Preclinical Stage Research Articles

The Prevalence of Mild Cognitive Impairment in China: Evidence from a Meta-Analysis and Systematic Review of 393,525 Adults.

This study aims to precisely determine the prevalence of mild cognitive impairment (MCI) in China, acknowledging its significance as a preclinical stage of dementia and a potential "intervention window." The acceleration of the aging process in China underscores the urgency of this research. A comprehensive search was conducted across PubMed, Embase, Web of Science, CNKI, WFD, VIP, and CBM databases from their inception until March 1, 2023. The Agency for Healthcare Research and Quality (AHRQ) methodology checklist guided our quality assessment. A random-effects model meta-analysis was employed to synthesize the pooled prevalence data of MCI in China. Our analysis encompassed 139 studies, incorporating data from 393,525 individuals aged 40 years and above. The studies were predominantly rated as moderate-to-high quality. The overall prevalence of MCI was determined to be 19.6% (95% CI: 17.7-21.6%). Subgroup analyses indicated variations in prevalence: 20.8% (95% CI: 18.9-22.7%) for P-MCI compared to 16.2% (95% CI: 11.7-20.7%) for DSM criteria. Geographically, prevalence in Southern China (21.0%, 95% CI: 18.1-23.9%) exceeded that in Northern China (17.6%, 95% CI: 15.9-19.4%). Notably, prevalence in hospitals (61.7%, 95% CI: 27.8-95.7%) was significantly higher than in nursing homes (16.1%, 95% CI: 14.3-17.9%) and communities (25.3%, 95% CI: 17.4-33.2%), especially after the COVID-19 outbreak. The study confirms a 19.6% prevalence rate of MCI in China, influenced by factors such as sample sources, beginning year of survey, and regional differences. It highlights the need for targeted screening and resource allocation to subpopulations at risk, aiming to prevent the progression to dementia.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Sociodemography, diabetes mellitus clinical parameters, and retinal morphology as predictors of neurodegeneration in preclinical diabetic retinopathy

Abstract PURPOSE: The current prediction of preclinical diabetic retinopathy (DR) in asymptomatic patients with diabetes mellitus (DM) is limited due to a lack of suitable indicators. This study aimed to identify the predictors of neurodegenerative changes in type 2 DM patients during the preclinical stage of DR using sociodemographic and DM clinical parameters and retinal morphology. METHODS: Fifty-six adult DM participants (mean age: 40.41 ± 7.281 years) were classified into three groups: DM without DR, DM with mild nonproliferative DR (NPDR), and DM with moderate-to-severe NPDR. Demographic data, including age, gender, race, DM duration, glycated hemoglobin levels, household income, comorbidities, and insulin dependency, were collected. Retinal morphology, including macular retinal layer thickness, peripapillary retinal nerve fiber layer, and vascular caliber, were analyzed. Multinomial logistic regression models explored these factors’ influence on NPDR prediction. RESULTS: Participants with moderate-to-severe NPDR were less likely to have DM without comorbidities (odds ratio [OR]: 0.048, 95% confidence interval [CI]: 0.003–0.823, P = 0.036). Those with longer DM duration were 27% more likely to develop moderate-to-severe NPDR (OR: 1.272, 95% CI: 1.035–1.564, P = 0.022). Retinal morphology parameters did not predict NPDR risk and severity levels in DM patients, except for mild NPDR, which had a 1.05 times higher risk of wider central retinal arteriolar equivalent (CRAE) (OR: 1.052, 95% CI: 1.002–1.105, P = 0.043). CONCLUSION: DM duration, comorbidity presence, and widened CRAE are critical parameters for assessing neurodegenerative changes in preclinical DR. These parameters could be incorporated into DR screening programs to mitigate NPDR progression and enhance long-term visual outcomes of DM patients.

Linking Dementia Pathology and Alteration in Brain Activation to Complex Daily Functional Decline During the Preclinical Dementia Stages: Protocol for a Prospective Observational Cohort Study.

Progressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer disease (AD) and other dementias. However, to justify early intervention, those at risk need to be detected earlier and more accurately. The decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (eg, eating and dressing). Our goal is to establish the neural signature of decline in CdF during the preclinical dementia period. Gait is central to many CdF and community-based activities. Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic approach to measuring gait-related brain activation while participants perform complex gait-based functional tasks. We hypothesize that dementia-related pathology during the preclinical period activates a unique gait-related electroencephalographic (grEEG) pattern that predicts a subsequent decline in CdF. We provide preliminary findings showing that older adults reporting CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and white matter hyperintensities in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical AD (plasma amyloid-β) and vascular (white matter hyperintensities) pathologies. We aim to (1) establish the unique grEEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; (2) determine associations between dementia-related pathologies and incidence of the neural signature of CdF; and (3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. By establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of ADs and other dementias. Our approach has important research and translational implications because grEEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real-world benefits. DERR1-10.2196/56726.

Allostatic load measures in older adults with subjective cognitive decline and mild cognitive impairment: A cross-sectional analysis from the Brazilian Memory and Aging Study

IntroductionAn increasing body of research suggests that stress and allostatic load are related to cognitive dysfunction and neurodegeneration. Objectivesto determine the relationship between allostatic load (AL) and cognitive status in older adults classified with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). MethodologyUsing the Brazilian Memory and Aging Study (BRAMS) database, we analyzed data from 57 older adults with SCD and MCI. Blood neuroendocrine (cortisol, DHEA-s), inflammatory (C-reactive protein, fibrinogen), metabolic (HbA1c, HDL-cholesterol, total cholesterol, creatinine), and cardiovascular (blood pressure, waist/hip ratio) were transformed into an AL index. ResultsDespite a significant difference in the univariate analysis between waist/hip ratio (0.94 in the MCI group vs. 0, 88 in the SCD group, p = 0.03), total cholesterol levels (194 vs. 160, p = 0.02), and AL index (36.9 % in the MCI group vs. 27.2 % in the SCD group, p = 0.04), AL was not associated with SCD or MCI in the multivariate analysis. ConclusionOur data suggest that different profiles of AL in MCI compared to individuals with SCD could be due to cofounding factors. These findings need to be confirmed in longitudinal studies investigating profiles of AL changes at preclinical and prodromal stages of Alzheimer’s disease.

Associations of tau, Aβ, and brain volume of the Papez circuit with cognition in Alzheimer's disease.

This study aimed to investigate the cross-sectional associations between regional Alzheimer's disease (AD) biomarkers, including tau, β-amyloid (Aβ), and brain volume, within the Papez circuit, and neuropsychological functioning across the preclinical and clinical spectrum of AD. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 251 Aβ-positive participants. Participants were categorized into three groups based on the Clinical Dementia Rating (CDR): 73 individuals with preclinical AD (CDR = 0), 114 with prodromal AD (CDR = 0.5), and 64 with clinical AD dementia (CDR ≥ 1). Linear regression analyses, adjusted for age, gender, and education years, were employed to evaluate the associations between five regions of interest (the hippocampus, para-hippocampus, entorhinal cortex, posterior cingulate cortex, and thalamus) and five neuropsychological tests across the three imaging modalities. In the preclinical stage of AD, flortaucipir PET was associated with impaired global cognition and episodic memory (range standardized β = 0.255-0.498, p < 0.05 corrected for multiple comparisons), while florbetapir PET and brain volume were marginally related to global cognition (range standardized β = 0.221-0.231, p < 0.05). In the clinical stages of AD (prodromal and dementia), both increased flortaucipir uptake and decreased brain volume were significantly associated with poorer global neuropsychological and episodic memory performance (range standardized β = 0.222-0.621, p < 0.05, most regions of interest survived correction for multiple comparisions). However, a slight relationship was observed between florbetapir uptake and poorer global cognitive function. The regions most affected by flortaucipir PET were the hippocampus, para-hippocampus, and posterior cingulate cortex. During the clinical stages, the hippocampus and entorhinal cortex exhibited the most significant volumetric changes. Tau PET and brain volume measurements within the Papez circuit are more sensitive indicators of early cognitive deficits in AD than Aβ PET. Furthermore, during the clinical stages of AD, both flortaucipir PET and brain volume of the Papez circuit are closely correlated with cognitive decline. These findings underscore the importance of integrating multiple biomarkers for the comprehensive evaluation of AD pathology and its impact on cognition.

Application of 3Rs in Caenorhabditis elegans Research for the Identification of Health-Promoting Natural Products.

The average age of the population is increasing worldwide, which has a profound impact on our society. This leads to an increasing demand for medicines and requires the development of new strategies to promote health during the additional years. In the search for resources and therapeutics for improved health during an extended life span, attention has to be paid to environmental exposure and ecosystem burdens that inevitably emerge with the extended consumption of medicines and drug development, even in the preclinical stage. The hereby introduced sustainable strategy for drug discovery is built on 3Rs, "R: obustness, R: eliability, and saving R: esources", inspired by both the 3Rs used in animal experiments and environmental protection, and centers on the usefulness and the variety of the small model organism Caenorhabditis elegans for detecting health-promoting natural products. A workflow encompassing a multilevel screening approach is presented to maximize the amount of information on health-promoting samples, while considering the 3Rs. A detailed, methodology- and praxis-oriented compilation and discussion of proposed C. elegans health span assays and more disease-specific assays are presented to offer guidance for scientists intending to work with C. elegans, thus facilitating the initial steps towards the integration of C. elegans assays in their laboratories.

Can immune therapy prevent pre-clinical cancer from progression? The impact of immune therapy on secondary cancer incidence.

2651 Background: 40% of people will develop cancer (Ca) in their lifetime, and 18% of those will develop secondary (2ry) Ca. Currently, there are no known therapeutic interventions to prevent Ca. Immune therapy (IT) revolutionized Ca care and increased survival in many Ca types. Because IT increases immune surveillance, it might halt pre-clinical Ca from progression into clinical disease. We hypothesize that IT acts to prevent or delay the development of 2ry Ca in those treated with IT for primary (1ry) Ca. Methods: We conducted a retrospective cohort study on Ca patients (pts) ≥ 18 years &amp; treated between 2010-2022 at Cleveland Clinic, Ohio. We included Ca diagnoses where IT was utilized in first line therapy, per 2022 NCCN guidelines. We excluded pts who were not treated or whose 1ry therapy was not determined. 2ry Ca was defined with strict criteria and excluded recurrent 1ry Ca. We collected the following data: 1ry Ca and stage, 2ry Ca type and incidence, type of first &amp; subsequent line therapy, comorbidities, smoking &amp; alcohol use. Molecular data and PD-1/PDL-1 are currently being collected. The comparison groups were pts who received IT +/- Chemotherapy (CTX) +/- radiation (RT) (IT-G) vs. pts who received CTX or targeted therapy +/- RT (Non-IT). IT included anti-(PD-1, PD-L1, LAG-3, CTLA4: 99.9% of cases) or others (IL-2, IL-12, IL-15, Inf α: 0.1%). Outcome was 2ry Ca-free survival. Multivariable regression was used to account for confounding. Results: The initial sample size was 19,253 pts, and 6,376 met the criteria. There was 10.2% bladder stage II-IV, 2.5% endometrial stage IV, 21.7% esophagus/gastric stage II-IV, 13% head/neck stage IV, 4.9% clear cell renal stage III/IV, 0.7% BRAF mutated melanoma stage IV, 28.2% lung adenoCa stage IIIb/IV, 9.1% squamous cell lung Ca stage IIIb/IV, and 10% small cell lung Ca stage IIIb/ IV. Baseline characteristics of comparison groups are presented in table below. 1,173 (18%) received first line and 1,023 (16%) received subsequent line IT. With a median follow up of 12.2 months for whole population, 319 2ry Ca were diagnosed. The two-year 2ry Ca free survival was 98% (CI: 97-99) in pts who received first line IT, compared to 93% (93-94) in pts who did not get first line IT. On multivariable regression, pts who received IT at any time compared to pts who received non-IT had a 77% decrease in 2ry Ca incidence (Hazard ratio: 0.33, 95CI 0.22-0.50, P&lt;0.001). Conclusions: Our study concludes that incidence of 2ry Ca in pts treated with IT was lower than pts who received non-IT. In this proof-of-concept study, we showed that IT may increase immune surveillance to prevent Ca in its pre-clinical stage. Future interventional studies are needed to explore if IT can be utilized in 1ry &amp; 2ry prevention in high risk, Ca-free populations. [Table: see text]

Neural markers of reduced arousal and consciousness in mild cognitive impairment.

People with Alzheimer's Disease (AD) experience changes in their level and content of consciousness, but there is little research on biomarkers of consciousness in pre-clinical AD and Mild Cognitive Impairment (MCI). This study investigated whether levels of consciousness are decreased in people with MCI. A multi-site site magnetoencephalography (MEG) dataset, BIOFIND, comprising 83 people with MCI and 83 age matched controls, was analysed. Arousal (and drowsiness) was assessed by computing the theta-alpha ratio (TAR). The Lempel-Ziv algorithm (LZ) was used to quantify the information content of brain activity, with higher LZ values indicating greater complexity and potentially a higher level of consciousness. LZ was lower in the MCI group versus controls, indicating a reduced level of consciousness in MCI. TAR was higher in the MCI group versus controls, indicating a reduced level of arousal (i.e. increased drowsiness) in MCI. LZ was also found to be correlated with mini-mental state examination (MMSE) scores, suggesting an association between cognitive impairment and level of consciousness in people with MCI. A decline in consciousness and arousal can be seen in MCI. As cognitive impairment worsens, measured by MMSE scores, levels of consciousness and arousal decrease. These findings highlight how monitoring consciousness using biomarkers could help understand and manage impairments found at the preclinical stages of AD. Further research is needed to explore markers of consciousness between people who progress from MCI to dementia and those who do not, and in people with moderate and severe AD, to promote person-centred care.

Nanomaterials in Drug Delivery: Strengths and Opportunities in Medicine.

There is a myriad of diseases that plague the world ranging from infectious, cancer and other chronic diseases with varying interventions. However, the dynamism of causative agents of infectious diseases and incessant mutations accompanying other forms of chronic diseases like cancer, have worsened the treatment outcomes. These factors often lead to treatment failure via different drug resistance mechanisms. More so, the cost of developing newer drugs is huge. This underscores the need for a paradigm shift in the drug delivery approach in order to achieve desired treatment outcomes. There is intensified research in nanomedicine, which has shown promises in improving the therapeutic outcome of drugs at preclinical stages with increased efficacy and reduced toxicity. Regardless of the huge benefits of nanotechnology in drug delivery, challenges such as regulatory approval, scalability, cost implication and potential toxicity must be addressed via streamlining of regulatory hurdles and increased research funding. In conclusion, the idea of nanotechnology in drug delivery holds immense promise for optimizing therapeutic outcomes. This work presents opportunities to revolutionize treatment strategies, providing expert opinions on translating the huge amount of research in nanomedicine into clinical benefits for patients with resistant infections and cancer.

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum.

The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum. We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis. CSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance. These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.

Non-linear relationship between serum cholesterol levels and cognitive change among older people in the preclinical and prodromal stages of dementia: a retrospective longitudinal study in Taiwan

BackgroundAdverse effects of rigorously lowering low-density lipoprotein cholesterol on cognition have been reported; therefore, we aimed to study the contribution of serum cholesterol in cognitive decline in older people with or without dementia.MethodsCognitive function was assessed by the Cognitive Abilities Screening Instrument (CASI). We investigated associations between serum cholesterol with cognitive decline using multiple regressions controlling for the effects of demographics, vascular risk factors, and treatments.ResultsMost associations between cholesterol and CASI scores could be explained by non-linear and inverted U-shaped relationships (R2 = 0.003–0.006, p < 0.016, Šidákcorrection). The relationships were most evident between changes in cholesterol and CASI scores in older people at the preclinical or prodromal stages of dementia (R2 = 0.02–0.064, p values < 0.016). There were no differences in level of changes in CASI scores between individuals in 1st decile and 10th decile groups of changes in cholesterol (p = 0.266–0.972). However, individuals in the 1st decile of triglyceride changes and with stable and normal cognitive functions showed significant improvement in CASI scores compared to those in the 10th decile (t(202) = 2.275, p values < 0.05).ConclusionThese findings could implicate that rigorously lowering cholesterol may not be suitable for the prevention of cognitive decline among older people, especially among individuals in preclinical or prodromal stages of dementia.

Therapeutic strategies in preclinical stages of rheumatoid arthritis.

Modern therapies and treatment algorithms, such as the treat‑to‑target strategy, have significantly improved outcomes in patients with rheumatoid arthritis (RA) over the past decades. Moreover, the concept of the "window of opportunity" has led to earlier diagnosis and better treatment outcomes. Nevertheless, progressive disease remains a significant clinical issue and socioeconomic burden, which warrants investigation of novel strategies. One of such innovative therapies is primary prevention: treating patients at risk for developing RA for a short period of time to prevent the disease before it occurs. The initiation of treatment in preclinical phases of RA is expected to delay, halt, or even prevent the disease onset or progression in the long term. This review summarizes this new concept, discusses current studies including an overview of therapeutic algorithms and findings, and provides a critical evaluation of pharmacologic approach in the preclinical stages of RA.

Recent Developments in Combination Immunotherapy with Other Therapies and Nanoparticle-Based Therapy for Triple-Negative Breast Cancer (TNBC).

Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.

Analysis of the pharmacokinetics and efficacy of RBD1016 – A GalNAc-siRNA targeting Hepatitis B Virus X gene using semi-mechanistic PK/PD model

Small interference RNA (siRNA) is a class of short double-stranded RNA molecules that cause mRNA degradation through an RNA interference mechanism and is a promising therapeutic modality. RBD1016 is a siRNA drug in clinical development for the treatment of chronic Hepatitis B Virus (HBV) infection, which contains a conjugated with N-acetylglucosamine moiety that can facilitate its hepatic delivery. We aimed to construct a semi-mechanistic model of RBD1016 in pre-clinical animals, to elucidate the pharmacokinetic/pharmacodynamic (PK/PD) profiles in mice and PK profiles in monkeys, which can lay the foundation for potential future translation of RBD1016 PK and PD from the pre-clinical stage to the clinic stage. The proposed semi-mechanistic PK/PD model fitted PK and PD data in HBV transgenic mice well and described plasma and liver concentrations in the monkeys well. The simulation results showed that our model has a reasonable predictive ability for Hepatitis B surface antigen (HBsAg) levels after multiple dosing in mice. Further PK and PD data for RBD1016, including clinical data, will assist in refining the model presented here. Our current effort focused on model building for RBD1016, we anticipate that the model could apply to other GalNAc-siRNA drugs.

Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study.

Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). Overexpression of HPSE is associated with various types of cancer, inflammation, and immune disorders, making it a highly promising therapeutic target. Previously developed HPSE inhibitors that have advanced to clinical trials are polysaccharide-derived compounds or their mimetics; however, these molecules tend to suffer from poor bioavailability, side effects via targeting other saccharide binding proteins, and heterogeneity. Few small-molecule inhibitors have progressed to the preclinical or clinical stages, leaving a gap in HPSE drug discovery. In this study, a novel small molecule that can inhibit HPSE activity was discovered through high-throughput screening (HTS) using an ultrasensitive HPSE probe. Computational tools were employed to elucidate the mechanisms of inhibition. The essential structural features of the hit compound were summarized into a structure-activity relationship (SAR) theory, providing insights into the future design of HPSE small-molecule inhibitors.

Unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop

The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.

Navigating the complexities of drug development for inflammatory bowel disease.

Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.

Progress on early diagnosing Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions. The disease follows a continuum, starting with preclinical stages, progressing to mild cognitive and behavioral impairment, ultimately leading to dementia. Early detection of AD is crucial for better diagnosis and more effective treatment. However, the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive, and mostly are still not able to detect early disease state. Consequently, there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD. Various non-cognitive manifestations, including behavioral abnormalities, sleep disturbances, sensory dysfunctions, and physical changes, have been observed in the preclinical AD stage before occurrence of notable cognitive decline. Recent research advances have identified several biofluid biomarkers as early indicators of AD. This review focuses on these non-cognitive changes and newly discovered biomarkers in AD, specifically addressing the preclinical stages of the disease. Furthermore, it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.

Evaluating the role of CD44 in oral squamous cell carcinoma and potentially malignant disorders – An immunohistochemical study

BackgroundOral squamous cell carcinoma (OSCC) accounts for 84–97 % of all cases of oral cancer. Oral submucous and leukoplakia are examples of potentially malignant disorders (PMDs) that are signs of the preclinical stage of oral cancerCD44 (Cluster of differentiation) is a cell surface glycoprotein that serves as a Cancer Stem Cell marker. AimThe purpose of the study was to look at the presence of CD44 immunohistochemically in oral epithelial dysplasia, oral submucous fibrosis, and OSCC and how it influences a patient's prognosis. Materials and methodsIn this retrospective study, the expression of CD44 were evaluated in 60 paraffin –embedded specimens (20 OSCC, 20 Dysplasia, 20 OSMF). This study was evaluated by spss 21. Differences in the mean number of CD 44-positive cells per field among epithelial dysplasia, oral submucous fibrosis and squamous cell carcinomas were assessed using one-way ANOVA and comparison between the groups were analysed by using Bonferroni post hoc test. Statistical significance was at P < 0.05. ResultsOn comparing the CD44 immuno-expression, the highest expression was seen in OSCC followed by dysplasia and OSMF. The OSCC group had a high mean total score of 7.90, followed by dysplasia at 5.40 and OSMF at 5.05. ConclusionAccording to our research, there was a discernible pattern of elevated CD44 expression in OSCC relative to OSMF and dysplasia. These findings set the premise for further research to better outline the role of CD44 in the diagnosis of OSCC.