Disease Progression Research Articles

Language to Support Dignity for Children With Advanced Cancer and Their Families.

Conversations about dignity are fundamental to person-centered care in pediatrics, yet practical language strategies to promote and support dignity remain understudied. To address this gap, we aimed to identify and characterize language used by pediatric oncologists to recognize and affirm dignity across advancing illness. In this longitudinal prospective study, we audio-recorded serial disease reevaluation encounters between pediatric oncologists, children with cancer, and families across 24 months or until the child's death. Using a hybrid deductive-inductive qualitative approach, we defined dignity language a priori on the basis of existing descriptions of dignity in the literature and then conducted a content analysis to refine the definition specific to pediatric cancer care before coding serial medical encounters. Thematic frequencies were reported by using descriptive statistics. A total of 91 discussions at timepoints of disease progression were audio-recorded for 36 patients and their families. No dignity language was identified in nearly half (45%) of "bad news" encounters, and the time spent by the oncologist engaging in dignity language represented a minority (<7%) of overall recorded dialogue. Within coded dialogue, we characterized 3 key themes upholding dignity language (empowerment, autonomy, respect). Opportunities exist to improve dignity communication in childhood cancer, and the authors propose a conceptual model ("Lend an EAR") to guide dignity-based communication in pediatric cancer. Future research should emphasize patient and parent perspectives on language to support dignity for children with advanced cancer, with stakeholder-driven refinement of the Lend an EAR model before integration and testing in communication skills training programs.

Mapping small metabolite changes after traumatic brain injury using AP-MALDI MSI.

Traumatic brain injury (TBI) is an alteration of brain function caused by a sudden transmission of an external force to the head. The biomechanical impact induces acute and chronic metabolic changes that highly contribute to injury evolution and outcome. TBI heterogeneity calls for approaches allowing the mapping of regional molecular and metabolic changes underpinning disease progression, with mass spectrometry imaging (MSI) as an efficient tool to study the spatial distribution of small metabolites. In this study, we applied an innovative targeted atmospheric pressure-MALDI mass spectrometry imaging (AP-MALDI MSI) approach, starting from an extensive list of metabolites, representative of different metabolic pathways, individually validated on the tissue under analysis with original standards using 2,5-dihydroxybenzoic acid (DHB), to characterize the impact of TBI on regional changes to small metabolites in the brain. Brains from sham and TBI mice obtained 21days post-injury were analyzed to examine the spatial metabolic profile of small metabolites belonging to different metabolic pathways. By a whole brain analysis, we identified four metabolites (alanine, lysine, histidine, and inosine) with higher abundance in TBI than sham mice. Within the TBI group, lysine, histidine, and inosine were higher in the hemisphere ipsilateral to the biomechanical impact vs. the contralateral one. Images showed a major involvement of the ipsilateral thalamus characterized by the increase of arginine, lysine, histidine, and inosine and a significant reduction of glutamic acid, and N-acetylaspartic acid compared to the contralateral thalamus. These findings indicate high-resolution imaging mass spectrometry as a powerful tool to identify region-specific changes after a TBI to understand the metabolic changes underlying brain injury evolution.

Comprehensive macro and micro views on immune cells in ischemic heart disease.

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.

Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.

Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed. The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry. Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.

Trastuzumab Deruxtecan in Advanced Solid Tumors With Human Epidermal Growth Factor Receptor 2 Amplification Identified by Plasma Cell-Free DNA Testing: A Multicenter, Single-Arm, Phase II Basket Trial.

HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 (HER2)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing. Patients exhibited advanced solid tumors with HER2 amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity. Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease. T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2-amplified solid tumors determined with cfDNA testing.

Maintenance with mirvetuximab soravtansine plus bevacizumab vs bevacizumab in FRα-high platinum-sensitive ovarian cancer.

At first recurrence, platinum-sensitive ovarian cancer (PSOC) is frequently treated with platinum-based chemotherapy doublets plus bevacizumab, then single-agent bevacizumab. Most patients' disease progresses within a year after chemotherapy, emphasizing the need for novel strategies. Mirvetuximab soravtansine-gynx (MIRV), an antibody-drug conjugate, comprises a folate receptor alpha (FRα)-binding antibody and tubulin-targeting payload (maytansinoid DM4). In FRα-high PSOC, MIRV plusbevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3months [95% CI: 8.3-18.3]; median duration of response, 12.9months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plusbevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab.Clinical Trial Registration: ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

The Potential of Metabolomics to Find Proper Biomarkers for Addressing the Neuroprotective Efficacy of Drugs Aimed at Delaying Parkinson’s and Alzheimer’s Disease Progression

The first objective is to highlight the lack of tools to measure whether a given intervention affords neuroprotection in patients with Alzheimer’s or Parkinson’s diseases. A second aim is to present the primary outcome measures used in clinical trials in cohorts of patients with neurodegenerative diseases. The final aim is to discuss whether metabolomics using body fluids may lead to the discovery of biomarkers of neuroprotection. Information on the primary outcome measures in clinical trials related to Alzheimer’s and Parkinson’s disease registered since 2018 was collected. We analysed the type of measures selected to assess efficacy, not in terms of neuroprotection since, as stated in the aims, there is not yet any marker of neuroprotection. Proteomic approaches using plasma or CSF have been proposed. PET could estimate the extent of lesions, but disease progression does not necessarily correlate with a change in tracer uptake. We propose some alternatives based on considering the metabolome. A new opportunity opens with metabolomics because there have been impressive technological advances that allow the detection, among others, of metabolites related to mitochondrial function and mitochondrial structure in serum and/or cerebrospinal fluid; some of the differentially concentrated metabolites can become reliable biomarkers of neuroprotection.

Enhanced Diabetes Prediction and Monitoring through Integration of Multimodal Data Using XGBoost

Abstract: Diabetes is a critical and become more complicated disease that can cause serious health problems if it is not adequately managed. The early diagnosis and treatment of diabetes is a critical component of the condition that can be greatly aided by data analysis and predictive algorithms. Through the use of data mining techniques, such as classification and prediction models, it is possible to analyse various elements of diabetes data and extract useful information that can be used for the early detection and prediction of the condition. One machine learning technique that can effectively and highly precisely predict diabetes is the XGBoost classifier. This method makes use of the gradient-boosting architecture and can handle large and intricate datasets with independent high-dimensional feature sets. Conversely, it is crucial to remember that the choice of the best algorithm for diabetes prediction could depend on the specifics of the data as well as the area of study being investigated. Data analysis and prediction methods can be applied not only to anticipate diabetes but also to monitor the disease's progression, find risk factors for diabetes and its complications, and assess the effectiveness of treatment. By using these techniques, medical professionals can obtain important insights into the disease's underlying causes, which helps them make informed decisions about patient management. The early detection and management of diabetes, a chronic disease that is rapidly expanding and poses major health risks, has the potential to be significantly improved through the application of data analysis and prediction algorithms. An accuracy rate of 89% was achieved by the XGBoost classifier, which demonstrated the highest level of performance.

Identification of Time-Series Pattern Marker in Its Application to Mortality Analysis of Pneumonia Patients in Intensive Care Unit

Electronic Health Records (EHRs) are a significant source of big data used to track health variables over time. The analysis of EHR data can uncover medical markers or risk factors, aiding in the diagnosis and monitoring of diseases. We introduce a novel method for identifying markers with various temporal trend patterns, including monotonic and fluctuating trends, using machine learning models such as Long Short-Term Memory (LSTM). By applying our method to pneumonia patients in the intensive care unit using the MIMIC-III dataset, we identified markers exhibiting both monotonic and fluctuating trends. Specifically, monotonic markers such as red cell distribution width, urea nitrogen, creatinine, calcium, morphine sulfate, bicarbonate, sodium, troponin T, albumin, and prothrombin time were more frequently observed in the mortality group compared to the recovery group throughout the 10-day period before discharge. Conversely, fluctuating trend markers such as dextrose in sterile water, polystyrene sulfonate, free calcium, and glucose were more frequently observed in the mortality group as the discharge date approached. Our study presents a method for detecting time-series pattern markers in EHR data that respond differently according to disease progression. These markers can contribute to monitoring disease progression and enable stage-specific treatment, thereby advancing precision medicine.

Association between Oral Microbiome and Gastroesophageal Reflux Severity

Background/Objectives: Gastroesophageal reflux disease (GORD) is caused by gastric contents refluxing back into the oesophagus and oral cavity. It can lead to injuries to the mucosa in the form of erosion and ulcers. Our past research have shown acid reflux severity and disease progression is associated with alternations in the microbiota of the distal oesophagus. The aim of this study was to explore whether changes in the oral microbiota occurred in GORD patients and establish any associations with reflux severity. Methods: Fresh mouthwash samples were collected from 58 patients experiencing reflux symptoms referred for 24 h pH monitoring. The participants were categorised into three groups based on their DeMeester scores: Normal (&lt;14.72), Mild (14.2–50), and Moderate/severe (&gt;51). Microorganism identity and diversity were generated using hypervariable tag sequencing and analysing the V1–V3 region of the 16S rRNA gene. Results: No differences in microbiota diversity were found in oral microbiota between groups using the Chiao1 diversity index and Shannon diversity index. Microbiota in the Mild group showed reductions in Rothia dentocariosa and Lautropia, while Moryella and Clostridiales_1 were increased compared with the Normal group. In the Moderate/severe group, the abundance of Rothia aeria was reduced compared with the Normal group, while Schwartzia, Rs_045, Paludibacter, S. satelles, Treponema, and T. socranskii all had increased abundance. The abundance of Prevotella pallens was higher in the Mild group compared with Moderate/severe, while S. satelles and Paludibacter abundances were lower. Conclusions: Our study shows the oral microbiome show significant differences between acid reflux severity groups, as categorised by DeMeester score.

Outcome Measures in Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

No association between markers of systemic inflammation and endothelial dysfunction with Alzheimer's disease progression: a longitudinal study.

Systemic inflammation and endothelial dysfunction are potentially modifiable factors implicated in Alzheimer's disease (AD), which offer potential therapeutic targets to slow disease progression. We investigated the relationship between baseline circulating levels of inflammatory (TNF-α, IL-1ß) and endothelial cell markers (VCAM-1, ICAM-1, E-selectin) and 18-month cognitive decline (ADAS-cog12) in 266 mild-to-moderate AD patients from the NILVAD study. We employed individual growth models to examine associations, potential mediation, and interaction effects while adjusting for confounders. The average increase in ADAS-cog12 scores over all patients was 8.1 points in 18months. No significant association was found between the markers and the rate of cognitive decline. Mediation analysis revealed no mediating role for endothelial cell markers, and interaction effects were not observed. Our results do not support the role of systemic inflammation or endothelial dysfunction in progression in persons with AD.

The Use of Telerehabilitation to Improve Movement-Related Outcomes and Quality of Life for Individuals With Parkinson Disease: Pilot Randomized Controlled Trial.

Individuals with Parkinson disease (PD) can improve their overall mobility and participation in daily activities as they engage in frequent exercise. Despite the need for individually tailored exercises, persons with PD often face barriers to accessing physical rehabilitation professionals who can provide them. Telerehabilitation (TR) may facilitate access to necessary and individually tailored rehabilitation for individuals with PD. The purpose of this study was to assess the feasibility of TR for individuals with PD and explore clinical outcomes compared to in-person care. This was a pilot randomized controlled trial conducted at 2 outpatient neurorehabilitation clinics with 3 study groups: clinic+TR, TR-only, and usual care (UC). TR was administered using a web-based application with a mobile app option. One-hour interventions were performed weekly for 4 weeks, in-person for the clinic+TR and UC groups and virtually for the TR-only group. Home exercises were provided on paper for the UC group and via the web-based platform for the clinic+TR and TR-only groups. Feasibility was assessed by recruitment and retention success and patient and therapist satisfaction, as rated in surveys. Clinical outcomes were explored using performance and patient-reported measures in between- and within-group analyses. Of 389 patients screened, 68 (17.5%) met eligibility criteria, and 20 (29.4% of those eligible) were enrolled (clinic+TR, n=6; TR-only, n=6; and UC, n=8). One patient (TR-only) was withdrawn due to a non-study-related injurious fall. Regardless of group allocation, both patients and therapists generally rated the mode of care delivery as "good" or "very good" across all constructs assessed, including overall satisfaction and safety. In the analysis of all groups, there were no differences in clinical outcomes at the discharge visit. Within-group differences (from baseline to discharge) were also generally not significant except in the UC group (faster 5-time sit-to-stand time and higher mini balance evaluation systems test balance score) and clinic+TR group (higher mini balance evaluation systems test balance score). High satisfaction amongst patients and clinicians regardless of group, combined with nonsignificant between-group differences in clinical outcomes, suggest that TR is feasible for individuals with PD in early-moderate stages. Future trials with a larger sample are necessary to test clinical effectiveness. As larger trials enroll patients with diverse characteristics (eg, in terms of age, disease progression, caregiver support, technology access and capacity, etc), they could begin to identify opportunities for matching patients to the optimal utilization of TR as part of the therapy episode. ClinicalTrials.gov NCT06246747; https://clinicaltrials.gov/study/NCT06246747.

Research Progress on the Role of M6A in Regulating Economic Traits in Livestock

Reversible regulation of N6-methyladenosine (m6A) methylation of eukaryotic RNA via methyltransferases is an important epigenetic event affecting RNA metabolism. As such, m6A methylation plays crucial roles in regulating animal growth, development, reproduction, and disease progression. Herein, we review the latest research advancements in m6A methylation modifications and discuss regulatory aspects in the context of growth, development, and reproductive traits of livestock. New insights are highlighted and perspectives for the study of m6A methylation modifications in shaping economically important traits are discussed.

Clinical and molecular insights into A97S variants in hereditary transthyretin amyloid polyneuropathy in South China

Objective This study aims to delineate the clinical profiles of the hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) patients with A97S variant from southern China and the molecular characteristics of this mutant protein. Methods Fifteen ATTRv-PN patients with heterozygous A97S and one patient with homozygous A97S were included in the study. Serum TTR tetramer concentration was quantified through ultra-performance liquid chromatography. Stabilities of A97S-TTR were assessed through in vitro urea-mediated tryptophan fluorescence experiments, and nephelometry was employed in drug response assessment. Results All patients were late-onset (≥50 years) with a mean age of onset at 59.26 ± 5.06 years old. Patients displayed a mixed phenotype featuring sensory-motor neuropathy with autonomic dysfunction and cardiac involvement, such as palpitations and chest pain. Electrophysiological studies showed generally axonal impairment of sensory and motor nerves. Tafamidis-treated patients showed significantly higher TTR tetramer concentrations, approaching healthy controls’ levels. In vitro assessment showed that A97S-TTR was more kinetically stable than the V122I-TTR, and tetramer stabilisers inhibited A97S-TTR amyloid formation by more than 70%. Conclusion This study provides valuable insights into the clinical and molecular characteristics of ATTRv-PN patients with A97S from South China, particularly regarding the differences in disease progression and stability features.

Molecular Evolutionary Dynamics of Coxsackievirus A6 Causing Hand, Foot, and Mouth Disease From 2021 to 2023 in China: Genomic Epidemiology Study.

Hand, foot, and mouth disease (HFMD) is a global public health concern, notably within the Asia-Pacific region. Recently, the primary pathogen causing HFMD outbreaks across numerous countries, including China, is coxsackievirus (CV) A6, one of the most prevalent enteroviruses in the world. It is a new variant that has undergone genetic recombination and evolution, which might not only induce modifications in the clinical manifestations of HFMD but also heighten its pathogenicity because of nucleotide mutation accumulation. The study assessed the epidemiological characteristics of HFMD in China and characterized the molecular epidemiology of the major pathogen (CV-A6) causing HFMD. We attempted to establish the association between disease progression and viral genetic evolution through a molecular epidemiological study. Surveillance data from the Chinese Center for Disease Control and Prevention from 2021 to 2023 were used to analyze the epidemiological seasons and peaks of HFMD in Henan, China, and capture the results of HFMD pathogen typing. We analyzed the evolutionary characteristics of all full-length CV-A6 sequences in the NCBI database and the isolated sequences in Henan. To characterize the molecular evolution of CV-A6, time-scaled tree and historical population dynamics regarding CV-A6 sequences were estimated. Additionally, we analyzed the isolated strains for mutated or missing amino acid sites compared to the prototype CV-A6 strain. The 2021-2023 epidemic seasons for HFMD in Henan usually lasted from June to August, with peaks around June and July. The monthly case reporting rate during the peak period ranged from 20.7% (4854/23,440) to 35% (12,135/34,706) of the total annual number of cases. Analysis of the pathogen composition of 2850 laboratory-confirmed cases identified 8 enterovirus serotypes, among which CV-A6 accounted for the highest proportion (652/2850, 22.88%). CV-A6 emerged as the major pathogen for HFMD in 2022 (203/732, 27.73%) and 2023 (262/708, 37.01%). We analyzed all CV-A6 full-length sequences in the NCBI database and the evolutionary features of viruses isolated in Henan. In China, the D3 subtype gradually appeared from 2011, and by 2019, all CV-A6 virus strains belonged to the D3 subtype. The VP1 sequences analyzed in Henan showed that its subtypes were consistent with the national subtypes. Furthermore, we analyzed the molecular evolutionary features of CV-A6 using Bayesian phylogeny and found that the most recent common ancestor of CV-A6 D3 dates back to 2006 in China, earlier than the 2011 HFMD outbreak. Moreover, the strains isolated in 2023 had mutations at several amino acid sites compared to the original strain. The CV-A6 virus may have been introduced and circulating covertly within China prior to the large-scale HFMD outbreak. Our laboratory testing data confirmed the fluctuation and periodic patterns of CV-A6 prevalence. Our study provides valuable insights into understanding the evolutionary dynamics of CV-A6.

Effects of Different Exercise Intensities on the Rat Model of Heart Failure.

Heart failure (HF) is a clinical syndrome caused by the progression of various cardiac diseases to severe stages, and exercise training plays a positive role in the development of HF. This study aimed to investigate the impact of different intensities of exercise training on HF rats.In this study, we established two HF rat models by intraperitoneal injection of isoproterenol at 2.5 mg/kg/day and abdominal aortic coarctation. After exercise training for 4 weeks, the heart weight/body weight ratio and echocardiography results were measured. Moreover, the regulatory effect of different exercise intensities on myocardial function in HF model rats was verified using tissue staining, western blotting, and reagent kits.Exercise training had a bidirectional adjust effect on HF. A running training program of 20 minutes/time had the most significant effect on improving myocardial function in HF rats, whereas exercise intensity of 40 minutes/time or 50 minutes/time did not significantly improve myocardial function in HF rats. Moreover, exercise intensities of 20 minutes/time and 30 minutes/time could reduce the expression levels of the HF markers NT-proBNP and BNP in rats, but the effect was more significant at a duration of 20 minutes/time. We also found that compared with other exercise intensities, 20 minutes/time exercise intensity could significantly improve myocardial fibrosis, promote cardiomyocyte autophagy, and reduce apoptosis in combating HF.Furthermore, an exercise intensity of 20 minutes/time can significantly ameliorate the progression of HF. However, the degree of significance of increasing exercise intensity in improving HF progression is weakened or has no significant effect.

Prevalence and progression of chronic kidney disease among adults undergoing creatinine testing in South African public healthcare facilities: a study leveraging data from South Africa’s National Health Laboratory Service (NHLS)

BackgroundChronic kidney disease (CKD) has emerged as a substantial global health challenge, with a marked rise in associated mortality. However, it often goes undetected until advanced stages, particularly in low-income...

Progranulin inhibits autophagy to facilitate intracellular colonization of Helicobacter pylori through the PGRN/mTOR/DCN axis in gastric epithelial cells

Helicobacter pylori (H. pylori) infection is the primary risk factor for the progress of gastric diseases. The persistent stomach colonization of H. pylori is closely associated with the development of gastritis and malignancies. Although the involvement of progranulin (PGRN) in various cancer types has been well-documented, its functional role and underlying mechanisms in gastric cancer (GC) associated with H. pylori infection remain largely unknown. This report demonstrated that PGRN was up-regulated in GC and associated with poor prognosis, as determined through local and public database analysis. Additionally, H. pylori induced the up-regulation of PGRN in gastric epithelial cells both in vitro and in vivo. Functional studies have shown that PGRN promoted the intracellular colonization of H. pylori. Mechanistically, H. pylori infection induced autophagy, while PGRN inhibited autophagy to promote the intracellular colonization of H. pylori. Furthermore, PGRN suppressed H. pylori-induced autophagy by down-regulating decorin (DCN) through the mTOR pathway. In general, PGRN inhibited autophagy to facilitate intracellular colonization of H. pylori via the PGRN/mTOR/DCN axis. This study provides new insights into the molecular mechanisms underlying the progression of gastric diseases, suggesting PGRN as a potential therapeutic target and prognostic predictor for these disorders.

Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease

Parkinson’s disease is highly heterogeneous across disease symptoms, clinical manifestations and progression trajectories, hampering the identification of therapeutic targets. Despite knowledge gleaned from genetics analysis, dysregulated proteome mechanisms stemming from genetic aberrations remain underexplored. In this study, we develop a three-phase system-level proteogenomic analytical framework to characterize disease-associated proteins and dysregulated mechanisms. Proteogenomic analysis identified 577 proteins that enrich for Parkinson’s disease-related pathways, such as cytokine receptor interactions and lysosomal function. Converging lines of evidence identified nine proteins, including LGALS3, CSNK2A1, SMPD3, STX4, APOA2, PAFAH1B3, LDLR, HSPB1, BRK1, with potential roles in disease pathogenesis. This study leverages the largest population-scale proteomics dataset, the UK Biobank Pharma Proteomics Project, to characterize genetically-driven protein disturbances associated with Parkinson’s disease. Taken together, our work contributes to better understanding of genome-proteome dynamics in Parkinson’s disease and sets a paradigm to identify potential indirect mediators connected to GWAS signals for complex neurodegenerative disorders.