Initial Stages Of Disease Research Articles

Research progress on V delta 1+ T cells and their effect on pathogen infection

The ongoing high occurrence of harmful infectious diseases significantly threatens human health. Existing methods used to control such diseases primarily involve targeting the pathogens, usually neglecting the vital role of host factors in disease advancement. Gamma delta (γδ) T cells act as a bridge between innate and adaptive immunity, playing a crucial role in combating pathogen invasion. Among these γδT cell subsets, which are categorized based on T cell receptor delta variable expression patterns, V delta (δ) 1+ T cells possess unique recognition abilities and regulatory characteristics and actively engage in various immune responses. The differentiation, development, and immune reactivity of Vδ1+ T cells are closely associated with the initial and progressive stages of infectious diseases. This article provides an overview of the classification, distribution, differentiation, and development of Vδ1+ T cells and their mechanisms in combating pathogenic infections, offering new insights for disease diagnosis and treatment.

Microvascular Reconstructions in Elderly Patients With Oral Squamous Cell Carcinoma - Too Old for Surgical Treatment?

Study Design Retrospective cohort study. Objective A major risk factor for oral squamous cell carcinoma (OSCC) is advanced age. Ablative surgery combined with microvascular reconstruction has become routine for OSCC. Nevertheless, there is an interdisciplinary debate about the appropriateness of surgery combined with prolonged general anesthesia in the elderly. In the present study, the ablative and microvascular strategies in OSCC were evaluated in terms of oncologic safety and surgical morbidity in relation to age. Methods A total of 345 patients with primary OSCC who underwent ablative tumor surgery and neck dissection according to the German national guideline for OSCC together with microvascular reconstruction from September 2010 to October 2017 were examined. General clinical data was analyzed descriptively with a special focus on perioperative morbidity of an elderly (≥70y) subgroup of 56 patients. Oncological outcome was estimated using Log Rank testing and Kaplan Meier plotting. Results Estimated 5 year overall survival (OS) and disease-free survival (DFS) was 69.6% (≥70y) vs. 76.7% (<70y) and 62.9% (≥70y) vs. 78.2% (<70y) respectively with no significant difference between the 2 age groups. In multivariate cox regression, only initial stage of disease revealed significant impact on OS. Analysis of perioperative death/complications, flap loss, operation time, dependence on tracheostomy and hospitalization revealed no significant differences between the 2 groups. Conclusions Tumor surgery including neck dissection in combination with primary microvascular reconstruction is a safe therapy in patients of advanced age. This results in excellent oncological outcome with no significant disadvantages in terms of perioperative morbidity, hospitalization or flap failure.

Functional activity, functional connectivity and complex network biomarkers of progressive hyposmia Parkinson's disease with no cognitive impairment: evidences from resting-state fMRI study.

Olfactory dysfunction stands as one of the most prevalent non-motor symptoms in the initial stage of Parkinson's disease (PD). Nevertheless, the intricate mechanisms underlying olfactory deficits in Parkinson's disease still remain elusive. This study collected rs-fMRI data from 30 PD patients [15 with severe hyposmia (PD-SH) and 15 with no/mild hyposmia (PD-N/MH)] and 15 healthy controls (HC). To investigate functional segregation, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were utilized. Functional connectivity (FC) analysis was performed to explore the functional integration across diverse brain regions. Additionally, the graph theory-based network analysis was employed to assess functional networks in PD patients. Furthermore, Pearson correlation analysis was conducted to delve deeper into the relationship between the severity of olfactory dysfunction and various functional metrics. We discovered pronounced variations in ALFF, ReHo, FC, and topological brain network attributes across the three groups, with several of these disparities exhibiting a correlation with olfactory scores. Using fMRI, our study analyzed brain function in PD-SH, PD-N/MH, and HC groups, revealing impaired segregation and integration in PD-SH and PD-N/MH. We hypothesize that changes in temporal, frontal, occipital, and cerebellar activities, along with aberrant cerebellum-insula connectivity and node degree and betweenness disparities, may be linked to olfactory dysfunction in PD patients.

Ameliorating Effect of Grape (Vitis vinifera L.) Seed and Peel Extracts with Selenium on Ochratoxin-A Exposed Renal Dysfunction in Male Wistar Rats

Background and AimDrug-induced nephrotoxicity is extensively documented as the initial stage of kidney disease that particularly results in acute renal injury and chronic renal dysfunction. The single and combined effect of grape peel extract (GPE), grape seed extracts (GSE) and selenium (Sel) were investigated in current study for controlling of renal injury induced by Ochratoxin-A (OTA) in male rats. MethodsForty nine male Wistar rats weighing 200 ± 10 g were injected with OTA (0.5 mg/kg bw) to induce nephrotoxicity, then treated with singleand combined applications of GSE, GPE and Sel. In addition, the OTA induced nephrotoxicity rats were screened for various biological and physiological parameters like food ingestion, body weight gain, liver weight, serum kidney biomarkers, serum lipid fractions, enzymatic and non-enzymatic lipid peroxidation indicators and histopathological studies. ResultsOur findings suggested that the combination of GSE 2 % and Sel (50–50) treatment reduced renal dysfunction in OTA-induced rats by significantly lowering lipid peroxidation indicators, lipid and kidneys profiles and enhancing enzymatic and non-enzymatic antioxidants biomarkers followed by GSE 2 % then Selenium (0.4 mg/kg) in OTA. Histological analysis of the kidney revealed more severe renal tubule degeneration in OTA-induced rats, While GSE and GPE combonation showed only moderate glomerular tuft enlargement and minimal renal tubule deterioration. Furthermore, the combination of GSE 2 %+Sel (50–50) revealed normal histological structure. ConclusionsGrape seed extracts along with selenium mightbe used as dietary supplements to reduce renal toxicity induced by chemicals or compounds that cause nephrotoxicity.

Long-term outcomes in antibody-negative autoimmune encephalitis: a retrospective study.

Despite constituting one-third of suspected autoimmune encephalitis (AE) patients, antibody-negative cases without typical AE features are understudied. We aim to characterize the clinical phenotypes and long-term outcomes of "possible only" and "probable" AE cases. We conducted a retrospective analysis of adult patients evaluated at Mayo Clinic's Autoimmune Neurology Clinic (01/01/2006-12/31/2020), meeting diagnostic criteria for "possible only" or "probable but antibody-negative" AE, with ≥ 1year of follow-up. All patients underwent neural antibody testing. Among fifty-one patients, six had a change in diagnosis (non-autoimmune, 2) and were excluded from further analysis. Forty-five patients were analyzed [median age, 61years (range 20-88); female, 21 (47%); median follow-up, 36months (range 12-174)]. A nadir modified Rankin Scale (mRS) ≥ 3 was recorded in 41/45 (91%). CSF was inflammatory in 20/44 (45%) and MRI had encephalitic changes in 21/45 (47%). Unclassified neural-specific IgG staining on tissue-based assay was detected in five (11%). Two patients (4%) had paraneoplastic causation. Relapses (> 3months from onset) were noted in 14 (31%). Memory dysfunction (69%), attention deficits (38%), and gait instability (29%) were the most frequent at the last follow-up. Most patients (76%) were independent at the last follow-up and only two required an assistive device to ambulate; 11 patients (24%) had poor neurological outcome (mRS ≥ 3). Higher mRS score and gait assistance requirement at 3months were predictive of poor outcome (P ≤ 0.01). Despite significant disability at initial disease stages, most antibody-negative AE patients regain independent functioning. Early functional status and gait assistance requirements may predict long-term prognosis.

Exploring the Renoprotective Potential of Bioactive Nutraceuticals in Chronic Kidney Disease Progression: A Narrative Review.

Chronic kidney disease (CKD) is a condition that is characterized by progressive loss of kidney function over time. A substantial increase in the burden of CKD is evident globally, attributed to multifactorial conditions like an expanding aging population, rising diabetes and hypertension rates, and more significant exposures to risk factors associated with the environment and lifestyle. Nutraceuticals are substances that are usually considered a food or an active part of a food that provides medical or health benefits, including the prevention and treatment of a disease. The aim is to review the positive role of nutraceuticals in managing CKD. A narrative review is generated, extracting the papers from databases like Web of Science, Scopus, ScienceDirect, ResearchGate, and PubMed. Animal and human trials focusing on the effect of different nutraceuticals on the initial stage of kidney disease, i.e., stages 1, 2, and 3 of CKD, were included. The review's outcome is understanding the effectiveness of nutraceuticals that have shown positive results in CKD conditions. Active compounds include ubiquinone, curcumin, nitrates, nitrites, lycopene, and resveratrol. These bioactive components are also beneficial for other comorbid conditions like diabetes, hypertension, and cardiovascular conditions that have an eminent adverse effect on CKD. Lycopene, coenzyme Q10 (CoQ10), resveratrol, curcumin, and flavonoids have positively impacted CKD complications. Nutraceuticals hold great promise for individuals with CKD in the coming years, offering diverse potential benefits. These include delivering vital antioxidant and anti-inflammatory support to alleviate oxidative stress and inflammation, helping to regulate blood pressure and lipid levels for improved cardiovascular health, promoting optimal renal function to sustain kidney health, assisting in maintaining electrolyte balance, warding off complications, influencing gut microbiota for enhanced digestive well-being, and ultimately elevating the overall quality of life, for those managing CKD.

Amyloid-Negative, Neurodegeneration-Negative Amnestic Mild Cognitive Impairment.

The concept of amnestic mild cognitive impairment (aMCI) was developed to identify patients at an initial stage of Alzheimer's disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology or neuronal injury. To know the natural history of amyloid-negative and neurodegeneration-negative patients with aMCI, namely to ascertain: 1) whether these patients remain cognitively stable or they present a slow decline in neuropsychological tests; 2) whether the memory complaints subside with the apparently benign clinical course of the disorder or if they persist along the time. Patients who fulfilled criteria for aMCI with no biomarkers of amyloid pathology or neuronal injury were selected from a large cohort of non-demented patients with cognitive complaints, and were followed with clinical and neuropsychological assessments. Twenty-one amyloid-negative and neurodegeneration-negative aMCI patients were followed for 7.1±3.7 years. At the baseline they had more pronounced deficits in verbal learning (California Verbal Learning Test) and were also impaired in Word Recall and Logical Memory. However, they did not decline in any cognitive test during follow-up. The patients maintained a high level of subjective memory complaints from baseline (9.7±4.1) to the follow-up visit (9.2±4.1, a non-significant difference), in spite of a statistically significant decrease in the depressive symptoms, with Geriatric Depression Scale (15 items) score 4.9±2.8 at baseline and 3.2±1.8 at the follow-up visit. Amyloid-negative, neurodegeneration-negative aMCI is a chronic clinical condition characterized by the long-term persistence of cognitive deficits and distressing memory complaints. Adequate strategies to treat this condition are needed.

Epidermal proteomics demonstrates Elafin as a psoriasis-specific biomarker and highlights increased anti-inflammatory activity around psoriatic plaques.

Eczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different. Further molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data. In this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins. Our findings confirmed the psoriasis-associated cytokine IL-36γ as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36γ and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment. Overall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease.

Comprehensive analysis of hyperspectral features for monitoring canopy maize leaf spot disease

Accurate quantification of hyperspectral features altered by plant disease infection is pivotal for effective disease management. However, the sensitivity of hyperspectral features to plant disease progression remains elusive, primarily because these features are often influenced by plant growth and environmental factors in addition to the specific disease. This study explores the sensitivity of biophysical and spectral features as indicators for maize adaptation to leaf spot disease. Using high-resolution UAV hyperspectral imaging, we captured maize adaptation dynamics over 30 days post-infection. We evaluated the sensitivity and importance of hyperspectral features for disease monitoring, including biophysical parameters retrieved by the PROSAIL model, and spectral features, including spectral reflectance, vegetation indices (VIs), and wavelet features (WFs). Our findings reveal that WFs first indicate disease response as early as 6 days after infection (DAI), followed by VIs at DAI 8, and variations in chlorophyll content (Cab) become apparent by DAI 10. The Cab, plant senescence reflectance index (PSRI), and normalized photosynthetic reflectance index (NPRI) are determined to be important features at the early stage of the disease. Our experimental results show that the different feature sets are complementary at the early and severe stages of the disease. Our classification models integrating Cab, VIs, and WFs showed higher overall accuracy than models using only spectral features or VIs, with a maximum improvement of 9.36 %. However, these feature sets are redundant in the mild and initial severe disease stages, where models using only spectral features achieve the highest overall accuracy of 86.21 %. This study underscores the novel insights by offering an understanding of plant responses to disease infection and enhancing early detection strategies.

#2137 Systemic inflammation as a main factor in CKD-MBD development

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive disorder that affects more than 10% of the general population worldwide. Despite great achievements in the field of treatment of CKD, patient mortality remains at a high level. Research into the pathophysiology and correction of this condition in the early stages of development is ongoing. The aim of the study was to establish relationship between systemic inflammation and mineral disorders in any stage of CKD. Method We investigated 5 groups of patients with different stages (I to V) of CKD 19-22 persons in each (total amount 106 patients), aged 49,6 years and 19 healthy individuals aged 41,9 years as control group. We examined the blood level of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), C-reactive protein (CRP) and c-terminal fragment of fibroblast factor 23 (FGF-23) in all patients and control group. Results The course of CKD is accompanied by systemic inflammation, which is characterized by an increase in IL-1β in the I stage of chronic kidney disease ((13,41 ± 3,36) pg/ml) (p < 0.01), IL-6 in the III stage of chronic kidney disease (29,31 ± 5,49) pg/ml (p < 0.01), IL-8 in the II stage of chronic kidney disease ((11,56 ± 2,72) pg/ml) (p < 0.05) and CRP in the IV stage of chronic kidney disease ((7,22 (1,81; 10,8)) mg/ml (p < 0.01), compared to the control group ((5,93 ± 3,65), (6,01 ± 1,67), (7,99 ± 1,17) pg/ml and (0,66 (0,41; 0,85)) mg/ml accordingly), and progresses with a decrease in glomerular filtration rate. Growing already at the initial stage of chronic kidney disease, the level of FGF-23 reached a statistical difference from the control group at the 2nd stage of CKD. A strong statistically significant relationship was found between FGF-23 and IL-6 (R = 0.84; p < 0.01), IL-1β at GFR > 15 ml/(min•1.73 m2) (R = 0.45; p < 0.01) and IL-8 at GFR > 15 ml/(min•1.73 m2) (R = 0.57; p < 0.01). Conclusion Systemic inflammation appears in the initial stages of CKD, being a trigger for further kidney dysfunction and the development of mineral and bone disorders. Systemic inflammation treatment in patients with CKD is staying a magnetic but still unattainable goal that needs further efforts to invest.

Diagnostic and classification criteria of heart failure in the practice of doctors at the prehospital stage

The article deals with an overview of heart failure with an emphasis on identification criteria and models of its classification based on literary sources from the MEDLINE database on the PubMed, Web of Science, Scopus, and Google Scholar platforms. The subjective and objective signs of chronic heart failure accor­ding to the Framingham Heart Study using the methods of clinical epidemiology and presented with modern data in the international guidelines are shown. Clinical manifestations of acute heart failure in patients with myocardial infarction are outlined. In chronological order, the hemodynamic classification of heart failure is reproduced with the definition of systolic and diastolic dysfunction as markers for ranking patients in practical work. Based on the materials of international guidelines developed by the experts of the American College of Cardiology, American Heart Association, Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, the diagnostic indicators of cardiac decompensation are summarized. Given the modern perception, the diagnostic value of the left ventricular ejection fraction has been proven for determining heart failure phenotypes. The classification of heart failure of the New York Heart Association plays a significant role in determining the functional class; this was reflected in the article. Based on the provisions of international guidelines, the importance of natriuretic peptides as potential biomarkers of acute and chronic heart failure is proved. The advantages of assessing the structural and functional parameters of the heart in patients for detecting the preclinical stage of heart failure, association with clinical events and control of treatment are described. An update version of heart failure classification is presented with the identification of four stages and highlighting their characteristics. According to this classification, a relevant preventive measure is to shift the therapeutic focus to the initial stages of diseases that trigger heart failure.

Parkinson's Disease and Dementia withLewy Bodies: One and the Same.

The question whether Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are expressions of the same underlying disease has been vigorously debated for decades. The recently proposed biological definitions of Lewy body disease, which do not assign any particular importance to the dopamine system over other degenerating neurotransmitter systems, has once more brought the discussion about different types of Lewy body disease to the forefront. Here, we briefly compare PDD and DLB in terms of their symptoms, imaging findings, and neuropathology, ultimately finding them to be indistinguishable. We then present a conceptual framework to demonstrate how one can view different clinical syndromes as manifestations of a shared underlying Lewy body disease. Early Parkinson's disease, isolated RBD, pure autonomic failure and other autonomic symptoms, and perhaps even psychiatric symptoms, represent diverse manifestations of the initial clinical stages of Lewy body disease. They are characterized by heterogeneous and comparatively limited neuronal dysfunction and damage. In contrast, Lewy body dementia, an encompassing term for both PDD and DLB, represents a more uniform and advanced stage of the disease. Patients in this category display extensive and severe Lewy pathology, frequently accompanied by co-existing pathologies, as well as multi-system neuronal dysfunction and degeneration. Thus, we propose that Lewy body disease should be viewed as a single encompassing disease entity. Phenotypic variance is caused by the presence of individual risk factors, disease mechanisms, and co-pathologies. Distinct subtypes of Lewy body disease can therefore be defined by subtype-specific disease mechanisms or biomarkers.

COVID-19 experience of people with severe mental health conditions and families in South Africa.

People with severe mental health conditions, such as schizophrenia, and their family caregivers are underserved in low- and middle-income countries where structured psychosocial support in the community is often lacking. This can present challenges to recovery and for coping with additional strains, such as a pandemic. This study explored the experiences and coping strategies of people with lived experience of a severe mental health condition, and family caregivers, in South Africa during the initial stages of the coronavirus disease 2019 (COVID-19) pandemic. This qualitative study was conducted in the Nelson Mandela Bay District, Eastern Cape, South Africa, in the most restrictive period of the COVID-19 lockdown. Telephonic qualitative interviews were conducted with people with lived experience (n = 14) and caregivers (n = 15). Audio recordings were transcribed and translated to English from isiXhosa. Thematic analysis was conducted with NVivo 12. Participants described negative impacts including increased material hardship, intensified social isolation and heightened anxiety, particularly among caregivers who had multiple caregiving responsibilities. Coping strategies included finding ways to not only get support from others but also give support, engaging in productive activities and taking care of physical health. The main limitation was inclusion only of people with access to a telephone. Support needs for people with severe mental health conditions and their families should include opportunities for social interaction and sharing coping strategies as well as bolstering financial security. These findings indicate that current support for this vulnerable group is inadequate, and resource allocation for implementation of additional community-based, recovery-focused services for families must be prioritised.

Mulberry and Hippophae-based solid beverage attenuate hyperlipidemia and hepatic steatosis via adipose tissue-liver axis.

Dyslipidemia and hepatic steatosis are the characteristics of the initial stage of nonalcohol fatty liver disease (NAFLD), which can be reversed by lifestyle intervention, including dietary supplementation. However, such commercial dietary supplements with solid scientific evidence and in particular clear mechanistic elucidation are scarce. Here, the health benefits of MHP, a commercial mulberry and Hippophae-based solid beverage, were evaluated in NAFLD rat model and the underlying molecular mechanisms were investigated. Histopathologic examination of liver and white adipose tissue found that MHP supplementation reduced hepatic lipid accumulation and adipocyte hypertrophy. Serum biochemical results confirmed that MHP effectively ameliorated dyslipidemia and decreased circulation-free fatty acid level. RNA-Seq-based transcriptomic analysis showed that MHP-regulated genes are involved in the inhibition of lipolysis of adipose tissue and thus may contribute to the reduction of hepatic ectopic lipid deposition. Furthermore, MHP upregulated ACSL1-CPT1a-CPT2 pathway, a canonical pathway that regulated mitochondrial fatty acid metabolism, and promoted liver and adipose tissue fatty acid β-oxidation. These results suggest that adipose tissue-liver crosstalk may play a key role in maintaining glucose and lipid metabolic hemostasis. In addition, MHP can also ameliorate chronic inflammation through regulating the secretion of adipokines. Our study demonstrates that MHP is able to improve dyslipidemia and hepatic steatosis through crosstalk between adipose tissue and liver and also presents transcriptomic evidence to support the underlying mechanisms of action, providing solid evidence for its health claims.

Self-Stigma in Patients with Endogenous Mental Disorders: A Cross-Sectional Comparative Study.

Self-stigma remains one of the most vexing issues in psychiatry. It complicates the treatment and social functioning of patients with endogenous psychiatric disorders. Identifying the specific features of self-stigma depending on the type and duration of the endogenous mental illness can help solve this problem. The aim of this study was to establish the level and specific features of self-stigma in patients with various types of chronic endogenous psychiatric disorders at different disease stages and to establish the correlation between the level of self-stigma and the attitude of the patient to his/her disease and treatment. Clinical psychopathology assessment, psychometric scales and questionnaires: "Positive and Negative Syndrome Scale" (PANSS), "Questionnaire for Self-Stigma Assessment in Mentally Ill Patients", and Russian versions of the "Insight Scale for Psychosis" (ISP), and "Drug Attitude Inventory" (DAI-10). The cross-sectional study included 86 patients with endogenous mental illnesses (bipolar affective disorder and schizophrenia spectrum disorders. The analysis of the results of the "Questionnaire for Self-Stigma Assessment in Mentally Ill Patients" showed that at the initial disease stages the highest level of self-stigma is observed in patients with bipolar affective disorder (M±σ=1.22±0.73; Me [Q1; Q3]=1.10 [0.83; 1.60]), while the lowest level was observed in patients with schizophrenia spectrum disorders (M±σ=0.86±0.53; Me [Q1; Q3]=0.77 [0.31; 1.25]). Patients with schizophrenia and schizoaffective disorder and a disease duration more than five years participating in a long-term comprehensive psychosocial rehabilitation program also demonstrated high rates of self-stigma (M±σ=1.20±0.57, Me [Q1; Q3]=1.26 [0.89; 1.47]). The study groups showed differences in terms of the structure of components of self-stigma and their severity; significant correlations were uncovered between the self-stigma parameters and the attitude of patients to their disease and therapy. The results of this study contribute to a better understanding of the specific features of self-stigma in patients with various endogenous disorders at different stages of the disease. These data can be used as part of a comprehensive psychosocial treatment program for this patient cohort, as well as for future research.

Abstract 2333: Methylation based phylogeny and timing in cancer

Abstract Knowing the chronological sequence of genetic alterations during cancer development and progression is crucial for understanding the process of transformation of normal tissue into malignant tumors. This can offer insights into the etiology and intrinsic cellular mechanisms of the process, presenting opportunities for early detection and treatment of initial disease stages, as well as highlight key events as potential therapeutic. Current methods of establishing progression histories of cancers rely either on direct sequencing of premalignant lesions, which are seldom available for tumors or on computational inference timing methods capable of reconstructing the history from primary tumor data. These methods require genome or exome sequencing data from a relatively large cohort of tumors and provide limited resolution due to overall scarcity of somatic mutations. We utilize a different source of genetic information, genome methylation, that also “records” historic information about acquisition and development of mutations. Over 28 million methylated CpG sites exist in the genome with several percent of them differentially methylated (DMS) between tissue types and tumor vs adjacent normal tissue. The several orders of magnitude higher density of distinctly methylated sites provides unprecedented resolution, needs fewer tumors, can be merged with driver mutation data and co-analyzed with “methylation clock” information that allows to establish early development, phylogeny and progression at unprecedented resolution. We developed methods for whole genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS) and Oxford Nanopore Technologies native methylation sequencing data. Somatic DMS sites have distinct properties from somatic point mutations, can appear and disappear in the process of tumor evolution and development allowing for unique configuration of methylated islands. Our tools perform single sample and cohort level “timing”, multi-sample phylogeny reconstruction and cancer population reconstruction by integrating methylation and mutation information from the same sample. These new methods will significantly contribute to our understanding of cancer initiation and progression at a resolution not available previously. Citation Format: Nataliya Guteneva, Eliezer Lichter, Ignaty Leshchiner. Methylation based phylogeny and timing in 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 2333.

Investigating the Effect of an Anti-Inflammatory Drug in Determining NURR1 Expression and Thus Exploring the Progression of Parkinson's Disease.

Nonsteroidal anti-inflammatory drugs are the most widely used drugs for Parkinson's disease (PD), of which ibuprofen shows positive effects in suppressing symptoms; however, the associated risk needs to be addressed in different pathological stages. Initially, we developed an initial and advanced stage of the Parkinson disease mouse model by intraperitoneal injection of MPTP (20 mg/kg; 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine) for 10 and 20 days, respectively. Subsequently, ibuprofen treatment was administered for 2 months, and a pole test, rotarod test, histology, immunohistochemistry, and western blotting were performed to determine neuronal motor function. Histological analysis for 10 days after mice were injected with MPTP showed the onset of neurodegeneration and cell aggregation, indicating the initial stages of Parkinson's disease. Advanced Parkinson's disease was marked by Lewy body formation after another 10 days of MPTP injection. Neurodegeneration reverted after ibuprofen therapy in initial Parkinson's disease but not in advanced Parkinson's disease. The pole and rotarod tests confirmed that motor activity in the initial Parkinson disease with ibuprofen treatment recovered (p<0.01). However, no improvement was observed in the ibuprofen-treated mice with advanced disease mice. Interestingly, ibuprofen treatment resulted in a significant improvement (p<0.01) in NURR1 (Nuclear receptor-related 1) expression in mice with early PD, but no substantial improvement was observed in its expression in mice with advanced PD. Our findings indicate that NURR1 exerts anti-inflammatory and neuroprotective effects. Overall, NURR1 contributed to the effects of ibuprofen on PD at different pathological stages.

Lipoprotein dysfunction in patients with chronic kidney disease (CKD). Pathogenesis and treatment of CKD dyslipidemia (literature review)

Dyslipidemia develops in the initial stages of chronic kidney disease (CKD) and worsens as nephropathy progresses. The main manifestation of dyslipidemia is hypercholesterolemia, especially in nephrotic syndrome. However, with CKD of stages 4-5, it is replaced by hypertriglyceridemia in combination with an increase in blood levels of lipoproteins low and very low density. Such changes are closely related to the development of cardiovascular pathology with high mortality. The content of high-density lipoproteins (HDL) in the blood is gradually decreasing, as well as the reversible transport of cholesterol. Thus, their anti-atherogenic, antioxidant and anti-inflammatory functions are lost. The main components of HDL – apolipoproteins ApoA-I and ApoA-II, which provide functionality, are replaced by acute-phase proteins, and HDL lose their cardioprotective potential and acquire a proinflammatory and proatherogenic phenotype. According to modern concepts, HDL dysfunction, along with metabolic shifts, is largely due to epigenetic disorders affecting gene expression and partially eliminated by prescribing drugs containing microRNAs (mRNAs) or antisense nucleotides. Drugs with interfering RNAs created in recent years have been successfully used not only for the treatment of dyslipidemia in nephrological patients, but also in patients with neoplastic processes, inflammatory arthritis, degenerative diseases of the central nervous system, porphyria, hemophilia and many other diseases. The proposed review is devoted to the mechanisms of disorders of the structure and functions of HDL in patients with CKD and the correction of these disorders.

In Vitro to In Vivo Scalars for Drug Clearance in Nonalcoholic Fatty Liver and Steatohepatitis.

In vitro-in vivo extrapolation (IVIVE) allows prediction of clinical outcomes across populations from in vitro data using specific scalars tailored to the biologic characteristics of each population. This study experimentally determined scalars for patients with varying degrees of nonalcoholic fatty liver disease (NAFLD), ranging from fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. Microsomal, S9, and cytosol fractions were extracted from 36 histologically normal and 66 NAFLD livers (27 nonalcoholic fatty liver [NAFL], 13 NASH, and 26 NASH with cirrhosis). Corrected microsomal protein per gram liver (MPPGL) progressively decreased with disease severity (26.8, 27.4, and 24.3 mg/g in NAFL, NASH, and NASH/cirrhosis, respectively, compared with 35.6 mg/g in normal livers; ANOVA, P < 0.001). Homogenate, S9, and cytosolic protein showed a consistent trend of decline in NASH/cirrhosis relative to normal control (post-hoc t test, P < 0.05). No differences across the groups were observed in homogenate, S9, cytosolic, and microsomal protein content in matched kidney samples. MPPGL-based scalars that combine protein content with liver size revealed that the reduction in MPPGL in NAFL and NASH was compensated by the reported increase in liver size (relative scalar ratios of 0.96 and 0.99, respectively), which was not the case with NASH/cirrhosis (ratio of 0.63), compared with healthy control. Physiologically based pharmacokinetics-informed global sensitivity analysis of the relative contribution of IVIVE scalars (hepatic CYP3A4 abundance, MPPGL, and liver size) to variability in exposure (area under the curve) to three CYP3A substrates (alprazolam, midazolam, and ibrutinib) revealed enzyme abundance as the most significant parameter, followed by MPPGL, whereas liver volume was the least impactful factor. SIGNIFICANCE STATEMENT: Nonalcoholic fatty liver disease-specific scalars necessary for extrapolation from in vitro systems to liver tissue are lacking. These are required in clearance prediction and dose selection in nonalcoholic fatty liver and steatohepatitis populations. Previously reported disease-driven changes have focused on cirrhosis, with no data on the initial stages of liver disease. The authors obtained experimental values for microsomal, cytosolic, and S9 fractions and assessed the relative impact of microsomal scalars on predicted exposure to substrate drugs using physiologically based pharmacokinetics.

Initial Stage of Disease Similar for White and Black Patients With Early-Onset Colorectal Cancer at a Safety-Net Hospital.

Non-Hispanic Black (NHB) patients with early-onset colorectal cancer (EOCRC) are more likely to present with advanced-stage disease than their Non-Hispanic White (NHW) counterparts. To further elucidate whether differences in tumor biology or disparities in access to care may be responsible, we examined the association between race/ethnicity and initial stage of disease, time to diagnosis, and tumor characteristics among NHW and NHB patients with EOCRC cared for in a safety-net health care setting. We performed a retrospective cohort study of NHW and NHB patients diagnosed with primary EOCRC who received care at Boston Medical Center between January 2000 and May 2020. We compared demographics, risk factors, presenting signs/symptoms, time to diagnosis, health care utilization, and tumor characteristics (stage, grade, location, and mutational status). We identified 103 patients (mean age 41.5±7.2 y, 53.4% men), including 40 NHWs and 63 NHBs, with EOCRC. NHB and NHW patients were similar with respect to demographics, presenting signs/symptoms, and risk factor distribution. There were also no significant differences between NHWs and NHBs with respect to the advanced stage of disease at presentation (45.0% vs. 42.9%, P=0.83), the median time to diagnosis [152 d (IQR, 40 to 341) vs. 160 d (IQR, 61 to 312), P=0.79] or tumor characteristics, except for a predilection for proximal disease among NHBs (30.2% vs. 15.0%). NHB patients were no more likely than NHW patients to present with advanced-stage disease, aggressive tumor histology, or experience delays in diagnosis within a safety-net health care system.