophin expression at the sarcolemma from baseline to week 12 (Part 1) and safety (over 260 weeks). Exploratory functional endpoints include the North Star Ambulatory Assessment and timed function tests (Cohorts 1, 2 and 4) and performance of the upper limb and pulmonary function tests (Cohorts 2 and 3). We present 1-year safety and functional data and 12-week expression data following treatment with commercially representative delandistrogene moxeparvovec material. Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy developed for targeted skeletal and cardiac muscle expression of a micro-dystrophin that is being studied in patients with Duchenne muscular dystrophy (DMD). Findings from ongoing Phase 1 and 2 trials demonstrate micro-dystrophin expression in patients treated with delandistrogene moxeparvovec clinical process material. ENDEAVOR (NCT04626674) is a two-part, open-label, Phase 1b study assessing the expression and safety of commercially representative delandistrogene moxeparvovec material in boys with DMD who represent different stages of disease progression. Four cohorts will be evaluated: Cohort 1: ≥4- to <8-year-old ambulatory boys; Cohort 2: ≥8- to <18-year-old ambulatory boys; Cohort 3: non-ambulatory boys; and cohort 4: ≥3- to <4-year-old ambulatory boys. Inclusion criteria include a genetic DMD diagnosis and stable steroid dosing (Cohorts 1 3 only, ≥12 weeks prior to screening). Participants received a single intravenous dose of commercially representative delandistrogene moxeparvovec material. The follow-up period consists of: Part 1, from post-infusion through to week 12, and Part 2, from week 12 through to week 260. The primary outcome measure is the change in micro-dystrophin protein expression from baseline to Week 12 (Part 1). Secondary outcome measures include change in micro-dystrophin expression at the sarcolemma from baseline to week 12 (Part 1) and safety (over 260 weeks). Exploratory functional endpoints include the North Star Ambulatory Assessment and timed function tests (Cohorts 1, 2 and 4) and performance of the upper limb and pulmonary function tests (Cohorts 2 and 3). We present 1-year safety and functional data and 12-week expression data following treatment with commercially representative delandistrogene moxeparvovec material.

P.61 Imaging Mass Cytometry reveals new clues to understand the pathogenesis of Becker muscular dystrophy

Muscular dystrophies are genetic diseases characterised by muscle fiber loss and its replacement by fibrotic and adipose tissue. Several cell types, including macrophages and fibroadipogenic precursor cells (FAPS) interact with degenerative muscle fibers locally in what is known as the degenerative niche. Recent technological advances known as spatial biology allow dissecting cell-to-cell interactions in vivo using samples of tissue, although this has not been applied to human muscle tissue yet. We analysed muscle biopsies of controls and patients with Becker muscular dystrophy (BMD) at early, moderate and advanced stages of degeneration using Hyperion Imaging Mass Cytometry (IMC). We labelled single sections of the biopsies with 40 markers labelling different components of the muscle structure. We developed a deep learning algorithm to analyse the images and studied changes in the composition and spatial correlations of the different markers across disease progression. We included 2 control and 8 muscle biopsies of BMD. We observed a progressive increase in the amount of collagen-I and III, that significantly correlated with the amount of CD68+ macrophages (R=0.93 and R=0.94), most of them positive for the M2 marker CD206. Fat and collagen I surrounded vessels during the first stages of disease progression, substituting muscle fibres in later stages. We observed a negative correlation between regenerative muscle fibers and collagen-I (R=-0.83) and with CD68 cells (R:-0.90). We also observed a modification in the number of satellite cells in the biopsies across disease progression. IMC enables the study of changes in muscle structure along disease progression in patients with muscular dystrophies establishing spatio-temporal correlations opening the door to confirm and understand new potential pathogenic pathways in vivo in human samples.

A case of fulminant respiratory diphtheria in a 24-year-old Afghan refugee in Austria in May 2022: a case report

PurposeRaising awareness of respiratory diphtheria and for the importance of early antitoxin administration.MethodsReport of a case of fulminant, imported respiratory diphtheria in an otherwise healthy 24-year-old Afghan refugee in Austria in May 2022.ResultThis was the first case of respiratory diphtheria in Austria since 1993. Diphtheria antitoxin was administered at an already progressed disease stage. This delay contributed to a fulminant disease course with multiorgan failure and death.ConclusionIn high-income countries with low case numbers, awareness of respiratory diphtheria and for the importance of early antitoxin administration must be raised.

The Role of Amino Acids in Tuberculosis Infection: A Literature Review.

Recently, there was an abundance of studies being conducted on the metabolomic profiling of tuberculosis patients. Amino acids are critical metabolites for the immune system, as they might contribute to providing nutrients for the host intracellular pathway. In tuberculosis, several amino acids play important roles in both the mycobacteria infection mechanism and the host. Individual studies showed how the dynamics of metabolite products that result from interactions between Mycobacterium tuberculosis (Mtb) and the host play important roles in different stages of infection. In this review, we focus on the dynamics of amino-acid metabolism and identify the prominent roles of amino acids in the diagnostics and treatment of tuberculosis infection. Online resources, including PubMed, ScienceDirect, Scopus, and Clinical Key, were used to search for articles with combination keywords of amino acids and TB. The inclusion criteria were full-text articles in English published in the last 10 years. Most amino acids were decreased in patients with active TB compared with those with latent TB and healthy controls. However, some amino acids, including leucine, isoleucine, valine, phenylalanine, aspartate, and glutamate, were found to be at higher levels in TB patients. Additionally, the biomarkers of Mtb infection included the ratios of kynurenine to tryptophan, phenylalanine to histidine, and citrulline to arginine. Most amino acids were present at different levels in different stages of infection and disease progression. The search for additional roles played by those metabolomic biomarkers in each stage of infection might facilitate diagnostic tools for staging TB infection.

Clinical Analysis of Non-AIDS Patients with Pulmonary Cryptococcosis and the Change in Their Clinical Features over 30 Years in a Tertiary Hospital in Beijing, China.

Over the past few decades, the clinical features of pulmonary cryptococcosis (PC) have progressed; however, there is a lack of data on the manifestations of PC over time. To investigate the differences in the clinical characteristics of PC across different time periods, we retrospectively reviewed 130 non-acquired immunodeficiency syndrome (AIDS) patients diagnosed with pathologically or microbiologically confirmed PC from 1990-2020. Among the 130 patients with PC, 24 (18.5%) exhibited immunosuppression, and 44 (33.8%) had underlying diseases. In radiology, 118 (90.8%) presented with subpleural lesions, and 68 (53.1%) presented with nodules with diameters ranging from 1-5 cm. Seventy-five (57.7%) patients underwent surgery alone. The clinical features of PC at different time periods showed that hospitalization days decreased (P = 0.009), and the number of patients with symptoms decreased over time. The number of patients exhibiting isolated lesions decreased (P = 0.022), and the number of patients exhibiting subpleural lesions increased (P = 0.020). In addition, the number of patients with lesions presenting 3-10 mm nodules increased (P = 0.028). In conclusion, an increasing number of patients have been diagnosed with PC over the last 30 years. The timing of PC diagnosis has shifted to the early stages of disease progression. Pulmonary lesions caused by cryptococcosis are easily misdiagnosed and may require unnecessary surgical treatment. Further research is needed to identify the lung lesions caused by cryptococcosis.

Idiopathic rapid eye movement sleep behavior disorder in Japan: An observational study

IntroductionIdiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. MethodsThis cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients’ demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG. ResultsNinety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score. ConclusionBoth DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

Economic evaluation of first-line nivolumab plus cabozantinib for advanced renal cell carcinoma in China.

BackgroundIn the Checkmate9ER trial, first-line treatment with nivolumab combined with cabozantinib (NI + CA) has shown efficacy for advanced renal cell carcinoma. This study aims to evaluate the impact of the health and economic outcomes of NI + CA in China.MethodsClinical efficacy data were derived from pivotal phase III CheckMate 9ER trial. A three-state partitioned survival model was established based on disease progression. Progression-free survival and overall survival of NI + CA vs. sunitinib were fitted with log-logistic and log-normal distributions, respectively. Mixture cure, non-mixture cure, and Royston/Parmar spline models were used to evaluate model robustness. The results derived the computational cost from the Chinese healthcare system perspective. The primary outcomes were quality-adjusted life-years (QALYs), total cost in US dollars, as well as incremental cost-effectiveness ratios (ICERs) at the willingness-to-pay threshold in China. One-way and probabilistic sensitivity analysis were also used to assess the robustness of the model.ResultsIn the base-case analysis result, 0.86 additional QALYs could be obtained in the NI+CA (3.84 QALYs) versus the sunitinib strategy (2.97 QALYs). The ICER of NI+CA compared with the sunitinib strategy was US$292,945 per QALY. The ICER value in the NI+CA strategy was higher than the Chinese willingness-to-pay threshold of US$38,024 per QALY. Although NI+CA can improve long-term patient survival significantly over sunitinib in the treatment of advanced renal cell carcinoma, it is unlikely to be cost-effective due to high cost. The results of the one-way sensitivity analysis showed that drug cost, health utility value at the stage of disease progression, and subsequent treatment proportion had a greater impact on the stability of ICER values.ConclusionsNivolumab combined with cabozantinib can prolong the life of patients with advanced renal cell carcinoma and improve their quality of life, but there is a corresponding increase in medical cost. The NI + CA strategy is unlikely to be considered cost-effective in the treatment of advanced RCC from the perspective of Chinese healthcare system.

The single-sample network module biomarkers (sNMB) method reveals the pre-deterioration stage of disease progression.

The progression of complex diseases generally involves a pre-deterioration stage that occurs during the transition from a healthy state to disease deterioration, at which a drastic and qualitative shift occurs. The development of an effective approach is urgently needed to identify such a pre-deterioration stage or critical state just before disease deterioration, which allows the timely implementation of appropriate measures to prevent a catastrophic transition. However, identifying the pre-deterioration stage is a challenging task in clinical medicine, especially when only a single sample is available for most patients, which is responsible for the failure of most statistical methods. In this study, a novel computational method, called single-sample network module biomarkers (sNMB), is presented to predict the pre-deterioration stage or critical point using only a single sample. Specifically, the proposed single-sample index effectively quantifies the disturbance caused by a single sample against a group of given reference samples. Our method successfully detected the early warning signal of the critical transitions when applied to both a numerical simulation and four real datasets, including acute lung injury, stomach adenocarcinoma, esophageal carcinoma, and rectum adenocarcinoma. In addition, it provides signaling biomarkers for further practical application, which helps to discover prognostic indicators and reveal the underlying molecular mechanisms of disease progression.

The Metabolomic Profile in Amyotrophic Lateral Sclerosis Changes According to the Progression of the Disease: An Exploratory Study.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative pathology of the upper or lower motor neuron. Evaluation of ALS progression is based on clinical outcomes considering the impairment of body sites. ALS has been extensively investigated in the pathogenetic mechanisms and the clinical profile; however, no molecular biomarkers are used as diagnostic criteria to establish the ALS pathological staging. Using the source-reconstructed magnetoencephalography (MEG) approach, we demonstrated that global brain hyperconnectivity is associated with early and advanced clinical ALS stages. Using nuclear magnetic resonance (1H-NMR) and high resolution mass spectrometry (HRMS) spectroscopy, here we studied the metabolomic profile of ALS patients’ sera characterized by different stages of disease progression—namely early and advanced. Multivariate statistical analysis of the data integrated with the network analysis indicates that metabolites related to energy deficit, abnormal concentrations of neurotoxic metabolites and metabolites related to neurotransmitter production are pathognomonic of ALS in the advanced stage. Furthermore, analysis of the lipidomic profile indicates that advanced ALS patients report significant alteration of phosphocholine (PCs), lysophosphatidylcholine (LPCs), and sphingomyelin (SMs) metabolism, consistent with the exigency of lipid remodeling to repair advanced neuronal degeneration and inflammation.

High-throughput sequencing unravels the cell heterogeneity of cerebrospinal fluid in the bacterial meningitis of children

Bacterial meningitis (BM) is a common life-threatening infection in children that occurs in the central nervous system (CNS). The cytologic examination of cerebrospinal fluid (CSF) is a key parameter in the diagnosis of BM, but the heterogeneity of cells in the CSF has not been elucidated, which limits the current understanding of BM neuroinflammation. In this study, CSF samples were collected from a number of BM patients who were in different stages of disease progression. Single-cell RNA-sequencing (scRNA-seq), with additional bulk transcriptome sequencing, was conducted to decipher the characteristics of CSF cells in BM progression. A total of 18 immune cell clusters in CSF were identified, including two neutrophils, two monocytes, one macrophage, four myeloid dendritic cells, five T cells, one natural killer cell, one B cell, one plasmacytoid dendritic cell, and one plasma cell subtype. Their population profiles and dynamics in the initial onset, remission, and recovery stages during BM progression were also characterized, which showed decreased proportions of myeloid cells and increased proportions of lymphoid cells with disease progression. One novel neutrophil subtype, FFAR2+TNFAIP6+ neutrophils, and one novel monocyte subtype, THBS1+IL1B+ monocytes, were discovered, and their quantity changes positively correlated with the intensity of the inflammatory response in the CSF during BM. In addition, the CSF of BM patients with unsatisfactory therapeutic responses presented with different cell heterogeneity compared to the CSF of BM patients with satisfactory therapeutic responses, and their CSF featured altered intercellular communications and increased proportions of type II myeloid dendritic cells and plasmacytoid dendritic cells. Moreover, the bulk transcriptome profiles of autologous CSF cells and peripheral blood leukocytes of BM patients showed that the immune cells in these two physiological compartments exhibited distinct immune responses under different onset conditions. In particular, the CSF cells showed a high expression of macrophage characteristic genes and a low expression of platelet characteristic genes compared with peripheral blood leukocytes. Our study conducted an in-depth exploration of the characteristics of CSF cells in BM progression, which provided novel insights into immune cell engagement in acute CNS infection.

312TiP Impact of early palliative care integration on quality of life and symptom burden in patients with high-grade glioma

High-grade gliomas (HGG) have a poor prognosis despite improvements using a multimodal approach. The progressive decline in neurological function and quality of life can have a devastating impact on patients, and caregivers. Palliative Care (PC) follow-up has proven benefits in terms of quality of life and cost savings for health care services. Guidelines recommend integrating PC as early as possible in the cancer management plan. However it’s often done at a later stage of disease progression. MATERIALS AND METHODS: Prospective, unblinded, randomized, controlled study, assigning eligible patients according to a 1:1 distribution without stratification, in control and intervention arms. TARGET POPULATION: Patients with an initial diagnosis of HGG, referred to a Medical Oncology consultation. PRIMARY ENDPOINTS Quality of life and symptom burden. SECONDARY ENDPOINT Overall survival, number and time of hospitalizations, number of visits to the ER. RECRUITING TIME: 6 months (March-August 2022). FOLLOW-UP: 2 years INTERVENTION: After referral by multidisciplinary meeting, at the first Medical Oncology consultation, a proposal for integration in the project will be made and informed consents will be obtained. Patients included will be distributed in a 1:1 ratio between the control arm (CA) (standard of care at the institution) and the intervention arm (IA) (standard of care + early follow-up in PC consultation). The QLQ-C30 and FACT-L questionnaires will be applied and clinical and socio-demographic data will be collected. Patients in the IA will be called for PC consultation within 2 weeks. The frequency of PC follow-up will be individualized. In both arms, questionnaires and updated clinical data will be collected at baseline, one month later, and then every 2 months in the first year and every 4 months in the second year. The authors.

Abstract 128: Loss Of Gstm1 Augments Kidney Neutrophil Population In Angii-induced Hypertension

Background: Glutathione-S-transferase Mu1( Gstm1 ) gene, a member of Glutathione-S-transferases (GST) superfamily, encodes an enzyme that functions in the detoxification of electrophilic compounds. The common GSTM1 deletion variant in humans is associated with increased risks of chronic kidney disease (CKD) progression and incident end stage kidney failure. We reported that deletion of Gstm1 increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN) in mice. At 4 weeks of Ang II-HTN, neutrophils, CD4+T cells, and F4/80+ cells were significantly increased in Gstm1 knockout (KO) kidney. While a link between oxidative stress and immune activation in hypertension has been well documented, the molecular mechanism by which Gstm1 regulates immune cell activation in hypertension is unknown. Methods: To further characterize the inflammatory response in GSTM1 deficiency, Gstm1 KO and wild-type (WT) male mice at ~ 12 weeks of age were subjected to Angiotensin II at 1000 ng/kg per minute for 4 days via a mini osmotic pump. The kidney cells and bone marrow cells were isolated for flow cytometry analysis. Results: At baseline, there were no differences in inflammatory cell populations including neutrophils between WT and Gstm1 KO mice. At Day 4 of Ang II-HTN, Gstm1 KO kidneys exhibited about a 2.3 fold increase in neutrophil population (CD45 + Ly6G + CD11b + ), compared to WT control mice (10 WT and 8 Gstm1 KO mice, p=0.0075). Interestingly, CD45+ bone marrow cells isolated from both Gstm1 KO and WT mice have similar percentile of neutrophil populations ; however, neutrophils in Gstm1 KO bone marrow express relatively higher levels of CXCR2. Unlike at 4 weeks, there was no difference in other inflammatory cells at Day 4. Conclusion: Deletion of Gstm1 increases renal neutrophil population early in Ang II-HTN and CXCR2 expression in bone marrow neutrophils. Gstm1 may play a role in regulating neutrophil migration and recruitment. Further studies are needed to delineate whether GSTM1 deficiency drives kidney injury via early neutrophil migration, which could shed light on potential therapeutic target for CKD progression in those genetically susceptible.

CRITICAL UNDERSTANDING OF SHATAKRIYAKALA: A REVIEW

Ayurveda is an ancient bunch of knowledge that aims at maintaining the health of a healthy individual and curing the diseased one. This is brought by equalizing Dosha, Dhatu, and Mala. The term Kriyakala refers to recognising a disease's progress stage, which helps to determine appropriate measures to correct the imbalance in Doshas (biological factors). Ayurveda mentioned several concepts for understanding and preventing disease pathogenesis, and Shatakriyakala is one of them. It is a compound expression comprised of Kriya and Kala, where Kriya means the choice of treatment (medicine, food, and daily routine) used to improve the disturbance in Doshas, and Kala refers to the stage of progress of a disease. Shatakriyakala is mainly associated with six stages of disease progression and their possible management through Ayurveda principles. Shatakriyakala not only helps to diagnose diseases in the early stage but also helps to suppress their intensity. Kriyakala gives us the knowledge of diagnosis, prognosis, and the level of intervention to prevent disease establishment. A clear understanding of the stages of Kriyakala is an essential factor for early diagnosis and prognosis and for adopting appropriate preventing and curative measures to prevent the further establishment of disease &amp; thereby prevent the complications associated with it emphasized in this article

Conservative Iron Chelation for Neuroferritinopathy.

Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders. No treatment is currently available. We assessed conservative iron chelation with deferiprone at 30 mg/kg/day on the disease progression with controlled periods of discontinuation. Four patients with confirmed molecular diagnosis of neuroferritinopathy were given deferiprone at different stages of disease progression and with clinical and biological monitoring to control benefit and risk. The four patients showed slight to high improvement. In one case, we managed to stabilize disease progression for more than 11 years. In another case, we were able to reverse symptoms after a few months of treatment. The earliest the treatment was started, the most efficient it was on disease progression. Conservative iron chelation should be further assessed in neuroferritinopathy. © 2022 International Parkinson and Movement Disorder Society.