Decelerate Disease Progression Research Articles

Probiotics and Non-Alcoholic Fatty Liver Disease: Unveiling the Mechanisms of Lactobacillus plantarum and Bifidobacterium bifidum in Modulating Lipid Metabolism, Inflammation, and Intestinal Barrier Integrity.

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4+ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD.

Harnessing Mirror Neurons: A New Frontier in Parkinson's Disease Rehabilitation-A Scoping Review of the Literature.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as tremors, rigidity, and bradykinesia. Rehabilitation utilizing mirror neurons leverages the brain's capacity for action observation (AO) and motor imagery (MI) to enhance motor function. This approach involves patients imitating movements observed in therapists or videos, aiming to improve gait, coordination, and overall quality of life. Mirror neuron activation facilitates motor learning and may decelerate disease progression, thus enhancing patient mobility and independence. Methods: This scoping review aimed to map current evidence on PD therapies employing mirror neuron-based rehabilitation. Databases searched included PubMed, PEDro, and Cochrane. The review included randomized controlled trials (RCTs) and systematic reviews that examined the effects of AO and MI in PD rehabilitation. Results: Five studies met the inclusion criteria, encompassing various rehabilitation techniques focusing on AO and MI. These studies consistently demonstrated positive outcomes, such as reduced disease severity and improved quality of life, gait, and balance in PD patients. The activation of mirror neurons through AO and MI was shown to facilitate motor learning and contribute to improved functional mobility. Conclusions: Although the included studies support the beneficial impact of AO and MI techniques in PD rehabilitation, numerous questions remain unresolved. Further research is necessary to evaluate the potential integration of these techniques into standard physiotherapy routines for PD patients. This review highlights the promise of AO and MI in enhancing motor rehabilitation for PD, suggesting the need for more comprehensive studies to validate and refine these therapeutic approaches.

Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.

Reactive Oxygen Species and Mitochondrial Calcium's Roles in the Development of Atherosclerosis.

In the last decade, there has been increasing evidence connecting mitochondrial dysfunction to the onset and advancement of atherosclerosis. Both reactive oxygen species (ROS) and the disruption of mitochondrial calcium (Ca2+) regulation have garnered significant attention due to their involvement in various stages of atherosclerosis. This abstract discusses the potential therapeutic applications of targeting mitochondrial calcium (Ca2+) and reactive oxygen species (ROS), while also providing an overview of their respective roles in atherosclerosis. The abstract underscores the importance of mitochondrial Ca2+ homeostasis in cellular physiology, including functions such as energy production, cell death signaling, and maintaining redox balance. Alterations in the mitochondria's Ca2+ handling disrupt all these procedures and speed up the development of atherosclerosis. Reactive oxygen species (ROS), generated during mitochondrial respiration, are widely recognized as significant contributors to the development of atherosclerosis. Through modulating the function of calcium ion (Ca2+) transport proteins, ROS can impact the regulation of mitochondrial Ca2+ handling. These oxidative modifications lead to vascular remodeling and plaque formation by impairing endothelial function, encouraging the recruitment of inflammatory cells, and promoting smooth muscle cell proliferation. Preclinical investigations indicate that interventions aimed at regulating the production and elimination of reactive oxygen species (ROS) hold promise for mitigating atherosclerosis. Targeting mitochondrial processes represents a prospective therapeutic strategy for addressing this condition. Further research is necessary to elucidate the intricate molecular mechanisms associated with mitochondrial dysfunction in atherosclerosis and develop effective therapeutic strategies to decelerate disease progression.

MMP13-responsive hydrogel microspheres for osteoarthritis treatment by precise delivery of celecoxib

Osteoarthritis (OA) is characterized by cartilage degradation, inflammatory responses, and osteophyte formation. Matrix metalloproteinase 13 (MMP13) is a hallmark of OA development, and increased MMP13 expression is closely associated with extracellular matrix degradation. MMP13 expression varies significantly at different stages of OA progression. While cyclooxygenase 2 (COX-2) inhibitors are commonly used to treat OA, their long-term systemic administration increases the risks of adverse effects. Therefore, with the aim of achieving localized and responsive delivery of the COX-2 inhibitor celecoxib, the current study investigated an innovative MMP13-responsive micro-nano hydrogel microsphere system. Celecoxib-loaded cationic liposomes are non-covalently attached within the microsphere, enabling controlled drug release for OA treatment. In an OA environment with elevated MMP13 expression, the system is degraded via the action of MMP13 substrate peptide (MMP13sp), facilitating accelerated release of drug-loaded liposomes to improve the inflammatory microenvironment and treat OA rapidly. Compared to a phosphate-buffered saline solution with hyaluronidase (HAase), the prepared hyaluronic acid methacrylate microspheres HAMA/MMP13sp/Lipo@celecoxib exhibited rapid degradation in a solution containing a physiological concentration of MMP13/HAase, demonstrating specific enzyme responsiveness for precise anti-inflammatory drug release. The MMP13-responsive hydrogel microsphere system achieves intelligent and controllable drug release in OA, effectively decelerating disease progression and promoting articular cartilage repair.

The Double Burden: Deciphering Chronic Limb-Threatening Ischemia in End-Stage Renal Disease

ObjectivesChronic Limb-Threatening Ischemia (CLTI) in patients with End-Stage Renal Disease (ESRD) poses significant challenges in clinical management due to its unique pathology and poor treatment outcomes. This review calls for a tailored classification and risk assessment for these patients to guide better revascularization choices with early minor amputation as a first-line strategy in advanced stages. MethodsThis review consolidates key findings from recent literature on CLTI in ESRD, focusing on disease mechanisms, treatment options, and patient outcomes. It evaluates the literature to clarify the decision-making process for managing CLTI in ESRD. ResultsCLTI in ESRD patients often results in worse clinical outcomes, such as non-healing wounds, increased limb loss, and higher mortality rates. While the literature reveals ongoing debates regarding the optimal revascularization method, recent retrospective studies and meta-analyses suggest potential benefits of Endovascular Treatment (EVT) over Open Bypass Surgery (OB) in reducing mortality and wound complications, with comparable Amputation-free Survival rates. ConclusionsThe selection of revascularization methods in ESRD patients with CLTI is complex, necessitating individualized strategies. The importance of early detection and timely intervention is critical to decelerate disease progression and improve revascularization outcomes. There is a shift in these treatments strategies towards less invasive endovascular procedures, acknowledging the limitations these patients face with open revascularization surgeries. Considering early minor amputations after revascularization could prevent worse consequences, reflecting a shift in the approach to managing CLTI in ESRD patients.

Erythrocyte membrane coated with nitrogen-doped quantum dots and polydopamine composite nano-system combined with photothermal treatment of Alzheimer's disease

Mitochondrial dysfunction and metal ion imbalance are recognized as pathological hallmarks of Alzheimer's Disease (AD), leading to deposition of β-amyloid (Aβ) thereby and inducing neurotoxicity, activating apoptosis, eliciting oxidative stress, and ultimately leading to cognitive impairment. In this study, the red blood cell membrane (RBC) was used as a vehicle for encapsulating carbon quantum dots (CQD) and polydopamine (PDA), creating a nanocomposite (PDA-CQD/RBC). This nanocomposite was combined with near-infrared light (NIR) for AD treatment. The RBC offers anti-immunorecognition properties to evade immune clearance, PDA exhibits enzyme-mimicking activity to mitigate oxidative stress damage, and CQD acts as a chelating agent for metal ions (Cu2+), effectively preventing Cu2+-mediated aggregation of Aβ. Furthermore, the local heating induced by near-infrared laser irradiation can dismantle the formed Aβ fibers and enhance the blood–brain barrier's permeability. Both in vitro and animal experiments have shown that PDA-CQD/RBC, in combination with NIR, mitigates neuroinflammation, and ameliorates behavioral deficits in mice. This approach targets multiple pathological pathways, surpassing the limitations of single-target treatments and enhancing therapeutic efficacy while decelerating disease progression.

Management and maintenance of oral health: Personalized primary prevention strategies and protocols in patients at risk of developing medication-related osteonecrosis of the jaw

Skeletal complications arising from osteoporosis or bone metastases are associated with considerable pain, increased mortality, and diminished quality of life. Agents that prevent bone resorption, such as bisphosphonates, denosumab, and antiangiogenic agents, prove effective in reducing fracture risk and find extensive use in patients with osteoporosis or bone cancer metastases. Medication-related osteonecrosis of the jaw (MRONJ) is a potentially serious adverse event associated with high cumulative doses of antiresorptive drugs. Other risk factors for osteonecrosis of the jaw include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, inappropriate dentures, and other MRONJ-related medications. Preventive strategies encompass completing necessary oral surgery before initiating antiresorptive drug therapy, administering antibiotics before and/or after the procedure, rinsing the mouth with chlorhexidine, ensuring adequate wound healing post-tooth extraction, and maintaining good oral hygiene. The primary goal of treatment is to improve the patient’s quality of life by managing pain and infection, preventing the development of new lesions, and decelerating disease progression. Dentists and dental hygienists, operating within a multi-professional team, play a key role in the primary prevention of MRONJ. However, a standardized multidisciplinary approach, fostering sustained dialog between specialists involved in the management of patients at risk for MRONJ, remains essential. This review describes the preventive and individualized oral hygiene management in patients at risk for this condition.

Atomically dispersed single-atom catalysts (SACs) and enzymes (SAzymes): synthesis and application in Alzheimer's disease detection.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Conventional diagnostic methods, such as neuroimaging and cerebrospinal fluid analysis, typically detect AD at advanced stages, limiting the efficacy of therapeutic interventions. Early detection is crucial for improving patient condition by enabling timely administration of treatments that may decelerate disease progression. In this context, single-atom catalysts (SACs) and single-atom nanozymes (SAzymes) have emerged as promising tools offering highly sensitive and selective detection of Alzheimer's biomarkers. SACs, consisting of isolated metal atoms on a support surface, deliver unparalleled atomic efficiency, increased reactivity, and reduced operational costs, although certain challenges in terms of stability, aggregation, and other factors persist. The advent of SAzymes, which integrate SACs with natural metalloprotease catalysts, has further advanced this field by enabling controlled electronic exchange, synergistic productivity, and enhanced biosafety. Particularly, M-N-C SACs with M-Nx active sites mimic the selectivity and sensitivity of natural metalloenzymes, providing a robust platform for early detection of AD. This review encompasses the advancements in SACs and SAzymes, highlighting their pivotal role in bridging the gap between conventional enzymes and nanozyme and offering enhanced catalytic efficiency, controlled electron transfer, and improved biosafety for Alzheimer's detection.

RSK1 Is an Exploitable Dependency in Myeloid Malignancies

Myeloid malignancies harbor distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. To delineate these hallmarks across the spectrum of myeloid disease states, we established the largest comprehensive atlas of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing and mass cytometry (CyTOF) of 370 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes, revealing aberrant of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. As a central mediator of these hyperactive signaling pathways, ribosomal S6 kinases (RSKs) represent potentially attractive novel therapeutic targets warranting further evaluation. Using both genetic approaches and a first-in-class oral RSK inhibitor, PMD-026, that is currently being evaluated in phase 1/1b clinical trials (NCT04115306) in metastatic and triple negative breast cancer, we found that RSK1 ( RPS6KA1) inhibition potently induced apoptosis and G2/M arrest in leukemia models in conjunction with suppression of PI3K/AKT/mTOR and NFκB signaling. Further NFκB cascade profiling following RSK1 perturbation revealed reduced phosphorylation of IKKα/β and p65/RELA and prevention of p65/RELA nuclear translocation. Using RNA-seq, ATAC-seq and H3K27ac CUT&Tag, we found that PMD-026 treatment altered chromatin accessibility and inhibited NFKB1, TNF, and cell cycle regulators CCNA1/2 and CDK1/2. In cytokine CyTOF, PMD-026 nearly abrogated all induction of inflammatory cytokines including TNF, IL-6, IL-8, CCL3, and CCL4 in primary MPN monocytes to levels substantially below basal conditions. We further extended our findings to de novo AML harboring FLT3 internal tandem duplication ( FLT3-ITD), where FLT3-ITD patients exhibited elevated RPS6KA1 expression and those who developed resistance to gilteritinib demonstrated progressively increased RPS6KA1 expression. FLT3-ITD cells exhibited preferentially sensitivity to RSK1 inhibition, where we uncovered bi-directional regulation. Through cycloheximide, MG-132, and ubiquitination assays, we found that RSK1 regulates FLT3-ITD activity and protein stability through deubiqutinase USP1, and where either RPS6KA1 or USP1 inhibition resulted in concomitant downregulation of FLT3 protein and cell lethality. Multivariate analysis of the TCGA and BeatAML cohorts (n= 568 patients) revealed high median USP1 or RPS6KA1 expression to be significantly associated with poor survival, thus defining a RSK1-USP1-FLT3 axis with prognostic relevance. Across in vivo models, PMD-026 ameliorated MPN disease features driven by MPL W515L including leukocytosis, splenomegaly, and bone marrow fibrosis, while prolonging survival, in conjunction with suppression of inflammatory cytokines including TNF, IL-6 and IL-1b. We then evaluated PMD-026 across five patient-derived xenograft (PDX) models spanning the spectrum of myeloid malignancies including myelofibrosis (MF), sAML, and chronic myelomonocytic leukemia (CMML) encompassing various driver and multiple high-risk mutations. Treatment in MF PDX mice decelerated disease progression, extended survival, and reduced splenomegaly, while in CMML/sAML PDXs, PMD-026 led to a 67 to 96 percent reduction in human CD45+ cells engraftment. Finally, PMD-026 treatment in both mice xenografted with MV4-11 cells and syngeneic Flt3ITDTet2KO mice significantly reduced leukemic cell engraftment and prolonged survival. These data indicate potent efficacy of RSK inhibition across diverse models of chronic and acute myeloid malignancies. Lastly, we investigated the impact of PMD-026 on hematological parameters from 41 breast cancer patients enrolled in the phase 1/1b clinical trial. Overall, there was no sustained suppressive effect on hematological parameters and there were no hematological PMD-026-related toxicities meeting criteria for dose modification during the trial period. These clinical data demonstrate that PMD-026 did not cause myelosuppression. Our findings uncover a novel therapeutic avenue for a conserved RSK1 dependency across chronic and acute myeloid neoplasms. The potent and consistent disease-ameliorating effects across numerous leukemia mouse models demonstrates promise for repurposing PMD-026 for the treatment of myeloid malignancies.

How immune breakthroughs could slow disease progression and improve prognosis in COVID-19 patients: a retrospective study.

Previous infections and vaccinations have produced preexisting immunity, which differs from primary infection in the organism immune response and may lead to different disease severities and prognoses when reinfected. The purpose of this retrospective cohort study was to investigate the impact of immune breakthroughs on disease progression and prognosis in patients with COVID-19. A retrospective cohort study was conducted on 1513 COVID-19 patients in Chengdu Public Health Clinical Medical Center from January 2020 to November 2022. All patients were divided into the no immunity group (primary infection and unvaccinated, n=1102) and the immune breakthrough group (previous infection or vaccination, n=411). The immune breakthrough group was further divided into the natural immunity subgroup (n=73), the acquired immunity subgroup (n=322) and the mixed immunity subgroup (n=16). The differences in clinical and outcome data and T lymphocyte subsets and antibody levels between two groups or between three subgroups were compared by ANOVA, t test and chi-square test, and the relationship between T lymphocyte subsets and antibody levels and the disease progression and prognosis of COVID-19 patients was assessed by univariate analysis and logistic regression analysis. The total critical rate and the total mortality rate were 2.11% and 0.53%, respectively. The immune breakthrough rate was 27.16%. In the no immunity group, the critical rate and the mortality rate were all higher, and the coronavirus negative conversion time was longer than those in the immune breakthrough group. The differences in the critical rate and the coronavirus negative conversion time between the two groups were all statistically significant (3.72% vs. 0.24%, 14.17 vs. 11.90 days, all p<0.001). In addition, in the no immunity group, although lymphocyte counts and T subsets at admission were higher, all of them decreased consistently and significantly and were significantly lower than those in the immune breakthrough group at the same time from the first week to the fourth week after admission (all p<0.01). The total antibody levels and specific Immunoglobulin G (IgG) levels increased gradually and were always significantly lower than those in the immune breakthrough group at the same time from admission to the fourth week after admission (all p<0.001). Moreover, in the natural immunity subgroup, lymphocyte counts and T subsets at admission were the highest, and total antibody levels and specific IgG levels at admission were the lowest. Then, all of them decreased significantly and were the lowest among the three subgroups at the same time from admission to one month after admission (total antibody: from 546.07 to 158.89, IgG: from 6.00 to 3.95) (all p<0.001). Those in the mixed immunity subgroup were followed by those in the acquired immunity subgroup. While lymphocyte counts and T subsets in these two subgroups and total antibody levels (from 830.84 to 1008.21) and specific IgG levels (from 6.23 to 7.51) in the acquired immunity subgroup increased gradually, total antibody levels (from 1100.82 to 908.58) and specific IgG levels (from 7.14 to 6.58) in the mixed immunity subgroup decreased gradually. Furthermore, T lymphocyte subsets and antibody levels were negatively related to disease severity, prognosis and coronavirus negative conversion time. The total antibody, specific IgM and IgG levels showed good utility for predicting critical COVID-19 patients and dead COVID-19 patients. Among patients with COVID-19 patients, immune breakthroughs resulting from previous infection or vaccination, could decelerate disease progression and enhance prognosis by expediting host cellular and humoral immunity to accelerate virus clearance, especially in individuals who have been vaccinated and previously infected. Chinese Clinical Trial Register ChiCTR2000034563.

Spotlight on iron and ferroptosis: research progress in diabetic retinopathy.

Iron, as the most abundant metallic element within the human organism, is an indispensable ion for sustaining life and assumes a pivotal role in governing glucose and lipid metabolism, along with orchestrating inflammatory responses. The presence of diabetes mellitus (DM) can induce aberrant iron accumulation within the corporeal system. Consequentially, iron overload precipitates a sequence of important adversities, subsequently setting in motion a domino effect wherein ferroptosis emerges as the utmost pernicious outcome. Ferroptosis, an emerging variant of non-apoptotic regulated cell death, operates independently of caspases and GSDMD. It distinguishes itself from alternative forms of controlled cell death through distinctive morphological and biochemical attributes. Its principal hallmark resides in the pathological accrual of intracellular iron and the concomitant generation of iron-driven lipid peroxides. Diabetic retinopathy (DR), established as the predominant cause of adult blindness, wields profound influence over the well-being and psychosocial strain experienced by afflicted individuals. Presently, an abundance of research endeavors has ascertained the pervasive engagement of iron and ferroptosis in the microangiopathy inherent to DR. Evidently, judicious management of iron overload and ferroptosis in the early stages of DR bears the potential to considerably decelerate disease progression. Within this discourse, we undertake a comprehensive exploration of the regulatory mechanisms governing iron homeostasis and ferroptosis. Furthermore, we expound upon the subsequent detriments induced by their dysregulation. Concurrently, we elucidate the intricate interplay linking iron overload, ferroptosis, and DR. Delving deeper, we engage in a comprehensive deliberation regarding strategies to modulate their influence, thereby effecting prospective interventions in the trajectory of DR's advancement or employing them as therapeutic modalities.

Decision trees to evaluate the risk of developing multiple sclerosis.

Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS. This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors. The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease. Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease.

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.

Subsiding of Periodontitis in the Permanent Dentition in Individuals with Papillon-Lefèvre Syndrome through Specific Periodontal Treatment: A Systematic Review.

Papillon-Lefèvre syndrome (PLS) is a rare hereditary disease characterized by palmoplantar hyperkeratosis (PPK) and periodontitis in the primary and permanent dentition, usually resulting in edentulism in youth. Subsiding of PLS-associated periodontitis through specific therapy has occasionally been reported. We aimed to systematically assess periodontal treatment strategies that may decelerate disease progression. A systematic literature search was conducted at PubMed/LIVIVO/Ovid (Prospero registration number CRD42021223253). Clinical studies describing periodontal treatment success-defined as loss of ≤four permanent teeth because of periodontitis and the arrest of periodontitis or probing depths ≤ 5 mm-in individuals with PLS followed up for ≥24 months. Out of the 444 primarily identified studies, 12 studies reporting nine individuals were included. The timely extraction of affected or, alternatively, all primary teeth, compliance with oral hygiene instructions, supra- and subgingival debridement within frequent supportive periodontal care intervals, and-in eight patients-adjunctive systemic antibiotic therapy (mostly amoxicillin/metronidazole) effected a halt in disease progression. The suppression of Aggregatibacter actinomycetemcomitans below the detection limit was correlated with the subsiding of periodontitis. Successful controlling of PLS-associated periodontitis may be achieved if high effort and patient compliance are provided.

CLASSIC PRESENTATION OF SCLERODERMA-RELATED INTERSTITIAL LUNG DISEASE IN A YOUNG FEMALE

CLASSIC PRESENTATION OF SCLERODERMA-RELATED INTERSTITIAL LUNG DISEASE IN A YOUNG FEMALE

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells.

The substantial socioeconomic burden of lung diseases, recently highlighted by the disastrous impact of the coronavirus disease 2019 (COVID-19) pandemic, accentuates the need for interventive treatments capable of decelerating disease progression, limiting organ damage, and contributing to a functional tissue recovery. However, this is hampered by the lack of accurate human lung research models, which currently fail to reproduce the human pulmonary architecture and biochemical environment. Induced pluripotent stem cells (iPSCs) and organ-on-chip (OOC) technologies possess suitable characteristics for the generation of physiologically relevant in vitro lung models, allowing for developmental studies, disease modeling, and toxicological screening. Importantly, these platforms represent potential alternatives for animal testing, according to the 3Rs (replace, reduce, refine) principle, and hold promise for the identification and approval of new chemicals under the European REACH (registration, evaluation, authorization and restriction of chemicals) framework. As such, this review aims to summarize recent progress made in human iPSC- and OOC-based in vitro lung models. A general overview of the present applications of in vitro lung models is presented, followed by a summary of currently used protocols to generate different lung cell types from iPSCs. Lastly, recently developed iPSC-based lung models are discussed.

Helping Relationships From Significant Others Scale: Chinese Version.

Using the helping relationships from significant others (HRSO) scale assists patients, such as those with chronic kidney disease (CKD), in adopting a healthy lifestyle to decelerate disease progression, complications, and mortality. To study the efficacy of the scale, we recruited a convenience sample (n = 250) of patients with CKD from a nephrology clinic in southern Taiwan. Principal axis factor analysis and a promax rotation revealed a 15-item, three-factor explanation of 68.44 % of the total variance. The confirmatory factor analysis showed a good fit. The Composite reliability was .91, .89, and .92 in the same factors. Cronbach's alpha was .90 for the 15-item scale, with the 3 subscales ranging from .86 to .91. The split reliability was .73. The HRSO is a valid and reliable scale to measure significant others' support of patients with CKD in maintaining a healthy lifestyle.

Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers: Anti-arrhythmic Drug for Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Current treatment guidelines for arrhythmogenic right ventricular cardiomyopathy (ARVC) mainly emphasize on prevention of ventricular arrhythmic events. Despite the progressive nature of ARVC, therapeutic options focusing on decelerating disease progression are scarce.Methods and Results: This retrospective observational cohort study included 311 patients [age, 39.1 ± 14.4 years; male, 233 (74.9%)] with a definite diagnosis of ARVC as determined by the 2010 Task Force Diagnostic Criteria. Among them, 113 patients (36.3%) received ACEI/ARB treatment. Disease progression was evaluated according to repeat transthoracic echocardiograms with a linear mixed model. Patients receiving ACEI/ARB treatment were associated with slower disease progression reflected by a gradual decrease in tricuspid annular plane systolic excursion than those not receiving ACEI/ARB treatment (0.37 vs. 0.61 mm per year decrease, P < 0.001) and slower dilation of right ventricular outflow tract (0.57 vs. 1.06 mm per year increased, P = 0.003). Cox proportional hazard regression models were used to evaluate the association between life-threatening ventricular tachycardia events and ACEI/ARB treatment. A reduced risk of life-threatening ventricular arrhythmia was associated with ACEI/ARB treatment compared to that without ACEI/ARB treatment (adjusted HR: 0.71, 95% CI: 0.52–0.96, P = 0.031).Conclusions: ACEI/ARB treatment is associated with slower disease progression and lower risk of life-threatening ventricular arrhythmia in patients with ARVC. Delaying disease progression may pave way for reducing life-threatening ventricular arrhythmia risk.

EPCR Signaling Controls the Activity of Hematopoietic Stem Cells Independent of Coagulation Regulation

BackgroundAll mature blood cells are derived from multipotent hematopoietic stem cells (HSCs) which are activated to meet the demand of the host during inflammation and injury. The endothelial cell protein C receptor (EPCR) is a marker for primitivity and quiescence of HSCs but the relative contributions of EPCR signaling versus anticoagulant functions in HSC maintenance are incompletely defined.AimsWe aimed to dissect functions of EPCR by studying anticoagulant and signaling function in HSC of EPCR C/S mice carrying a single intracellular point mutation abolishing normal trafficking of EPCR through endo-lysosomal compartments. We assessed the contributions of EPCR signaling to stem cell maintenance by analyzing HSC mobilization and leukemia progression.MethodsWe studied the frequency and cell cycle activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPC) by multicolor flow cytometry. Furthermore, we analyzed changes in hematopoiesis in steady state, after granulocyte colony stimulating factor (G-CSF)-induced mobilization, in the context of aging and in the context of leukemia, using the MLL-AF9-induced acute myeloid leukemia (AML) model.ResultsHSCs, lungs and isolated lung-derived smooth muscle cells of EPCR C/S mice showed protein expression levels and anticoagulant function indistinguishable from wildtype (WT). We found an increase of circulating HSCs in the peripheral blood of EPCR C/S mice compared to control under steady state conditions. Isolated HSC displayed diminished polarization of CDC42 and VLA-4 (α 4β 1 integrin) affinity to VCAM-1 in EPCR C/S versus strain-matched EPCR wt mice, indicating that EPCR signaling directly controls HSC retention via integrin affinity to the BM niche. In addition, we noticed a higher cell cycle activity in myeloid-restricted progenitors of EPCR C/S mice compared to control. G-CSF treatment led to increased mobilization of both BM neutrophils and HSCs into the peripheral blood of EPCR C/S mice compared to EPCR wt mice. A myeloid bias was also seen in serially transplanted aged mice, resulting in increased frequencies of myeloid-biased progenitors in the BM of EPCR C/S mice compared to control mice, accompanied by an increase of circulating neutrophils in the blood. Consistent with higher cell cycle activity of myeloid progenitors and an overall increase of myeloid-biased output in EPCR C/S mice, induction of AML by retroviral transduction of EPCR C/S BM cells with MLL-AF9-expressing retrovirus resulted in an increase of cell cycle activity of Lin - MLL-AF9 + leukemic BM blasts and a higher leukemic load in the peripheral blood of mice transplanted with MLL-AF9 + EPCR C/S BM compared to control. As a result, MLL-AF9 + EPCR C/S leukemia showed a more aggressive disease with shortened survival times compared to control. In contrast, chemotherapy of MLL-AF9 + EPCR C/S leukemia reduced leukemic load in the peripheral blood and decelerated disease progression. These data demonstrate that increased leukemia cell cycle activity conferred chemosensitivity.ConclusionWith a site-specific EPCR mutant knock-in mouse, we here demonstrate that EPCR signaling and anticoagulant function can be separated. We provide direct evidence that EPCR signaling plays a crucial role in maintaining HSC retention via VLA-4 affinity to VCAM-1, controls cell cycle activity and myeloid output in normal, stress-induced, and malignant hematopoiesis with implications for therapeutic approaches in acute myeloid leukemia. DisclosuresRuf: MeruVasimmune: Other: Ownership Interest; ARCA bioscience: Consultancy, Patents & Royalties; ICONIC Therapeutics: Consultancy.