Stages Of Disease Progression Research Articles

Detecting the FLJ22447 lncRNA in Ovarian Cancer with Cyclopentane-Modified FIT-PNAs (cpFIT-PNAs).

Ovarian cancer (OC) is one of the most lethal gynecologic cancers that is typically diagnosed at the very late stage of disease progression. Thus, there is an unmet need to develop diagnostic probes for early detection of OC. One approach may rely on RNA as a molecular biomarker. In this regard, FLJ22447 lncRNA is an RNA biomarker that is over-expressed in ovarian cancer (OC) and in cancer-associated fibroblasts (CAFs). CAFs appear early on in OC as they provide a metastatic niche for OC progression. FIT-PNAs (forced intercalation-peptide nucleic acids) are DNA analogs that are designed to fluoresce upon hybridization to their complementary RNA target sequence. In recent studies, we have shown that the introduction of cyclopentane PNAs into FIT-PNAs (cpFIT-PNA) results in superior RNA sensors. Herein, we report the design and synthesis of cpFIT-PNAs for the detection of this RNA biomarker in living OC cells (OVCAR8) and in CAFs. cpFIT-PNA was compared to FIT-PNA and the cell-penetrating peptide (CPP) of choice was either a simple one (four L-lysines) or a CPP with enhanced cellular uptake (CLIP6). The combination of CLIP6 with cpFIT-PNA resulted in a superior sensing of FLJ22447 lncRNA in OVCAR8 cells as well as in CAFs. Moreover, incubation of CLIP6-cpFIT-PNA in OVCAR8 cells leads to a significant decrease (ca. 60%) in FLJ22447 lncRNA levels and in cell viability, highlighting the potential theranostic use of such molecules.

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.

Apolipoprotein H-based prognostic risk correlates with liver lipid metabolism disorder in patients with HBV-related hepatocellular carcinoma

Background/Aim: Chronic hepatitis B patients often develop concomitant fatty liver disease, which is associated with increased risk of liver cirrhosis and hepatocarcinoma. Our previous studies have shown that apolipoprotein H (APOH) levels are gradually decreased in patients with chronic HBV infection at different stages of disease progression, and APOH deficiency disrupted hepatic lipid metabolism and caused fatty liver. We focus on the relationship between APOH and hepatocellular carcinoma (HCC) in the context of chronic HBV infection. Methods and resultsAPOH was downregulated at the transcriptional level in HBV-related HCC patients from open-source human liver transcriptome databases, and relatively high expression of APOH might be a favourable prognostic marker in HCC. APOH downregulation was positively associated with tumour grade and HCC subtypes. The analysis result of CHCC-HBV database showed that APOH-associated differential expression genes (DEGs) enriched in lipid metabolic pathways and downregulated APOH correlated with macrophage, neutrophil and CD8 T cell infiltration levels. Next, in vitro experiments were performed and APOH gene was silenced in HepG2.2.15 cells, an HBV producing human HCC cells. Further transcriptomic assay and analysis revealed the DEGs were enriched in cholesterol metabolism. The subsequent RT-qPCR experiments identified that CYP7A1 expression was higher upregulated in APOH silencing HepG2.2.15 cells than vehicle control cells (p < 0.05). Finally, demographic data of patients with HBV-related HCC were enrolled, and serum APOH levels were analysed using ELISA. Serum APOH levels were significantly lower in patients with HCC than in healthy controls (p < 0.05), and positively correlated with triglyceride level in healthy controls (p < 0.05). In HBV-HCC patients, serum APOH levels were positively correlated with albumin levels and negatively correlated with alkaline phosphatase (ALP), total bilirubin, and INR levels (p < 0.05). ConclusionAPOH downregulation disrupted liver lipid metabolism to potentially affect the overall survival in patients with HBV-related HCC.

The Immunomodulatory Effects and Mechanism of Wogonin for the Treatment of Multiple Sclerosis in a Murine Experimental Autoimmune Encephalomyelitis Model

Abstract Multiple sclerosis (MS) stands out as the most prevalent inflammatory autoimmune disease affecting the central nervous system (CNS). The primary driver of MS involves myelin-specific autoreactive T cells that infiltrate the CNS, initiating attacks on myelinated axons and triggering neuroinflammatory responses. Wogonin, a flavonoid, exhibits pharmacologic properties, including neuroprotective, anticancer, antiviral, anti-inflammatory, and anti-oxyradical effects. Our study demonstrates that wogonin significantly suppresses TLR-dependent DC activation, migration, and the expression of adhesion molecules in LPS-stimulated bone marrow-derived dendritic cells (BMDCs). In the experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with wogonin led to reduced lymphocyte infiltration, prevented demyelination in the CNS, and consequently mitigated disease symptoms. Moreover, wogonin suppressed the release of neuroinflammatory cytokines by activated microglial cells, Th1 cells, Th2 cells, and Th17 cells in vitro and exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that wogonin treatment may not only prevent the onset of MS by inhibiting DC activation and migration but also potentially ameliorate the progression of MS by reducing neuroinflammation. This opens avenues for the development of new approaches in the therapy of autoimmune diseases.

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.

Rediscovering Age-Related Macular Degeneration with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture

Swept-source OCT 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. Patients with AMD. Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. Swept-source OCT angiography 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. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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.

Disease staging of Alzheimer’s disease using a CSF-based biomarker model

Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0–5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.

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

https://youtu.be/b2S2VPwRthE 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 &amp;lt;0.001). The PSADC group showed a significant reduction (improvement) in UPDRS-III score (Pre: 32.8, Post: 27.5; p&amp;lt;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.