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Alzheimers disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimers disease. Here, we investigate whether genetic risk for Alzheimers disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimers Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimers disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimers disease, in addition to opening therapeutic windows for targeted interventions.

Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75ECD. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimised through a full factorial design of experiments (DOE) and response surface methodology (RSM). P-VFD has great potential in quantifying p75ECD in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75ECD ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.

Theories of psychotic illness suggest that abnormal intrinsic functional connectivity may explain its characteristic positive and disorganization symptoms as well as lead to impaired general functioning. Here we used resting state functional magnetic resonance imaging (fMRI) to evaluate associations between these symptoms and the degree to which global connectivity is abnormal in early psychosis (EP). Eighty-six healthy controls (HCs) and 108 individuals with EP with resting state fMRI data were included in primary analyses. The EP group included 83 participants with schizophrenia-spectrum disorders and 25 with bipolar disorder type I with psychotic features. A global intrinsic connectivity "similarity index" for each EP individual was determined by calculating its correlation with the average HC connectivity matrix extracted using Schaefer atlases of multiple parcellations (100, 200, 300, and 400 region parcellations). As hypothesized, connectivity similarity with the average HC matrix was negatively associated with Brief Psychiatric Rating Scale total score, Scale for the Assessment of Positive Symptoms total score, and disorganization symptoms. Similarity was also positively associated with Global Assessment of Functioning score. Results were not driven by sex or diagnosis effects and were consistent across parcellation schemes. These results support the hypothesis that changes in whole-brain connectivity patterns are associated with psychosis symptoms and support the use of functional connectivity as a biomarker for these symptoms in EP.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimers disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P

Parkinsons disease (PD) is a prevalent neurodegenerative disorder with a poorly understood etiology. An accurate diagnosis of idiopathic PD remains challenging as misdiagnosis is common in routine clinical practice. Moreover, current therapeutics focus on symptomatic management rather than curing or slowing down disease progression. Therefore, identification of potential PD biomarkers and providing a better understanding of the underlying disease pathophysiology are urgent. Herein, hydrophilic interaction liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-TOF MS) based metabolomics approaches were used to profile the serum metabolome of 50 patients with different stages of idiopathic PD (early, mid and advanced) and 45 age-matched controls. Levels of 57 metabolites including cysteine-S-sulfate and N-acetyl tryptophan were significantly higher in patients with PD compared to controls, with lower amounts of additional 51 metabolites including vanillic acid, and N-acetylaspartic acid. Xanthines, including caffeine and its downstream metabolites, were lowered in patients with PD relative to controls indicating a potential role caffeine and its metabolites against neuronal damage. Seven metabolites, namely cysteine-S-sulfate, 1-methylxanthine, vanillic acid, N-acetylaspartic acid, 3-N-acetyl tryptophan, 5-methoxytryptophol, and 13-HODE yielded a ROC curve with a high classification accuracy (AUC 0.977). Comparison between different PD stages showed that cysteine-S-sulfate levels were significantly increasing with the advancement of PD stages while LPI 20:4 was significantly decreasing with disease progression. Our findings provide new biomarker candidates to assist in the diagnosis of PD and monitor its progression. Unusual metabolites like cysteine-S-sulfate might point to therapeutic targets that could enhance the development of novel PD treatments, such as NMDA antagonists.

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide-a classical histotoxic hypoxia agent-we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

The relationship between the early-age activity of Mediterranean fruit flies (medflies) or other fruit flies and their lifespan has not been much studied, in contrast to the connections between lifespan and diet, sexual signaling, and reproduction. The objective of this study is to assess intra-day and day-to-day activity profiles of female Mediterranean fruit flies and their role as biomarker of longevity as well as to explore the relationships between these activity profiles, diet, and age-at-death throughout the lifespan. We use advanced statistical methods from functional data analysis (FDA). Three distinct patterns of activity variations in early-age activity profiles can be distinguished. A low-caloric diet is associated with a delayed activity peak, while a high-caloric diet is linked with an earlier activity peak. We find that age-at-death of individual medflies is connected to their activity profiles in early life. An increased risk of mortality is associated with increased activity in early age, as well as with a higher contrast between daytime and nighttime activity. Conversely, medflies are more likely to have a longer lifespan when they are fed a medium-caloric diet and when their daily activity is more evenly distributed across the early-age span and between daytime and nighttime. The before-death activity profile of medflies displays two characteristic before-death patterns, where one pattern is characterized by slowly declining daily activity and the other by a sudden decline in activity that is followed by death.

Cancer early detection and treatment response prediction continue to pose significant challenges. Cancer liquid biopsies focusing on detecting circulating tumor cells (CTCs) and DNA (ctDNA) have shown enormous potential due to their non-invasive nature and the implications in precision cancer management. Recently, liquid biopsy has been further expanded to profile glycoproteins, which are the products of post-translational modifications of proteins and play key roles in both normal and pathological processes, including cancers. The advancements in chemical and mass spectrometry-based technologies and artificial intelligence-based platforms have enabled extensive studies of cancer and organ-specific changes in glycans and glycoproteins through glycomics and glycoproteomics. Glycoproteomic analysis has emerged as a promising tool for biomarker discovery and development in early detection of cancers and prediction of treatment efficacy including response to immunotherapies. These biomarkers could play a crucial role in aiding in early intervention and personalized therapy decisions. In this review, we summarize the significant advance in cancer glycoproteomic biomarker studies and the promise and challenges in integration into clinical practice to improve cancer patient care.

IntroductionEarly risk stratification for clinical dementia could lead to preventive therapies. We identified and validated a magnetic resonance imaging (MRI) signature for Alzheimer's disease (AD) and related dementias (ARDR).MethodsAn MRI ADRD signature was derived from cortical thickness maps in Framingham Heart Study (FHS) participants with AD dementia and matched controls. The signature was related to the risk of ADRD and cognitive function in FHS. Results were replicated in the University of California Davis Alzheimer's Disease Research Center (UCD-ADRC) cohort.ResultsParticipants in the bottom quartile of the signature had more than three times increased risk for ADRD compared to those in the upper three quartiles (P

INTRODUCTION: The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles. OBJECTIVES: Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time. METHODS: In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression. RESULTS: We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P

BACKGROUND: Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. METHODS: In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. RESULTS: At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). CONCLUSION: While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

INTRODUCTION: Stroke leads to motor deficits, requiring rehabilitation therapy that targets mechanisms underlying movement generation. Cortical activity during the planning and execution of motor tasks can be studied using EEG, particularly via the Event Related Desynchronization (ERD). ERD is altered by stroke in a manner that varies with extent of motor deficits. Despite this consensus in the literature, defining precisely the temporality of these alterations during movement preparation and performance may be helpful to better understand motor system pathophysiology and might also inform development of novel therapies that benefit from temporal resolution. METHODS: Patients with chronic hemiparetic post-stroke (n = 27; age 59 ± 14 years) and age-matched healthy right-handed control subjects (n = 23; 59 ± 12 years) were included. They performed a shoulder rotation task following the onset of a stimulus. Cortical activity was recorded using a 256-electrode EEG cap. ERD was calculated in the beta frequency band (15-30 Hz) in ipsilesional sensorimotor cortex, contralateral to movement. The ERD was compared over time between stroke and control subjects using permutation tests. The correlation between upper extremity motor deficits (assessed by the Fugl-Meyer scale) and ERD over time was studied in stroke patients using Spearman and permutation tests. RESULTS: Patients with stroke showed on average less beta ERD amplitude than control subjects in the time window of -350 to 50 ms relative to movement onset (t(46) = 2.8, p = 0.007, Cohens d = 0.31, 95% CI [0.22: 1.40]). Beta-ERD values correlated negatively with the Fugl-Meyer score during the time window -200 to 400 ms relative to movement onset (Spearmans r = -0.54, p = 0.003, 95% CI [-0.77 to -0.18]). DISCUSSION: Our results provide new insights into the precise temporal changes of ERD after hemiparetic stroke and the associations they have with motor deficits. After stroke, the average amplitude of cortical activity is reduced as compared to age-matched controls, and the extent of this decrease is correlated with the severity of motor deficits; both were true during motor programming and during motor performance. Understanding how stroke affects the temporal dynamics of cortical preparation and execution of movement paves the way for more precise restorative therapies. Studying the temporal dynamics of the EEG also strengthens the promising interest of ERD as a biomarker of post-stroke motor function.

Attention plays an important role in not only the awareness and perception of tinnitus but also its interactions with external sounds. Recent evidence suggests that attention is heightened in the tinnitus brain, likely as a result of relatively local cortical changes specific to deafferentation sites or global changes that help maintain normal cognitive capabilities in individuals with hearing loss. However, most electrophysiological studies have used passive listening paradigms to probe the tinnitus brain and produced mixed results in terms of finding a distinctive biomarker for tinnitus. Here, we designed a selective attention task, in which human adults attended to one of two interleaved tonal (500 Hz and 5 kHz) sequences. In total, 16 tinnitus (5 females) and 13 age- and hearing-matched control (8 females) subjects participated in the study, with the tinnitus subjects matching the tinnitus pitch to 5.4 kHz (range = 1.9-10.8 kHz). Cortical responses were recorded in both passive and attentive listening conditions, producing no differences in P1, N1, and P2 between the tinnitus and control subjects under any conditions. However, a different pattern of results emerged when the difference was examined between the attended and unattended responses. This attention-modulated cortical response was significantly greater in the tinnitus than control subjects: 3.9-times greater for N1 at 5 kHz (95% CI: 2.9 to 5.0, p = 0.007, ηp2 = 0.24) and 3.0 for P2 at 500 Hz (95% CI: 1.9 to 4.5, p = 0.026, ηp2 = 0.17). We interpreted the greater N1 modulation as local neural changes specific to the tinnitus frequency and the greater P2 as global changes to hearing loss. These two cortical measures were used to differentiate between the tinnitus and control subjects, producing 83.3% sensitivity and 76.9% specificity (AUC = 0.81, p = 0.006). These results suggest that the tinnitus brain is more plastic than that of the matched non-tinnitus controls and that the attention-modulated cortical response can be developed as a clinically meaningful biomarker for tinnitus.

Friedreichs ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreichs ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreichs ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreichs ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreichs ataxia patients with tissue samples from affected areas in Friedreichs ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreichs ataxia patients, carriers and controls and 192 tissue data sets from Friedreichs ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreichs ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreichs ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreichs ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1s downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreichs ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreichs ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreichs ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreichs ataxia monitoring and therapeutic development, meriting additional research.

Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth.

Breast cancer (BC) remains among the most commonly diagnosed cancers in women worldwide. Triple-negative BC (TNBC) is a subset of BC characterized by aggressive behavior, a high risk of distant recurrence, and poor overall survival rates. Chemotherapy is the backbone for treatment in patients with TNBC, but outcomes remain poor compared to other BC subtypes, in part due to the lack of recognized functional targets. In this study, the expression of the tetraspan protein epithelial membrane protein 2 (EMP2) was explored as a predictor of TNBC response to standard chemotherapy. We demonstrate that EMP2 functions as a prognostic biomarker for patients treated with taxane-based chemotherapy, with high expression at both transcriptomic and protein levels following treatment correlating with poor overall survival. Moreover, we show that targeting EMP2 in combination with docetaxel reduces tumor load in syngeneic and xenograft models of TNBC. These results provide support for the prognostic and therapeutic potential of this tetraspan protein, suggesting that anti-EMP2 therapy may be beneficial for the treatment of select chemotherapy-resistant TNBC tumors.

Autophagy is a form of programmed cell degradation that enables the maintenance of homeostasis in response to extracellular stress stimuli. Autophagy is primarily activated by starvation and mediates the degradation, removal, or recycling of cell cytoplasm, organelles, and intracellular components in eukaryotic cells. Autophagy is also involved in the pathogenesis of human diseases, including several cancers. Human uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis; at present there are no effective therapies. Several studies have suggested that autophagy is important in UM. By understanding the mechanisms of activation of autophagy in UM it may be possible to develop biomarkers to provide more definitive disease prognoses and to identify potential drug targets for the development of new therapeutic strategies. This article reviews the current information regarding autophagy in UM that could facilitate biomarker and drug development.

BACKGROUND: Research has shown that fatty acid metabolism genes are closely related to the development of rheumatoid arthritis. Therefore, exploring the progression of rheumatoid arthritis based on fatty acid metabolism genes is of clinical significance. OBJECTIVE: To investigate whether fatty acid metabolism genes can serve as reliable biomarkers for predicting the progression of rheumatoid arthritis. METHODS: Gene data related to synovial tissue were downloaded from the Gene Expression Comprehensive Database (GEO). STRING was used to construct the protein-protein interaction network analysis. Cytoscape was utilized for biological annotation (gene ontology) and signaling pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes). Fatty acid metabolism related genes were screened from the molecular feature database (MSigDB). Least absolute shrinkage and selection operator and support vector machine recursive feature elimination feature were used to screen for potential biomarkers. Immune cell infiltration levels in normal individuals and rheumatoid arthritis patients were assessed using the CIBERSORT algorithm. Finally, the expression levels of fatty acid metabolism related genes were verified using the receiver operating characteristic curve in GSE77298. RESULTS AND CONCLUSION: 361 differentially expressed genes in rheumatoid arthritis were identified, of which 13 overlapped with the reported fatty acid metabolism related genes. Based on machine learning algorithms, five genes were selected, and the receiver operating characteristic curve showed that five genes (PCK1, PDK1, PTGS2, PLA2G2D, and DPEP2) could predict the development of rheumatoid arthritis. The CIBERSORT algorithm results showed that five genes were associated with activated mast cells, neutrophils, resting mast cells, and memory resting CD4+ T cells. The receiver operating characteristic curve showed that PLA2G2D and PCK1 have high diagnostic value. To conclude, the expression characteristics of fatty acid metabolism related genes can serve as potential biomarkers for predicting clinical outcomes, which can further improve the accuracy of prediction in RA patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Traumatic spinal cord injury primarily relies on scale assessment and imaging examinations in clinical practice. However, there are limitations in predicting the prognosis of the injury. Therefore, the use of metabolomics technology for biomarker screening is significant for estimating the extent of damage, injury and recovery, as well as developing new therapies. OBJECTIVE: To characterize the metabolic features of patients with traumatic spinal cord injury using metabolomics technology and explore potential biomarkers and disrupted metabolic pathways. METHODS: Serum and urine samples were collected from 20 patients with traumatic spinal cord injury (observation group) and 10 healthy subjects (control group). Metabolites were analyzed and multivariate statistical analysis was then performed for data processing to screen differential metabolites. Metabolic pathway enrichment was performed using Metabo Analyst software. Logistic regression was applied to construct a biomarker combination model, and its relationship with the American Spinal Injury Association grading was analyzed. RESULTS AND CONCLUSION: Significant differences in 160 and 73 metabolites were detected in the serum and urine samples of the two groups, respectively. Pathway enrichment analysis showed evident disturbances in lipid metabolism after traumatic spinal cord injury, including sphingolipid, arachidonic acid, α-linolenic acid, and arachidonic acid metabolism, as well as glycerophospholipid and inositol phosphate biosynthesis. The combination of two identified biomarkers, telmisartan and quercetin glycoside, showed a correlation with the American Spinal Injury Association grading in both serum and urine levels. Thus, metabolomics technology provides assistance in further understanding the pathological mechanisms of traumatic spinal cord injury and screening therapeutic targets. The identified metabolic biomarker combination may serve as a reference for assessing the severity of traumatic spinal cord injury. [ABSTRACT FROM AUTHOR]

Preventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. Leveraging large-scale genome-wide association studies, we conducted Mendelian randomization analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study on Aging cohort (N = 8299). We repeated Mendelian randomization analyses based on the UK Biobank, INTERVAL, and EPIC (European Prospective Investigation into Cancer)–Norfolk studies. After validating Mendelian randomization assumptions and colocalization evidence, we found that a 1 SD increase in genetically predicted circulating abundances of eicosapentaenoate and docosapentaenoate was associated with odds ratios of 0.72 (95% CI, 0.65–0.79) and 0.63 (95% CI, 0.55–0.72), respectively, for bipolar disorder. Genetically increased Ω -3 unsaturated fatty acids abundance and Ω -3-to-total fatty acids ratio, as well as genetically decreased Ω -6-to- Ω -3 ratio, were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of 3 N -acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum odds ratio of 1.31 (95% CI, 1.18–1.44) per 1 SD increase. Furthermore, a 1 SD increase in genetically predicted circulating abundance of hypotaurine was associated with an odds ratio of 0.85 (95% CI, 0.78–0.93) for depression. The biological mechanisms that underlie Ω -3 unsaturated fatty acids, NAT8-catalyzed N -acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. We analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aβ PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aβ accumulation, and thickness, accounting for age and APOE ε4 allele variations. The cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aβ deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. The study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment. • We explored the association between human glymphatic function, cMD, cortical Aβ deposition, and cortical thickness. • Significant associations were identified between glymphatic function and cMD in AD-susceptible brain regions. • Associations among DTI-ALPS, aging, and cortical thickness were noted. • We suggested the potential of DTI-ALPS as a biomarker of glymphatic function in PTSD. • Moreover, changes in DTI-ALPS occur in PTSD, possibly due to glymphatic system impairment. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). Methods: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1β, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. Results: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1β and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1β: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). Conclusions: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). Methods: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0–17, Intermediate: 18–30, High: 31–100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). Results: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04–0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06–0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. Conclusion: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required. [ABSTRACT FROM AUTHOR]

Gut dysbiosis has been implicated in the pathogenesis of hepatocellular carcinoma (HCC) arising from diverse etiological factors. Microbe-associated molecular patterns (MAMPs), microbial metabolites, and fungi are capable of modulating the metabolic pathways and immune composition of the HCC microenvironment. The gut microbiome holds potential as a novel tool for early diagnosis and evaluation of the outcome response, especially to immune checkpoint inhibitors (ICIs). Targeted manipulation of the gut microbiome through diets, antibiotics, probiotics, fecal microbiota transplantation (FMT), and nano-delivery systems may augment therapeutic efficacy in the management of HCC. The gut microbiome can play a crucial role in hepatocellular carcinoma (HCC) progression through the enterohepatic circulation, primarily acting via metabolic reprogramming and alterations in the hepatic immune microenvironment triggered by microbe-associated molecular patterns (MAMPs), metabolites, and fungi. In addition, the gut microbiome shows potential as a biomarker for early HCC diagnosis and for assessing the efficacy of immunotherapy in unresectable HCC. This review examines how gut microbiota dysbiosis, with varied functional profiles, contributes to HCCs of different etiologies. We discuss therapeutic strategies to modulate the gut microbiome including diets, antibiotics, probiotics, fecal microbiota transplantation, and nano-delivery systems, and underscore their potential as an adjunctive treatment modality for HCC. [ABSTRACT FROM AUTHOR]

Leptomeningeal melanoma metastases (LMM) are associated with poor survival. Diagnosis is based on clinical presentation, brain MRI and cerebrospinal fluid (CSF) analysis. Inconclusive findings at initial presentation can delay treatment. In this single‐center case series, detection of BRAFV600‐ and NRASQ61‐mutant cell‐free tumor DNA (cfDNA) in CSF was evaluated as a complementary diagnostic biomarker. In 12 patients with clinical suspicion of LMM, a retrospective analysis of MRI, CSF cytology and cfDNA analysis on 1 mL of CSF using the Idylla® platform was carried out. Nine patients displayed MRI abnormalities suggesting LMM. CSF analysis identified malignant cells in three patients (including one without MRI abnormalities). BRAFV600‐ or NRASQ61‐mutant cfDNA was detected in CSF of nine patients (eight with and one without MRI abnormalities; all patients with positive CSF cytology). Subsequent follow‐up confirmed LMM in all patients with positive and in one patient with a negative CSF cfDNA analysis (sensitivity 81.8%; specificity 100%). Our findings suggest that analyzing BRAFV600‐ and NRASQ61‐mutant cfDNA in CSF using the Idylla® platform holds promise as a sensitive and specific complementary diagnostic biomarker for LMM, particularly in case of inconsistency between imaging and CSF cytology. The 110‐min analysis can facilitate urgent treatment decisions. [ABSTRACT FROM AUTHOR]

Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant metastases is limited to a year, yet‐to‐be‐defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision‐making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox‐Lasso regression machine learning, adapted to a high‐dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis‐free interval) at first diagnosis of metastatic disease as predictors for time‐to‐treatment failure and overall survival. Taken together, the risk stratification models, built by our machine‐learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases. [ABSTRACT FROM AUTHOR]

Chronic lung allograft dysfunction (CLAD) limits survival following lung transplant, but substantial lung damage occurs before diagnosis by traditional methods. We hypothesized that small airway gene expression patterns could identify CLAD risk before spirometric diagnosis and predict subsequent graft failure. Candidate genes from 4 rejection-associated transcript sets were assessed for associations with CLAD or graft failure in a derivation cohort of 156 small airway brushes from 45 CLAD cases and 37 time-matched controls with >1-year stable lung function. Candidate genes not associated with CLAD and time to graft failure were excluded, yielding the Airway Inflammation 2 (AI2) gene set. Area under the receiver operating curve (AUC) for CLAD and competing risks of death or graft failure were assessed in an independent validation cohort of 37 CLAD cases and 37 controls. Thirty-two candidate genes were associated with CLAD and graft failure, comprising the AI2 score, which clustered into 3 subcomponents. The AI2 score identified CLAD before its onset, in early and late post-CLAD brushes, as well as in the validation cohort (AUC 0.69-0.88). The AI2 score association with CLAD was independent of positive microbiology, CLAD stage, or CLAD subtype. However, transcripts most associated with CLAD evolved over time from CLAD onset. The AI2 score predicted time to graft failure and retransplant-free survival in both cohorts (p ≤ 0.03). This airway inflammation gene score is associated with CLAD development, graft failure, and death. Future studies defining the molecular heterogeneity of airway inflammation could lead to endotype-targeted therapies. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented. We performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively). At baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity. Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations. Limitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD. [ABSTRACT FROM AUTHOR]

Introduction: Serum heat shock protein (HSP) concentrations have been reported as potential biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigate the role of serum HSP70, HSP90, and DNAJC7 as biomarkers for ALS. Methods: Serum samples were collected from ALS patients and volunteer controls from three different clinical cohorts (in Germany, Ireland, and Italy). Serum HSP concentrations were determined using enzyme-linked immunosorbent assay. Descriptive statistics, generalized logistic regression, and Cox proportional hazards models were used to model associations between log serum HSP concentrations and ALS risk. Results: In total, 251 ALS patients and 184 healthy volunteers were included. Logistic regression models failed to find associations between ALS risk and log serum concentration of HSP70 (OR 0.43, 95% CI: 0.10–1.78, p = 0.242), HSP90 (OR 0.95, 95% CI: 0.39–2.37, p = 0.904), or DNAJC7 (OR 1.55, 95% CI: 0.90–2.68, p = 0.118). Survival of ALS patients was not associated with log serum concentration of HSP HSP70 (HR1.06, 95% CI: 0.36–3.14, p = 0.916), HSP90 (HR 1.17, 95% CI: 0.67–2.02, p = 0.584), or DNAJC7 (HR 0.83, 95% CI: 0.57–1.21, p = 0.337). Discussion: We did not replicate previous findings that serum HSP70 and HSP90 concentrations were associated with risk of ALS. DNAJC7 was not associated with ALS risk, and there were no obvious longitudinal patterns in log serum concentrations of HSP70, HSP90, or DNAJC7. In addition, serum HSP concentrations were not associated with ALS survival. [ABSTRACT FROM AUTHOR]

For an effective control of tuberculosis (TB), there is a persistent need for biomarkers that can report true estimates of TB infection (TBI) and predict its progression towards active TB disease. We investigated whether the cell‐mediated immune responses to Mycobacterium tuberculosis (Mtb) antigens could provide such biomarkers. The study subjects (n = 174) comprised a cohort of smear‐positive, drug‐sensitive, HIV‐negative pulmonary TB patients (n = 54) and their household contacts (HC, n = 120). Whole blood cultures, in the presence or absence of Mtb antigens‐ membrane (MtM), purified protein derivative (PPD) and alpha‐crystallin (Acr), or the mitogen PHA were subjected to determinations, by flow cytometry, for T cell proliferative and, by ELISA, for IFN‐γ, TNF‐α, and IL‐6 cytokine responses. Additionally, serum levels of the three cytokines were also estimated. The strongest cell‐proliferative and cytokine responses were induced by MtM and IL‐6 was the most abundantly produced cytokine. While none of the responses induced by Mtb antigens or the serum cytokines levels could discriminate between TB and HC, the ex vivo cytokine responses induced by PHA or 'spontaneously' could apparently do so. The concentrations of IFN‐γ induced by PHA in TB blood cultures were significantly lower than in HC cultures (AUC = 0.72). Conversely, the spontaneous IFN‐γ or TNF‐α secretions in TB cultures were significantly higher than in HC cultures (AUC = 0.66). Our results suggest that IL‐6 responses to MtM could be a sensitive indicator of TBI, and low levels of PHA‐induced or high levels of spontaneous IFN‐γ secretions in HC blood cultures may indicate a progressive infection. [ABSTRACT FROM AUTHOR]

Background: Amyloid-targeting therapies for Alzheimer's disease (AD) might become available in Germany soon. The combination of a large pool of prevalent cases and a complex diagnostic process to determine eligibility for these treatments is likely to challenge health systems' capacity. Objective: To analyze Germany's healthcare system capacity to identify treatment-eligible patients in a timely and equitable manner. Methods: We modeled patients' diagnostic journey and projects wait times due to capacity constraints for AD specialist visits and PET scans from 2024 to 2043. Model parameters were derived from published data and expert input. Results: Wait times would be ∼50 months over the model horizon, if patients were referred to specialists based on a brief cognitive assessment in primary care. Wait times for patients with social health insurance are projected to be 1.9 times those of patients with private insurance, with peak wait times of around 76 and 40 months, respectively. Adding a blood test for the AD pathology as additional triage step would reduce wait times to below 24 months. Conclusions: In spite of having a well-resourced health system, Germany is projected to be unable to cope with the demand for biomarker-based AD diagnosis, if a disease-modifying AD treatment were introduced. As these treatments might become available by the end of 2024, decisive action, in particular dissemination of high-performing AD blood tests for triage in primary care, will be needed to prevent delays in access and potentially avoidable and inequitable disease progression. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between interleukin‐8 (IL‐8) levels in gingival crevicular fluid (GCF) and total oral fluid (TOF) and the responsiveness to steps 1 and 2 of periodontal therapy. Materials and Methods: One‐hundred and fifty‐nine patients affected by periodontitis received steps 1 and 2 of periodontal therapy. At baseline, TOF and GCF samples were collected and analysed for IL‐8 (Il‐8TOF/IL‐8GCF) using flow cytometry. Therapy outcomes were relative proportions of residual periodontal pockets (PPD%), pocket closure (PC) rates and pocket probing depth (PPD) reductions; these were associated with IL‐8TOF/IL‐8GCF. Results: High IL‐8TOF was significantly associated with higher residual PPD% (p = 0.044) and lower PPD reduction compared to low IL‐8TOF (high 0.79 ± 1.20 mm vs. low 1.20 ± 1.20 mm, p < 0.001) in non‐smokers, while in smokers high IL‐8GCF was related to lower PPD reduction (high 0.62 ± 1.22 mm vs. low 0.84 ± 1.12 mm, p = 0.009). Furthermore, high baseline IL‐8TOF was significantly associated with poorer PC rates compared to medium and low concentrations in both non‐smokers (high 41% vs. medium 55% vs. low 58%, p < 0.001) and smokers (high 34% vs. medium 44% vs. low 46%, p < 0.001). Conclusion: High IL‐8 concentrations at baseline had a significant impact on residual PPD%, PC rates and PPD reduction. The findings suggest that, especially in non‐smokers, baseline IL‐8 levels collected from the TOF could serve as a component in the estimation of responsiveness to steps 1 and 2 of periodontal therapy. [ABSTRACT FROM AUTHOR]

Objective: Emerging evidence suggests that the endometrial microbiome plays important roles in the development of endometrial cancer (EC). Here, we evaluate stage‐specific roles of microbial dysbiosis and metabolic disorders in patients with EC, patients with endometrial hyperplasia (EH), and patients afflicted with benign uterine conditions (CK). Methods: This prospective cohort study included 33 women with EC, 15 women with endometrial EH, and 15 women with benign uterine conditions (CK) from November 2022 to September 2023. Different typical endometrial samples were imaged with a scanning electron microscope and a transmission electron microscope. The endometrial microbiome was assessed by sequencing the V3–V4 region of the 16S rRNA gene and the ITS1 to fill the gap in relation to the study of the uterine fungal microbiome. Moreover, liquid chromatography‐mass spectrometry‐based metabolomics was used to identify and quantify metabolic changes among these groups. Results: The endometrial microbiome revealed that there is a structural microbiome shift and an increase in the α‐diversity in the EC and EH cases, distinguishable from the benign cases, especially the fungal community structure. The fungal microbiome from patients with EC and EH was altered relative to controls and dominated by Penicillium sp. By contrast, Sarocladium was more abundant in controls. Significant differences were observed in the composition and content of compounds between benign cases and EC, especially estradiol‐like metabolism‐related substances. Altered microbiota was correlated with the concentrations of interleukin‐6 (IL‐6), IL‐11, transforming growth factor‐beta, and β‐glucuronidase activity especially the relative abundance increase of Penicillium sp. Conclusions: This study suggested that the endometrial microbiome is complicit in modulating the development of EC such as estrogen activity and a pro‐inflammatory response. Our work provides a new insight into the endometrial microbiome from a perspective of stages, which opens up new avenues for EC prognosis and therapy. Synopsis: This study suggested that the endometrial microbiome is complicit in modulating the development of endometrial cancer. [ABSTRACT FROM AUTHOR]

The clinical landscape for endometrial cancer in the UK is evolving to include new management guidelines and targeted treatment options. An understanding of current treatment and management practices in the UK will help services plan and adapt to upcoming changes. The purpose of this survey was to understand current and anticipated real-world practices for endometrial cancer care in the UK and potential areas for optimisation. Telephone interviews were conducted in November/December 2021 with UK-based healthcare professionals involved in endometrial cancer management. Questions were aligned with the British Gynaecological Cancer Society/European Society for Medical Oncology recommendations, covering the pathway from diagnosis and treatment to follow-up. A total of 63 healthcare professionals (HCPs) involved in the management of patients with endometrial cancer participated in telephone interviews. The results highlighted variations in management and treatment practices for endometrial cancer and suggest that current UK practice appears to diverge from national and international guidance in some instances. While somatic mismatch repair deficiency testing was used by 89.7% of respondents as mainstream testing, the survey highlighted a lack of access to other key molecular biomarker tests, such as polymerase epsilon (POLE) sequencing (used by only 9.8% of HCPs at the time of the survey). The results highlighted several perceived practical barriers to the swift adoption of new therapeutic options, including funding access, limited staff, treatment-related resources, staff education, and support. Our findings support the need for better access to biomarkers that could enable more effective and targeted treatments. • This survey describes the recent UK treatment landscape for endometrial cancer. • Respondents reported a wide degree in variation in practice across the UK. • There is a lack of access to certain molecular biomarker tests e.g., POLE tests. • Practical barriers may prevent swift adoption of new therapeutic options. • Areas for optimisation include additional education on immunotherapy treatment. [ABSTRACT FROM AUTHOR]

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β‐glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1‐associated PD (GBA1‐PD) is a current challenge. We previously demonstrated that α‐synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross‐sectional study investigates an unexplored cohort of GBA1‐PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α‐synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1‐PD from HC with sensitivity = 88.9% (95% CI 70.84–97.65), specificity = 88.5% (95% CI 69.85–97.55), and PPV = 88.9% (95% CI 73.24–95.90), AUC value = 0.927 (95% CI 0.859–0.996). No difference was found between GBA1‐PD patients and iPD, suggesting a common pathological pathway based on α‐synuclein oligomers. GCase score did not differ in GBA1‐PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1‐PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1‐PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749–0.961) with sensitivity = 85.2% (95% CI 66.27%–95.81%), specificity = 77.1% (95% CI 59.86%–89.58%), and PPV = 74.19% (60.53%–84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1‐PD from iPD and to their potential to stratify and monitor patients in the context of new pathway‐specific therapeutic options. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) is the most prevalent internal RNA modification in mammals. However, limited research has been conducted on the role of m6A in coronary artery disease (CAD). We conducted methylated RNA immunoprecipitation sequencing and RNA sequencing to obtain a genome‐wide profile of m6A‐modified long noncoding RNAs (lncRNAs) in human coronary artery smooth muscle cells either exposed to oxidized low‐density lipoprotein treatment or not, and the characteristics of the expression profiles were explored using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The predictive effects of seven selected lncRNAs on CAD were evaluated in peripheral blood mononuclear cells (PBMCs). The differentially m6A‐modified and expressed lncRNAs related genes were predominantly enriched in small GTPase‐mediated signal transduction, ErbB signaling, and Rap1 signaling. Additionally, the expression levels of uc003pes.1, ENST00000422847, and NR_110155 were significantly associated with CAD, with uc003pes.1 identified as an independent risk factor and NR_110155 as an independent protective factor for CAD. NR_110155 and uc003pes.1 in PBMCs have the potential to serve as biomarkers for predicting CAD. [ABSTRACT FROM AUTHOR]

The development of microRNA (miRNA)-based biomarkers has gained significant attention due to their potential diagnostic, prognostic and therapeutic applications. However, the reproducibility of miRNA biomarker research faces unique challenges, primarily due to the influence of pre-analytical and analytical factors. The absence of standardized procedures contributes to inconsistencies across studies, alongside challenges in reference gene selection, data analysis methods and miRNA profiling platforms. Inter-laboratory comparison trials, or ring trials, offer a strategic approach to address technical and biological variability in miRNA biomarker studies. These trials promote standardization, identify sources of variability and strengthen the correlation between miRNAs and clinical outcomes. Despite their underutilization in miRNA biomarker research, ring trials represent a valuable tool for enhancing reproducibility and expediting the translation of miRNA-based biomarkers into clinical applications. [ABSTRACT FROM AUTHOR]

Objective: The timely identification of both malignant and nonmalignant pancreatic lesions has the potential to significantly enhance prognosis and implement risk management strategies across various levels. microRNAs (miRs) and their corresponding targets play a crucial role in the development of pancreatic lesions and can serve as valuable diagnostic and therapeutic targets. The objective of our study was to investigate potential diagnostic markers that can effectively differentiate between malignant and nonmalignant pancreatic lesions. Methods: Gene Expression Omnibus (GEO) database with GSE24279 dataset was utilized to screen differentially expressed miRNAs (DEMs). We utilized the TargetScanHuman database to predict the target genes associated with hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p. Furthermore, a cohort comprising healthy individuals (n = 52), chronic pancreatitis (CP; n = 34), and pancreatic adenocarcinoma (PAAD; n = 53) patients was recruited to ascertain the levels of plasma markers. Results: We identified 3 miRNAs (hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p) and 2 proteins (PCDH1 and AMN) as potential diagnostic markers for distinguishing between CP and PAAD. The area under the curve (AUC) values for all markers exceeded .800. Notably, a combination of plasma PCDH1 and AMN demonstrated excellent diagnostic performance (AUC = .921; 95% CI: .866-.977; sensitivity = .792; specificity = .941) in discriminating between CP and PAAD. In addition, the model of hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p yielded an AUC of .928, sensitivity of .830, and specificity of .912, respectively. Conclusion: Plasma levels of miRNAs (hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p) and their corresponding targets (PCDH1 and AMN) hold promise as potential biomarkers for predicting PAAD in patients with CP. [ABSTRACT FROM AUTHOR]

Introduction/Aims: One of the most distinct clinical features of facioscapulohumeral muscular dystrophy (FSHD) is facial weakness. It leads to diminished facial expression and functional impairments. Despite its clinical relevance, little else is known about orofacial muscle involvement. We therefore evaluated orofacial muscle involvement in a sizeable cohort of FSHD participants with muscle ultrasound. Methods: Muscle ultrasound images of the following orofacial muscles were scored visually and quantitatively: depressor anguli oris (DAO), orbicularis oris (OO), buccinator, temporalis, masseter, digastric, zygomaticus major and minor bilaterally, and the geniohyoid. Reliability analyses of both visual and quantitative evaluations were performed. Ultrasound results were correlated with other measures: the FSHD clinical score, facial weakness score, and facial function scale. Results: We included 107 FSHD participants (male 54%; age 52 ± 14 years), of whom 92% showed signs of facial weakness. The reliability of visual ultrasound analysis varied widely (κ 0.0–1.0). Quantitative ultrasound reliability was high (intraclass correlation analysis ≥ 0.96). The DAO, buccinator, OO, temporalis, and zygomaticus minor muscles were affected most often (15%–39%). The digastric, geniohyoid, zygomaticus major, and masseter muscles were least often affected (<5%). The ultrasound compound score correlated weakly to moderately with other outcome measures used (ρ = 0.3–0.7). Discussion: This study adds to the understanding of orofacial weakness in FSHD, confirming the involvement of the muscles of facial expression in FSHD using ultrasound. We showed that orofacial muscle ultrasound is feasible and reliable when quantitatively assessed. Future studies should evaluate orofacial muscle ultrasound longitudinally, alongside clinical and patient‐reported facial weakness outcome measures, to assess their potential as outcome measures. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Somatosensory evoked potentials (SSEPs) are described as a supportive tool to diagnose chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); however, there is a lack of studies determining the effectiveness of SSEPs in monitoring the clinical course of individuals with this condition. The aims of this study are to evaluate the utility of SSEPs in monitoring patients with CIDP and to assess their association with clinical outcomes following immunomodulatory therapy. Methods: This was a single‐center retrospective observational study that included patients who met European Federation of Neurological Societies and Peripheral Nerve Society criteria for CIDP between 2018 and 2023. SSEPs were performed at diagnosis and during follow‐up after the start of immunomodulatory treatment. Fisher's exact test was employed to assess the association between clinical improvement and SSEP improvement. Results: Eighteen patients were included in the study. Ten patients had a typical CIDP pattern and 11 were male. In 17, SSEPs were abnormal prior to the start of immunomodulatory treatment. In patients who showed clinical improvement with immunomodulatory therapy, we observed that 15/17 had partial or complete improvement in SSEPs. Patients who showed no clinical improvement with first‐line treatment exhibited worsening SSEPs. There was a significant association between clinical and SSEPs improvement (p = 0.009). Discussion: We observed a positive association between improvement in SSEPs and clinical improvement in patients with CIDP. Our data suggest that SSEPs may be useful for monitoring the clinical course of patients with CIDP, but additional, larger studies are needed. [ABSTRACT FROM AUTHOR]

Identifying biomarkers that predict substance use disorder propensity may better strategize antiaddiction treatment. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus critically mediate interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. Surface EEG signals and real-time calcium (Ca2+) activities of lateral hypothalamus MCH neurons (Ca2+ MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+ MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+ MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. An EEG waveform derivative—a modified theta-delta-theta peak ratio (EEG TDT ratio)—accurately tracked real-time Ca2+ MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through vigilance states, sleep manipulations, and circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG TDT ratio, suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG TDT ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG TDT ratio also exhibited advantages over conventional REMS measures for the predictions. The identified EEG TDT ratio may serve as a noninvasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker for predicting drug use propensity. [ABSTRACT FROM AUTHOR]

Background: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge. Methods: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed. Results: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17. Conclusion: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy. [ABSTRACT FROM AUTHOR]

Background: The understanding of neuropathic pain remains incomplete, highlighting the need for research on biomarkers for improved diagnosis and treatment. This review focuses on identifying potential biomarkers in blood and cerebrospinal fluid for neuropathic pain in different neuropathies. Methods: Searches were performed in six databases: PubMed, Web of Science, Scopus, Cochrane Library, EMBASE, and CINAHL. Included were observational studies, namely cross-sectional, cohort, and case-control, that evaluated quantitative biomarkers in blood or cerebrospinal fluid. Data were qualitatively synthesized, and meta-analyses were conducted using R. The study is registered with PROSPERO under the ID CRD42022323769. Results: The literature search resulted in 16 studies for qualitative and 12 for quantitative analysis, covering patients over 18 years of age with painful neuropathies. A total of 1403 subjects were analyzed, identifying no significant differences in levels of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) between patients with and without pain. Despite the high inter-rater reliability and adequate bias assessment, the results suggest negligible differences in inflammatory biomarkers, with noted publication bias and heterogeneity among studies, indicating the need for further research. Conclusions: Our review underscores the complex nature of neuropathic pain and the challenges in identifying biomarkers, with no significant differences found in CRP, IL-6, and TNF-alpha levels between patients with and without pain. Despite methodological robustness, the results are limited by publication bias and heterogeneity. This emphasizes the need for further research to discover definitive biomarkers for improved diagnosis and personalized treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Heterogeneous nuclear ribonucleoprotein D (HNRNPD) can regulate expression of key proteins in various cancers. However, the prognostic predictive value and biology function of HNRNPD in non-small cell lung cancer (NSCLC) is unknown. First, we used the TCGA and GEO datasets to determine that HNRNPD predicts the prognosis of NSCLC patients. Following that, we knocked down HNRNPD in NSCLC cell lines in vitro and validated its biological function using CCK-8, transwell assays, wound healing tests, and Western blotting. Finally, we constructed tissue microarrays (TMAs) from 174 NSCLC patients and verified our findings using immunohistochemistry staining for HNRNPD from public databases. In both the public datasets, NSCLC tissues with elevated HNRNPD expression had shorter overall survival (OS). In addition, HNRNPD knockdown NSCLC cell lines showed significantly reduced proliferation, invasion, and metastatic capacity via the PI3K-AKT pathway. Finally, elevated HNRNPD expression in NSCLC TMAs was linked to a poorer prognosis and decreased PD-L1 expression levels. HNRNPD is associated with a poorer prognosis in NSCLC and affects tumor growth and metastasis via the PI3K-AKT pathway. [ABSTRACT FROM AUTHOR]

The identification of biomarkers for the early diagnosis of nonalcoholic fatty liver disease (NAFLD) is urgently needed. Here, we aimed to identify NAFLD biomarkers in the early stages of steatosis (SS) and nonalcoholic steatohepatitis (NASH) based on differential gene expression from bioinformatics data. A meta-analysis was performed from transcriptomic databases retrieved from public repositories containing data from biopsies of patients at various stages of NAFLD development. The status of the selected molecules was validated in the serum of patients with NAFLD by ELISA. : We identified 121 differentially expressed genes (DEGs) associated with SS and 402 associated with NASH. Gene Ontology (GO) enrichment revealed that the altered genes were primarily associated with dysfunction of primary cellular processes, and pathway analyses were mainly related to cholesterol metabolism. We identified ACSS2, PCSK9, and CYP7A1 as candidate biomarkers for SS and ANGPTL3, CD36, CYP51A1, FASN, FAS, FDFT1, and LSS as candidate biomarkers for NASH. By experimental validation of bioinformatics data from patients with NAFLD, we identified promising biomarkers for detecting SS and NASH that might be useful for screening and diagnosing early NAFLD stages in humans. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is a major cause of mortality in patients with chronic kidney disease (CKD), and diagnosis is challenging. Moreover, no specific biomarker for HFpEF has been validated in patients with CKD. The present study aimed to investigate the association between serum osteoprotegerin (OPG) levels and the risk of left ventricular diastolic dysfunction (LVDD), a surrogate of HFpEF, in patients with pre-dialysis CKD. Methods: A total of 2039 patients with CKD at stage 1 to pre-dialysis 5 were categorized into quartiles (Q1 to Q4) by serum OPG levels, and were cross-sectionally analyzed. The study outcome was LVDD, which was operationally defined as the ratio of early transmitral blood flow velocity to early diastolic velocity of the mitral annulus (E/e') > 14. Results: In the analysis of baseline characteristics, higher serum OPG levels were clearly related to the risk factors of HFpEF. A scatter plot analysis revealed a moderate correlation between serum OPG levels and E/e' (R = 0.351, P < 0.001). Logistic regression analysis demonstrated that the risk of LVDD in Q3 (adjusted odds ratio 2.576, 95% confidence interval 1.279 to 5.188) and Q4 (adjusted odds ratio 3.536, 95% confidence interval 1.657 to 7.544) was significantly higher than that in Q1. Conclusions: Elevated serum OPG levels are associated with the risk of LVDD in patients with pre-dialysis CKD. The measurement of serum OPG levels may help the diagnosis of LVDD, which is an important echocardiographic feature of HFpEF. [ABSTRACT FROM AUTHOR]

Objective: This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. Methods: We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response's relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. Results: The median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative ("first-in-indication") with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA's special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs' HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a 'high-value' ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062). Conclusions: Over the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life. [ABSTRACT FROM AUTHOR]

Introduction: The basophil activation test (BAT) has shown evidence of high sensitivity and high specificity to support the diagnosis of IgE-mediated allergy. It is a functional test that uses live cells analyzed by flow cytometry and thus needs to be performed within 24h of blood collection. BAT has shown to be reproducible and reliable when tested in a clinical diagnostic laboratory with standardized protocols and flow cytometry settings. Areas covered: In this review, we summarize the evidence to support clinical use of BAT and the next steps required for clinical implementation for an improve clinical care for patients with suspected IgE-mediated food allergy. Expert opinion: BAT has recently been included in Clinical Guidelines of Food Allergy Diagnosis and its implementation in clinical practice depends largely on availability. Proposed clinical applications of the BAT include: distinction between food allergy and asymptomatic IgE sensitization; determination of food allergic status to peanut, tree nuts and seeds in polysensitized children; evaluation of tolerance to baked egg and baked milk in egg and milk allergic children; identification of patients at high-risk of severe allergic reactions; monitoring for spontaneous resolution of food allergy; confirmation of eligibility for specific treatments of food allergy; prediction and monitoring of response to immunomodulatory treatments. [ABSTRACT FROM AUTHOR]