Stages Of Disease Progression Research Articles

Quality of life and strength, but not cytokines, are associated with DAS-28 in active and inactive rheumatoid arthritis

Objective: Evaluate and correlate data between relevant cytokines, disease progression, and handgrip and quality of life among RA patients at different stages of disease progression. Method: Thirty-three RA patients were recruited for analysis, using comparisons and correlations, between levels of circulating cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-17, IL-1β, and TNF receptors I and II), activity of the disease (evaluated using the DAS-28), handgrip (Hydraulic dynamometer), and quality of life (SF-36). Result: RA patients in different disease stages showed increases of IL-6 and IL-10 compared control group. Positive correlation between IL-6 with TNF-α, and IL-4 with IL-10 was found. Handgrip strength and quality of life were not related to cytokine levels. However, remission patients had better strength and quality of life indices compared to the active patients. In addition, handgrip of the non-dominant side, physical functions, role limitations physical health, pain, energy/fatigue and social functions have a negative correlation with the DAS28-PCR. Conclusion: High levels of IL-6 and IL-10 were observed in the chronic RA patients, but the values did not show correlation with disease activity, handgrip strength and quality of life. Disease activity show correlation with handgrip strength and quality of life. Furthermore, remission patients had better strength and quality of life indices compared to the active patients.

Key aspects of papillomavirus infection influence the host cervicovaginal microbiome in a preclinical murine papillomavirus (MmuPV1) infection model.

Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States and are a major etiological agent of cancers in the anogenital tract and oral cavity. Growing evidence suggests changes in the host microbiome are associated with the natural history and ultimate outcome of HPV infection. We sought to define changes in the host cervicovaginal microbiome during papillomavirus infection, persistence, and pathogenesis using the murine papillomavirus (MmuPV1) cervicovaginal infection model. Cervicovaginal lavages were performed over a time course of MmuPV1 infection in immunocompetent female FVB/N mice and extracted DNA was analyzed by qPCR to track MmuPV1 viral copy number. 16S ribosomal RNA (rRNA) gene sequencing was used to determine the composition and diversity of microbial communities throughout this time course. We also sought to determine whether specific microbial communities exist across the spectrum of MmuPV1-induced neoplastic disease. We, therefore, performed laser-capture microdissection to isolate regions of disease representing all stages of neoplastic disease progression (normal, low- and high-grade dysplasia, and cancer) from female reproductive tract tissue sections from MmuPV1-infected mice and performed 16S rRNA sequencing. Consistent with other studies, we found that the natural murine cervicovaginal microbiome is highly variable across different experiments. Despite these differences in initial microbiome composition between experiments, we observed that MmuPV1 persistence, viral load, and severity of disease influenced the composition of the cervicovaginal microbiome. These studies demonstrate that papillomavirus infection can alter the cervicovaginal microbiome.IMPORTANCEHuman papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States. A subset of HPVs that infect the anogenital tract (cervix, vagina, anus) and oral cavity cause at least 5% of cancers worldwide. Recent evidence indicates that the community of microbial organisms present in the human cervix and vagina, known as the cervicovaginal microbiome, plays a role in HPV-induced cervical cancer. However, the mechanisms underlying this interplay are not well-defined. In this study, we infected the female reproductive tract of mice with a murine papillomavirus (MmuPV1) and found that key aspects of papillomavirus infection and disease influence the host cervicovaginal microbiome. This is the first study to define changes in the host microbiome associated with MmuPV1 infection in a preclinical animal model of HPV-induced cervical cancer. These results pave the way for using MmuPV1 infection models to further investigate the interactions between papillomaviruses and the host microbiome.

Block-wise imputation EM algorithm in multi-source scenario: ADNI case

Alzheimer’s disease is the most common form of dementia and the early detection is essential to prevent its proliferation. Real data available has been of paramount importance in order to achieve progress in the automatic detection despite presenting two major challenges: Multi-source observations containing Magnetic resonance (MRI), Positron emission tomography (PET) and Cerebrospinal fluid data (CSF); and also missing values within all these sources. Most machine learning techniques perform this predictive task by using a single data modality. Nevertheless, the integration of all these sources of evidence could possibly bring a higher performance at different stages of disease progression. The Expectation Maximization (EM) algorithm has been successfully employed to handle missing values, but it is not designed for typical Machine Learning scenarios where an imputation model is created over training data and subsequently applied on a testing set. In this work, we propose EMreg-KNN, a novel supervised and multi-source imputation algorithm. Based on the EM algorithm, EMreg-KNN builds a regression ensemble model for the imputation of future data thus allowing the further utilization of any vector-based Machine Learning method to automatically assess the Alzheimer’s disease diagnosis. Using the ADNI database, the proposed method achieves significant improvements on F1, AUC and Accuracy measures over classical imputation methods for this database using four classification algorithms. Considering these classifiers in four different classification scenarios, our algorithm is experimentally superior in terms of the F measure, in nearly 82% of the cases under evaluation.

Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism.

In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.

Knockdown of tgfb1a partially improves ALS phenotype in a transient zebrafish model.

Amyotrophic lateral sclerosis (ALS) corresponds to a neurodegenerative disorder marked by the progressive degeneration of both upper and lower motor neurons located in the brain, brainstem, and spinal cord. ALS can be broadly categorized into two main types: sporadic ALS (sALS), which constitutes approximately 90% of all cases, and familial ALS (fALS), which represents the remaining 10% of cases. Transforming growth factor type-β (TGF-β) is a cytokine involved in various cellular processes and pathological contexts, including inflammation and fibrosis. Elevated levels of TGF-β have been observed in the plasma and cerebrospinal fluid (CSF) of both ALS patients and mouse models. In this perspective, we explore the impact of the TGF-β signaling pathway using a transient zebrafish model for ALS. Our findings reveal that the knockdown of tgfb1a lead to a partial prevention of motor axon abnormalities and locomotor deficits in a transient ALS zebrafish model at 48 h post-fertilization (hpf). In this context, we delve into the proposed distinct roles of TGF-β in the progression of ALS. Indeed, some evidence suggests a dual role for TGF-β in ALS progression. Initially, it seems to exert a neuroprotective effect in the early stages, but paradoxically, it may contribute to disease progression in later stages. Consequently, we suggest that the TGF-β signaling pathway emerges as an attractive therapeutic target for treating ALS. Nevertheless, further research is crucial to comprehensively understand the nuanced role of TGF-β in the pathological context.

Rediscovering AMD with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture

Swept-source optical coherence tomography angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross-sectional and en face imaging strategies. Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30, 2022 PARTICIPANTS: Patients with AMD METHODS: Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. SS-OCTA imaging of AMD at different stages of disease progression. Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid. Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD.

263 Delayed-Release Budesonide in a Patient with Progressive IgA Nephropathy and Chronic Kidney Disease stage 4: A Case Report

263 Delayed-Release Budesonide in a Patient with Progressive IgA Nephropathy and Chronic Kidney Disease stage 4: A Case Report

Abstract 7304: Modulation of cytokine and chemokine profiles in pancreatic tumors and plasma via stage-specific intervention with Momordica Charantia juice in the LSL-KrasG12D/+, p48Cre/+ mouse model

Abstract According to the American Cancer Society ≈64,050 people will be newly diagnosed with pancreatic cancer in the United States, while ≈55, 550 (men and women numbers combined) will die of this malignancy in 2023 alone. Epidemiological studies have indicated that a diet rich in natural agents might reduce pancreatic ductal adenocarcinoma (PDAC) risk, prompting investigations into a natural agent with health benefits in pancreatic diseases [such as the fruits of Momordica Charantia (Bitter Melon)] as a potential natural and non-toxic anti-cancer approach against PDAC. Previously we have reported the protective effects of oral Bitter Melon Juice (BMJ-standardized-lyophilized powder) against growth and progression of PDAC in preclinical animal models (xenograft and patient-derived tumor models). In a recent study we reported the efficacy of BMJ against pancreatic cancer in the LSL-KrasG12D/+, p48Cre/+ transgenic mouse model [this model mimics the stage-specific progression of intraepithelial neoplasms to PDAC as it occurs in humans]. Both male and female LSL-KrasG12D/+, p48Cre/+ transgenic mice were subjected to BMJ intervention (daily oral gavage, dose: 200mg/kg body wt.) during different stages in disease progression. Intervention was started at 4 or 15 weeks of mice age and continued till study end (10 and 30 weeks of mice age respectively). Additionally, in one group of mice, intervention was initiated at 6 weeks of mice age and continued till 41 weeks of mice age (study end). Outcomes were compared with wild-type and disease-positive untreated control groups. Pancreatic tissue/tumors were harvested at study end and blood plasma was also collected. In the present study, we performed a stage specific evaluation of tissue and plasma cytokine/chemokine profiling after BMJ intervention to gain detailed mechanistic insights into the potential of BMJ to mediate it is anti-pancreatic cancer effect via modulation of inflammatory pathways associated with PDAC growth and progression. BMJ (15 weeks of treatment) demonstrated a significant response in modulating cytokine/chemokine profiles in LSL KrasG12D/+, p48Cre/+ mice pancreatic cancerous tissues (30 weeks old mice). BMJ intervention specifically downregulated the levels of monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein-1 (MIP-1-gamma), tumor necrosis factor (TNF) receptor (TNFR1), Vascular cell adhesion molecule 1 (VCAM-1/CD106) and L-selectin (CD62L). Furthermore, Ingenuity Pathway Analysis indicated significant inhibitory predictions on TNF-α, NF-κB and MCP-1 (CCL-2) associated inflammatory pathways. Overall, these outcomes signify that the anti- cancer effects of BMJ in KRAS harboring PDAC tumors is associated with down-regulation of inflammatory pathways associated with growth and progression of pancreatic cancer. Citation Format: Lakshmi Sai Pratyusha Bugata, Robin Kumar, Md. Imtiazul Kabir, Rama Kant, Chapla Agarwal, Rajesh Agarwal, Komal Raina. Modulation of cytokine and chemokine profiles in pancreatic tumors and plasma via stage-specific intervention with Momordica Charantia juice in the LSL-KrasG12D/+, p48Cre/+ mouse model [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 7304.

Cloud-Connected Bracelet for Continuous Monitoring of Parkinson’s Disease Patients: Integrating Advanced Wearable Technologies and Machine Learning

Parkinson’s disease (PD) is one of the most unremitting and dynamic neurodegenerative human diseases. Various wearable IoT devices have emerged for detecting, diagnosing, and quantifying PD, predominantly utilizing inertial sensors and computational algorithms. However, their proliferation poses novel challenges concerning security, privacy, connectivity, and power optimization. Clinically, continuous monitoring of patients’ motor function is imperative for optimizing Levodopa (L-dopa) dosage while mitigating adverse effects and motor activity decline. Tracking motor function alterations between visits is challenging, risking erroneous clinical decisions. Thus, there is a pressing need to furnish medical professionals with an ecosystem facilitating comprehensive Parkinson’s stage evaluation and disease progression monitoring, particularly regarding tremor and bradykinesia. This study endeavors to establish a holistic ecosystem centered around an energy-efficient Wi-Fi-enabled wearable bracelet dubbed A-WEAR. A-WEAR functions as a data collection conduit for Parkinson’s-related motion data, securely transmitting them to the Cloud for storage, processing, and severity estimation via bespoke learning algorithms. The experimental results demonstrate the resilience and effectiveness of the suggested technique, with 86.4% accuracy for bradykinesia and 90.9% accuracy for tremor estimation, along with good sensitivity and specificity for each scoring class. The recommended approach will support the timely determination of the severity of PD and ongoing patient activity monitoring. The system helps medical practitioners in decision making when initially assessing patients with PD and reviewing their progress and the effects of any treatment.

Plastic compounds and liver diseases: Whether bisphenol A is the only culprit.

Plastics, while providing modern conveniences, have become an inescapable source of global concern due to their role in environmental pollution. Particularly, the focus on bisphenol A (BPA) reveals its biohazardous nature and association with liver issues, specifically steatosis. However, research indicates that BPA is just one facet of the problem, as other bisphenol analogues, microplastics, nanoplastics and additional plastic derivatives also pose potential risks. Notably, BPA is implicated in every stage of non-alcoholic fatty liver disease (NAFLD) onset and progression, surpassing hepatitis B virus as a primary cause of chronic liver disease worldwide. As plastic contamination tops the environmental contaminants list, urgent action is needed to assess causative factors and mitigate their impact. This review delves into the molecular disruptions linking plastic pollutant exposure to liver diseases, emphasizing the broader connection between plastics and the rising prevalence of NAFLD.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. To develop a new composite score to improve the prediction of outcome change. We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

A Comprehensive Review of the Role of Biomarkers in Early Diagnosis of Parkinson's Disease.

Parkinson's disease (PD) is a complex neurological, degenerative clinical condition depicted by the advancing loss of dopaminergic neurons in the substantia nigra pars compacta, which manifests itself as a myriad of sensorimotor and non-motor signs in patients. The disease occurs due to the reduced levels of the neurotransmitter dopamine in the brain, which is primarily associated with functional characteristics regarding mobility and cognition. The basal ganglion is mainly involved in the generation of cognitive functions and thereforeis the most significantly associated area in PD. Since the classical diagnosis and assessment of PD depends majorly on the appearance of motor characteristics, which only arise when ~60-80% of the dopamine neuronal cell death has already occurred, it is imperative we focus on identifying biomarkers that can help us assess and diagnose PD in the earlier stages of disease progression, thus providing a better prognosis for the patients. This review article will focus on the different biomarkers that are currently available and in use, divided under the headings of clinical, biological, imaging, and genetic biomarkers, and assess their specificity and sensitivity towardproviding an early assessment of Parkinson's for the patients and the future of preclinical diagnostics using molecular biomarkers. PD affects over 1% of the population worldwide and only ranks secondto Alzheimer's disease in the context of its incidence and consequent socioeconomic burden. While recent breakthroughs in biomarkers have dramatically improved patients' odds of survival and prognosis, it still remains primarilya symptomatic diagnostic tool. It is an area of research that requires to focus on creating more advanced approaches towarddiagnosing PD early, involving clinical diagnostics, neuroimaging technology, and molecular biology collaborations to provide the highest degree of care and quality of life that a Parkinson's patient deserves.

Impact of incidental synucleinopathy in mild cognitive impairment due to Alzheimer disease.

Recent evidence suggests that the presence of α-synuclein Lewy bodies (LBs) correlates with accelerated disease progression in patients with Alzheimer disease (AD) but it is unclear whether this effect is also exerted in the mild cognitive impairment (MCI) phase of AD. We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with a faster rate of cognitive decline compared to MCI controls without LB pathology. We identified patients within the National Alzheimer's Coordinating Center (NACC) database with MCI due to AD and stratified the cohort by the presence or absence of synucleinopathy. We utilized a repeated measures longitudinal analysis of Mini-Mental State Examination (MMSE) scores to determine whether the decline in performance occurred at a greater rate in the synucleinopathy patients. A total of 206 participants were studied; 80 had coincident synucleinopathy. The rate of decline in MMSE scores between the groups did not differ. This may suggest that a synergistic effect of LB and AD neuropathology is only appreciable in the later stages of disease progression. Further investigation into the effect of mixed LB and AD pathology in the early stages of cognitive impairment is warranted to highlight opportunities for targeted early intervention in patients.

PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer

BackgroundPar-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis.MethodsThe essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis.ResultsPARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner.ConclusionThis study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

PATIENT-SPECIFIC ADAPTIVE DYNAMIC CYCLING IS ASSOCIATED WITH IMPROVED PD SYMPTOMS

BACKGROUND High-cadence dynamic cycling is an effective therapy for improving motor symptoms in individuals with Parkinson’s Disease (PD), as measured by the Unified Disease Parkinson’s Rating Scale-Motor III (UPDRS-III). However, there is significant variability in individual responses to this therapy. Our lab developed a patient-specific adaptive dynamic cycling (PSADC) paradigm that manipulates entropy of cadence to optimize exercise prescriptions for individuals at various stages of disease progression. The purpose of this study is to evaluate the effectiveness of 12 sessions of PSADC on motor symptom improvement (UPDRS-III score) in individuals with PD. METHODS Twenty-three individuals with idiopathic PD (were randomized into two groups: PSADC (n=13) or active control (n=10). All individuals completed 12 sessions (3 sessions per week for 4 weeks) of dynamic cycling on a SMART (Speed Manipulated Adaptive Rehabilitation Therapy) bicycle. Each session consisted of a 5-minute warm-up at 60 revolutions per minute (rpm), 30-minute exercise session (80 rpm), and 5-minute cool-down (60 rpm). Individuals in the PSADC group followed an adaptive exercise prescription in which resistance level was optimized on a weekly basis, based on the individual’s entropy of cadence, and cycling effort. Individuals in the active control group remained at a constant resistance level for the entirety of the intervention. UPDRS-III was assessed in all participants prior to and following the 12-session intervention. Two-way analysis of variance (ANOVA) and paired samples t-tests were performed to detect statistical differences in UPDRS-III score between the groups. RESULTS There was a significant group by time interaction (F= 18.746, p <0.001). The PSADC group showed a significant reduction (improvement) in UPDRS-III score (Pre: 32.8, Post: 27.5; p<0.001), while the active control group showed no significant change in UPDRS-III score (Pre: 28.2, Post: 32.4, p=0.08). CONCLUSIONS 12 sessions of PSADC significantly improved UPDRS-III score, compared to non-adaptive high-cadence dynamic cycling. These results suggest that optimizing entropy of cadence is valuable for motor symptom improvement. Future studies will develop machine learning algorithms designed to predict appropriate clinical exercise prescriptions for individuals with PD.

A case report of chronic hepatitis-C genotype 4c infection: Non-specific symptoms can become contextually relevant in clinical diagnosis

Chronic hepatitis C (CHC) infection is one of the leading causes of liver disease worldwide and its early diagnosis is often considered a challenge because of its non-symptomatic presentation until late disease progression stages. We report the case of a 52-year-old, South-Indian male with CHC genotype 4c infection. We start with the patient’s initial presentation 12 weeks before the diagnosis with seemingly non-specific symptoms of pedal edema, purpura, peripheral neuropathy, arthralgia, and recent onset of diabetes mellitus (DM). We then present the employed direct-acting antiviral (DAA) management regimen and the patient’s response over the span of 48 weeks. Correlating with observations from recent literature highlighting CHC’s extra-hepatic role in inducing cryoglobulinemic vasculitis (CV) and pancreatic dysfunction, we discuss some educational perspectives on how CV and DM-related symptoms may sometimes become contextually specific in clinically suspecting, assessing risk, and warranting CHC screening and diagnostic confirmation.

Relation of Langerhans cell size to buccal carcinoma

ABSTRACT Oral cancer decreases quality of life despite timely medical management. The carcinogens in tobacco products and their role in tumorigenesis are well documented. Langerhans cells (LCs) are a subset of antigen-presenting cells (APCs) that monitor the tumor microenvironment and engulf carcinogens and foreign bodies. We investigated the distribution and size of LCs and their relation to the mode of tobacco consumption and clinical outcome in patients with buccal carcinoma. We recruited patients with oral cancer who were scheduled for tumor excision and men with urethral stricture undergoing substitution urethroplasty using buccal mucosa. Normal and tumor-adjacent tissues were stained with CD1a antibody. The distribution and mean diameter of 100 LCs/patient were determined. We found significantly smaller LCs in patients who chewed only tobacco compared to those who consumed tobacco by other means. The size of LCs decreased significantly with progressive stages of malignant disease. We found that patients with larger LCs survived longer than those with smaller LCs during an average follow-up of 24 months. We suggest a relation between the size of LCs and clinical outcomes in patients with buccal carcinoma.

The potential and prospects of sleep biomarkers in early Alzheimer's disease diagnosis

Alzheimers disease (AD), often accompanied by sleep disturbances, is a neurodegenerative disease. Sleep disruptions have the potential to serve as biomarkers for early diagnosis because they can be observed in the initial stages of disease progression in the sleep-wake cycle. This paper summarizes the latest findings on AD manifestations during non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, sleep oscillations, and cognitive impairment. It provides a detailed overview of diagnostic bioindicators for primary Alzheimers disease, including invasive cerebrospinal fluid (CSF) markers, non-invasive electroencephalography (EEG), and plasma biomarkers, and compares their advantages and limitations in diagnosing early AD. The accuracy and reliability of sleep biomarkers in early diagnosis are evaluated, along with their clinical application prospects. The paper also proposes improvements in the use of sleep clinical markers for early Alzheimers disease diagnosis, aiming for greater breakthroughs in this field. The significance of this review lies in its in-depth exploration of the association between sleep disturbances and the early period of the disease, along with the introduction of potential biomarkers that can serve as tools for early determining and monitoring of this neurodegenerative health issue.

Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state. We used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state. SOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals. By directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.

Unveiling DNA methylation in Alzheimer's disease: a review of array-based human brain studies.

The intricacies of Alzheimer's disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms, particularly DNA methylation. This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer's disease neuropathology. The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer's disease progression. The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus. Notably, ANK1 hypermethylation, a protein implicated in neurofibrillary tangle formation, was recurrently identified in the entorhinal cortex. Further, the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3, RHBDF2, and MCF2L, potentially influencing neuroinflammatory processes. The complex role of BIN1 in late-onset Alzheimer's disease is underscored by its association with altered methylation patterns. Despite the disparities across studies, these findings highlight the intricate interplay between epigenetic modifications and Alzheimer's disease pathology. Future research efforts should address methodological variations, incorporate diverse cohorts, and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer's disease progression.