Potential Clinical Significance Research Articles

PLEKHA4 is a novel prognostic biomarker that reshapes the tumor microenvironment in lower-grade glioma.

Lower-grade glioma (LGG) is a primary intracranial tumor that carry a high risk of malignant transformation and limited therapeutic options. Emerging evidence indicates that the tumor microenvironment (TME) is a superior predictor for tumor progression and therapy response. PLEKHA4 has been demonstrated to be a biomarker for LGG that correlate with immune infiltration. However, the fundamental mechanism by which PLEKHA4 contributes to LGG is still poorly understood. Multiple bioinformatic tools, including Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA2), Shiny Methylation Analysis Resource Tool (SMART), etc., were incorporated to analyze the PLEKHA4. ESTIMATE, ssGSEA, CIBERSORT, TIDE and CellMiner algorithms were employed to determine the association of PLEKHA4 with TME, immunotherapy response and drug sensitivities. Immunohistochemistry (IHC)-based tissue microarrays and M2 macrophage infiltration assay were conducted to verify their associations. PLEKHA4 expression was found to be dramatically upregulated and strongly associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in LGG patients, as well as their poor clinicopathological characteristics. Cox regression analysis identified that PLEKHA4 was an independent prognostic factor. Methylation analysis revealed that DNA methylation correlates with PLEKHA4 expression and indicates a better outcome in LGG. Moreover, PLEKHA4 was remarkably correlated with immune responses and TME remodeling, as evidenced by its positive correlation with particular immune marker subsets and the putative infiltration of immune cells. Surprisingly, the proportion of M2 macrophages in TME was strikingly higher than others, inferring that PLEKHA4 may regulate the infiltration and polarization of M2 macrophages. Evidence provided by IHC-based tissue microarrays and M2 macrophage infiltration assay further validated our findings. Moreover, PLEKHA4 expression was found to be significantly correlated with chemokines, interleukins, and their receptors, further supporting the critical role of PLEKHA4 in reshaping the TME. Additionally, we found that PLEKHA4 expression was closely associated with drug sensitivities and immunotherapy responses, indicating that PLEKHA4 expression also had potential clinical significance in guiding immunotherapy and chemotherapy in LGG. PLEKHA4 plays a pivotal role in reshaping the TME of LGG patients, and may serve as a potential predictor for LGG prognosis and therapy.

What is the clinical significance of 'heteroresistance' in non-fermenting Gram-negative strains?

The aim of this study was to discuss the potential clinical significance of heteroresistance in non-fermenting Gram-negative bacilli (GNB). Recently, heteroresistance has been considered potentially responsible for clinical failure in Acinetobacter baumannii infections. This raised a scientific debate, still open, about the potential clinical significance of heteroresistance in non-fermenting GNB. We reviewed the literature of last 20 years and found a limited number of studies evaluating the relationship between heteroresistance and clinical outcome in non-fermenting GNB. Unlike Gram-positive bacteria, heteroresistance is reported in a significant proportion of non-fermenting GNB with some studies describing it in all tested strains and for several antibiotics (including tigecycline, carbapenems, levofloxacin, cefiderocol, colistin). One important issue is the need for validated detection method since the population analysis profile test, that is considered the gold standard, requires high costs and time. Studies evaluating the correlation between heteroresistance and clinical outcome are contrasting and have several limitations. Although in-vitro detection of heteroresistance in non-fermenting GNB has not been associated with in-vivo treatment failure, its presence may suggest to prefer combination regimens instead monotherapy when treating infections by nonfermenters. Further studies are needed to clarify the clinical significance of heteroresistance.

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

Development of a predictive nomogram for acute respiratory distress syndrome in patients with acute pancreatitis complicated with acute kidney injury

Background Acute respiratory distress syndrome (ARDS) is a common complication in patients with acute pancreatitis (AP), especially when patients complicated with acute kidney injury (AKI), resulting in increased duration of hospitalization and mortality. It is of potential clinical significance to develop a predictive model to identify the the high-risk patients. Method AP patients complicated with AKI from January 2019 to March 2022 were enrolled in this study and randomly divided into training cohort and validation cohort at a ratio of 2:1. The Least absolute shrinkage and selection operator(LASSO) regression and machine learning algorithms were applied to select features. A nomogram was developed based on the multivariate logistic regression. The performance of the nomogram was evaluated by AUC, calibration curves, and decision curve analysis. Results A total of 292 patients were enrolled in the study, with 206 in the training cohort and 86 in the validation cohort. Multivariate logistic analysis showed that IAP (Odds Ratio (OR)=4.60, 95%CI:1.23-18.24, p = 0.02), shock (OR = 12.99, 95%CI:3.47-64.04, p < 0.001), CRP(OR= 26.19, 95%CI:9.37-85.57, p < 0.001), LDH (OR = 13.13, 95%CI:4.76-40.42, p < 0.001) were independent predictors of ARDS. The nomogram was developed based on IAP, shock, CRP and LDH. The nomogram showed good discriminative ability with an AUC value of 0.954 and 0.995 in the training and validation cohort, respectively. The calibration curve indicating good concordance between the predicted and observed values. The DCA showed favorable net clinical benefit. Conclusion This study developed a simple model for predicting ARDS in AP patients complicated with AKI. The nomogram can help clinicians identify high-risk patients and optimize therapeutic strategies.

A Paratope-Enhanced Method to Determine Breadth and Depth TCR Clonal Metrics of the Private Human T-Cell Vaccine Response after SARS-CoV-2 Vaccination.

Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context.

Pharmacological activation of the Nrf2 pathway by Taxifolin remodels articular cartilage microenvironment for the therapy of Osteoarthritis.

Osteoarthritis (OA) is a widely prevalent degenerative disease marked by extracellular matrix (ECM) degradation, inflammation, and apoptosis. Taxifolin (TAX) is a natural antioxidant possessing various pharmacological benefits, such as combating inflammation, oxidative stress, apoptosis, and serves as a potential chemopreventive agent by regulating genes through an antioxidant response element (ARE)-dependent mechanism. Currently, no studies have investigated the therapeutic impact and precise mechanism of TAX on OA. The aim of this study is to examine the potential role and mechanism of TAX in reshaping the cartilage microenvironment, thereby offering a stronger theoretical foundation for pharmacologically activating the Nrf2 pathway to manage OA. The pharmacological effects of TAX were examined in chondrocytes through in vitro studies and in a destabilization of the medial meniscus (DMM) rat model for in vivo analysis. TAX suppresses IL-1β triggered secretion of inflammatory agents, chondrocyte apoptosis, and ECM degradation, contributing to the remodeling of the cartilage microenvironment. In vivo experiment results demonstrated that TAX counteracted cartilage degeneration induced by DMM in rats. Mechanistic investigations revealed that TAX hinders OA development by reducing NF-κB activation and ROS production through the activation of the Nrf2/HO-1 axis. TAX reshapes the articular cartilage microenvironment by suppressing inflammation, mitigating apoptosis, and decreasing ECM degradation through the activation of the Nrf2 pathway. As a result, pharmacological activation of the Nrf2 pathway by TAX holds potential clinical significance in remodeling the joint microenvironment for OA treatment.

Potential Candidate Genes for Therapeutic Targeting in Chronic Myeloid Leukemia: A Pilot Study.

Chronic myeloid leukemia (CML) is a prevalent hematological malignancy known for the presence of the Philadelphia chromosome and activation of the BCR-Abl kinase activity. Although tyrosine kinase inhibitors are widely used as the standard treatment, resistance remains a concern among certain patients. This study aimed to investigate the gene expression profile of a group of CML patients in comparison to a control group in order to identify novel candidate genes associated with the disease. Whole transcriptome sequencing was performed, and gene expression levels were validated using quantitative real-time PCR. Additionally, single nucleotide and insertion/deletion variants were analyzed in the selected candidate genes among 10 CML patients and 4 healthy control subjects. Analysis revealed a set of differentially expressed genes, whose up- or downregulation was further confirmed by qRT-PCR. Among the upregulated genes in the patient group were ribosomal protein like (RPL) members, specifically RPL9, RPL34, RPL36A, and RPL39, while downregulation was observed in CCDC170, LDB1, and SBF1 compared to the healthy subjects. Furthermore, gene variant studies identified novel genetic changes in these candidate genes, suggesting potential clinical significance in CML. This study highlights RPL9, RPL34, RPL36A, RPL39, CCDC170, LDB1, and SBF1 as potential targets in CML. Additionally, it underscores the importance of investigating these genes and their variants in larger cohort studies to assess their clinical significance in CML patients.

Human factors in the clinical implementation of deep learning-based automated contouring of pelvic organs at risk for MRI-guided radiotherapy.

Deep neural nets have revolutionized the science of auto-segmentation and present great promise for treatment planning automation. However, little data exists regarding clinical implementation and human factors. We evaluated the performance and clinical implementation of a novel deep learning-based auto-contouring workflow for 0.35T magnetic resonance imaging (MRI)-guided pelvic radiotherapy, focusing on automation bias and objective measures of workflow savings. An auto-contouring model was developed using a UNet-derived architecture for the femoral heads, bladder, and rectum in 0.35T MR images. Training data was taken from 75 patients treated with MRI-guided radiotherapy at our institution. The model was tested against 20 retrospective cases outside the training set, and subsequently was clinically implemented. Usability was evaluated on the first 30 clinical cases by computing Dice coefficient (DSC), Hausdorff distance (HD), and the fraction of slices that were used un-modified by planners. Final contours were retrospectively reviewed by an experienced planner and clinical significance of deviations was graded as negligible, low, moderate, and high probability of leading to actionable dosimetric variations. In order to assess whether the use of auto-contouring led to final contours more or less in agreement with an objective standard, 10 pre-treatment and 10 post-treatment blinded cases were re-contoured from scratch by three expert planners to get expert consensus contours (EC). EC was compared to clinically used (CU) contours using DSC. Student's t-test and Levene's statistic were used to test statistical significance of differences in mean and standard deviation, respectively. Finally, the dosimetric significance of the contour differences were assessed by comparing the difference in bladder and rectum maximum point doses between EC and CU before and after the introduction of automation. Median (interquartile range) DSC for the retrospective test data were 0.92(0.02), 0.92(0.06), 0.93(0.06), 0.87(0.04) for the post-processed contours for the right and left femoral heads, bladder, and rectum, respectively. Post-implementation median DSC were 1.0(0.0), 1.0(0.0), 0.98(0.04), and 0.98(0.06), respectively. For each organ, 96.2, 95.4, 59.5, and 68.21 percent of slices were used unmodified by the planner. DSC between EC and pre-implementation CU contours were 0.91(0.05*), 0.91*(0.05*), 0.95(0.04), and 0.88(0.04) for right and left femoral heads, bladder, and rectum, respectively. The corresponding DSC for post-implementation CU contours were 0.93(0.02*), 0.93*(0.01*), 0.96(0.01), and 0.85(0.02) (asterisks indicate statistically significant difference). In a retrospective review of contours used for planning, a total of four deviating slices in two patients were graded as low potential clinical significance. No deviations were graded as moderate or high. Mean differences between EC and CU rectum max-doses were 0.1±2.6Gy and -0.9±2.5Gy for pre- and post-implementation, respectively. Mean differences between EC and CU bladder/bladder wall max-doses were -0.9±4.1Gy and 0.0±0.6Gy for pre- and post-implementation, respectively. These differences were not statistically significant according to Student's t-test. We have presented an analysis of the clinical implementation of a novel auto-contouring workflow. Substantial workflow savings were obtained. The introduction of auto-contouring into the clinical workflow changed the contouring behavior of planners. Automation bias was observed, but it had little deleterious effect on treatment planning.

Morphological analysis of C2-C7 spinous process bifurcation in Chinese population: a study using three-dimensional reconstruction of computed tomography.

This study aimed to investigate the anatomical morphology of the C2 to C7 spinous process (SP) bifurcation (SPB) in the Chinese population and reveal its potential clinical significance. Measurement parameters of the three-dimensional (3D) reconstructions of neck computed tomography scans (n = 92 scans) were retrospectively analysed. The 3D reconstruction and measurements were performed using Mimics Research 19.0 and 3-Matic Research 11.0. Two independent investigators reviewed all the data, including parameters such as the length and angle of the SPB. The effects of age and sex were also analysed. We identified four morphological types of SPB: fully bifid (n = 252, 45.65%), partially bifid (n = 65, 11.78%), non-bifid (n = 226, 40.94%) and unilateral branch (n = 9, 1.63%). The Kappa coefficients indicated good inter-observer reproducibility (0.776), and the intraclass correlation coefficients (ICC) values demonstrated excellent intra-rater reliability (ICC = 0.9, p < 0.0001) in the classification and measurement of SPB parameters. The percentage of general bifid SP was more than 70% in C2-5 and about 21% in C6, while all C7 SPs presented non-bifid. Morphology was symmetrical in bifid and partially bifid SP, while unilateral SP was not. The classification system of SPB in this study proved consistent and reliable, despite the subjective bias. Identifying the cervical level by C6 bifurcation is unreliable, as nearly 80% of C6 SP is non-bifid. Our work provides an accurate and effective anatomical reference for SPB studies in the Chinese population.

Low mindfulness is related to poor sleep quality from middle adolescents to emerging adults: a process model involving resilience and emotional dysfunction

ObjectivesTransitions from middle adolescence into merging adulthood, a life stage between age 15–25, has a high prevalence of sleep problems. Mindfulness is a trait defined as being attentive to the present moment which positively relates to sleep quality. In this study, we aimed to investigate how resilience and emotional dysfunction may influence the relationship between trait mindfulness and sleep quality.MethodsThe Five Facet Mindfulness Questionnaire, Connor-Davidson Resilience Scale, Pittsburgh Sleep Quality Index and Depression Anxiety Stress Scales were used to measure the key variables through an online survey of 497 participants between middle adolescence and emerging adults (317 females, mean age 18.27 ± 0.76 years). A process model was built to investigate the mediating roles of resilience and emotional dysfunction in the impact of trait mindfulness on sleep quality, together with the relationships between their specific components.ResultsWe found a positive association between mindfulness and sleep quality through resilience and through emotional dysfunction, and through the sequential pathway from resilience to emotional dysfunction. Of note, acting with awareness (mindfulness facet) showed significant indirect effects on sleep quality, mediated by resilience and emotional dysfunction.ConclusionsOur findings may unveil the underlying mechanisms of how low mindfulness induces poor sleep quality. The findings indicate that conceiving mindfulness as a multifaceted construct facilitates comprehension of its components, relationships with other variables, and underscores its potential clinical significance given its critical implications for mental health.

Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer's disease.

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme found in the mitochondrial matrix that plays a central role in alcohol and aldehyde metabolism. A common ALDH2 polymorphism in East Asians descent (called ALDH2*2 or E504K missense variant, SNP ID: rs671), present in approximately 8% of the world's population, has been associated with a variety of diseases. Recent meta-analyses support the relationship between this ALDH2 polymorphism and Alzheimer's disease (AD). And AD-like pathology observed in ALDH2-/- null mice and ALDH2*2 overexpressing transgenic mice indicate that ALDH2 deficiency plays an important role in the pathogenesis of AD. Recently, the worldwide increase in alcohol consumption has drawn attention to the relationship between heavy alcohol consumption and AD. Of potential clinical significance, chronic administration of alcohol in ALDH2*2/*2 knock-in mice exacerbates the pathogenesis of AD-like symptoms. Therefore, ALDH2 polymorphism and alcohol consumption likely play an important role in the onset and progression of AD. Here, we review the data on the relationship between ALDH2 polymorphism, alcohol, and AD, and summarize what is currently known about the role of the common ALDH2 inactivating mutation, ALDH2*2, and alcohol in the onset and progression of AD.

TMEM44 as a Novel Prognostic Marker for Kidney Renal Clear Cell Carcinoma is Associated with Tumor Invasion, Migration and Immune Infiltration

Transmembrane (TMEM) proteins are integral membrane proteins that traverse biological membranes. Several members of the TMEM family have been linked to the development and progression of various tumors. However, the specific role and mechanism of TMEM44 in tumor biology remain largely unexplored. In this study, we initially conducted an extensive analysis using the TCGA database to investigate the expression patterns and survival associations of TMEM44 across various human tumors. Subsequently, we focused on KIRC and found a significant correlation between TMEM44 expression and this particular cancer type. To validate our findings, we performed western blot and quantitative polymerase chain reaction (qPCR) assays to confirm the expression levels of TMEM44 in KIRC. Following this, we employed a series of functional assays, including CCK8 viability assay, EDU incorporation assay, wound healing assay, and transwell migration assay, to investigate the biological role of TMEM44 in KIRC. We observed a significant upregulation of TMEM44 expression in KIRC, indicating its potential involvement in the pathogenesis of this cancer. We intervened in the expression of TMEM44 in KIRC cells and found significant inhibitory effects on cell proliferation, migration, and invasion in KIRC cells. Furthermore, our findings indicated that TMEM44 could serve as an independent prognostic factor in KIRC, highlighting its potential clinical significance. Consequently, TMEM44 holds promise as both a prognostic biomarker and a prospective therapeutic target for KIRC.

Association between glyphosate exposure and cognitive function, depression, and neurological diseases in a representative sample of US adults: NHANES 2013–2014 analysis

Glyphosate, the most widely used herbicide globally, has been linked to neurological impairments in some occupational studies. However, the potential neurotoxic effects of glyphosate exposure in the general population are still not fully understood. We conducted analyses on existing data collected from 1532 adults of the 2013–2014 National Health and Nutrition Examination Survey (NHANES) to explore the possible relationship between glyphosate exposure and cognitive function, depressive symptoms, disability, and neurological medical conditions. Our results showed a significant negative association between urinary glyphosate levels and the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD-WLT) trial 3 recall and delayed recall scores in both models, with ß coefficients of −0.288 (S.E. = 0.111, P = 0.021) and −0.426 (S.E. = 0.148, P = 0.011), respectively. Furthermore, the odds ratio did not show a significant increase with the severity of depressive symptoms with a one-unit increase in ln-glyphosate levels. However, the odds ratio for severe depressive symptoms was significantly higher than for no symptoms (odds ratio = 4.148 (95% CI = 1.009–17.133), P = 0.049). Notably, the odds ratio showed a significant increase for individuals with serious hearing difficulty (odds ratio = 1.354 (95% CI = 1.018–1.800), P = 0.039) with a one-unit increase in ln-glyphosate levels, but not for other neurological medical conditions. In conclusion, our findings provide the first evidence that glyphosate exposure may be associated with neurological health outcomes in the US adult population. Additional investigation is necessary to understand the potential mechanisms and clinical significance of these correlations.

Effect of impaction on third molar development and age estimation—A study in a Lebanese population

The effect of impaction on third molar development is disputable as the scientific literature is not uniform. In parallel, population-specific studies have been encouraged in dental age estimation. This study aimed to investigate the effect of impaction on third molar formation in a sample of Lebanese individuals. The sample consisted of 518 panoramic radiographs of females (n=229) and males (n=289) between 15 and 23.9 years. Mandibular third molars were classified based on their position as non-impacted and impacted (with horizontal, vertical, mesioangular, and distoangular impaction). Dental development was classified according to Demirjian's 8-level staging system. Most teeth presented mesioangular impaction (#38=29.7%, #48=33%). Developing third molars were predominantly distributed between stages D and G. The mean age of most developmental stages was higher among impacted teeth, meaning that third molar mineralization could be slower in the presence of impaction. In general, the delayed dental development did not have statistically significant effects (P<0.05). However, descriptive data pointed out differences between (impacted and non-impacted) mean ages of >12 months-suggesting a potential clinical significance (despite the lack of a statistical one). Furthermore, differences changed based on sex and side (#38/#48). Therefore, dental age estimation from third molars in the selected Lebanese population should preferably be performed in non-impacted third molars whenever available.

Effects of wrist posture and stabilization on precision grip force production and muscle activation patterns.

Most of the power for generating forces in the fingers arises from muscles located in the forearm. This configuration maximizes finger joint range of motion while minimizing finger mass and inertia. The resulting multiarticular arrangement of the tendons, however, complicates independent control of the wrist and the digits. Actuating the wrist impacts sensorimotor control of the fingers and vice versa. The goal of this study was to systematically investigate interactions between isometric wrist and digit control. Specifically, we examined how the need to maintain a specified wrist posture influences precision grip. Fifteen healthy adults produced maximum precision grip force at 11 different wrist flexion/extension angles, with the arm supported, under two conditions: 1) the participant maintained the desired wrist angle while performing the precision grip and 2) a robot maintained the specified wrist angle. Wrist flexion/extension posture significantly impacted maximum precision grip force (P < 0.001), with the greatest grip force achieved when the wrist was extended 30° from neutral. External wrist stabilization by the robot led to a 20% increase in precision grip force across wrist postures. Increased force was accompanied by increased muscle activation but with an activation pattern similar to the one used when the participant had to stabilize their wrist. Thus, simultaneous wrist and finger requirements impacted performance of an isometric finger task. External wrist stabilization can promote increased precision grip force resulting from increased muscle activation. These findings have potential clinical significance for individuals with neurologically driven finger weakness, such as stroke survivors.NEW & NOTEWORTHY We explored the interdependence between wrist and fingers by assessing the influence of wrist posture and external stabilization on precision grip force generation. We found that maximum precision grip force occurred at an extended wrist posture and was 20% greater when the wrist was Externally Stabilized. The latter resulted from amplification of muscle activation patterns from the Self-Stabilized condition rather than adoption of new patterns exploiting external wrist stabilization.

Integrated Analysis Identifies Upregulated SAMD9L as a Potential Biomarker Correlating with the Severity of Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease with lymphocytic infiltration of the salivary and lachrymal glands, whose present disease-specific objective indicators are few and have shortcomings that should be addressed. An integrated analysis of sequencing data from different cohorts has the potential to unveil novel biomarkers in pSS. We identified 3 GEO datasets, including gene expression data from minor salivary gland (MSG) biopsy samples of 49 patients with pSS and 31 non-pSS and whole blood cells of 30 pSS patients and 30 healthy controls (HCs). Differentially expressed genes (DEGs) involved in pSS were identified from these datasets. Function Enrichment Analyses of common upregulated DEGs and PPI (protein-protein interaction) networks were performed. Furthermore, we have carried out further analysis of these DEGs to explore their potential clinical significance and diagnostic efficacy as a biomarker for pSS. Sterile Alpha Motif Domain Containing 9 Like (SAMD9L), one of the DEGs, has been identified as a promising candidate biomarker that correlates with the severity of pSS. This has been validated by analyzing local clinical samples from 30 pSS and non-pSS patients' MSG biopsies, as well as serum samples of 18 pSS and HC individuals. Finally, we performed correlation analysis to understand the relationship between SAMD9L and infiltrated immune cells. We identified 10 common highly expressed DEGs in pSS of different tissues. These genes were mainly involved in virus infection-related pathways and inferno-related pathways. GEO data and our clinical data showed that SAMD9L increases with disease severity. Public and local cohorts showed that SAMD9L has high diagnostic performance (AUC=0.845-0.867) as a biomarker, and its AUC was comparable to the Focus score when combined with RF or SSA. Up-regulated SAMD9L may serve as a promising novel pSS diagnostic biomarker and have potential value for evaluating the severity of pSS.

Differential Expression Profiles of Plasma Exosomal microRNAs in Rheumatoid Arthritis.

Differential expression maps of microRNAs (miRNAs) are connected to the autoimmune diseases. This study sought to elucidate the expression maps of exosomal miRNA in plasma of rheumatoid arthritis (RA) patients and their potential clinical significance. In the screening phase, small RNA sequencing was performed to characterize dysregulated exosome-derived miRNAs in the plasma samples from six patients with RA and six healthy patients. At the independent verification stage, the candidate plasma exosomal miRNAs were verified in 40 patients with RA and 32 healthy patients by using qRT-PCR. The correlation of miRNA levels and clinical characteristics was tested in patients with RA. The value of these miRNAs in diagnosing RA was assessed with the receiver operating characteristic curve. During the screening phase, 177 and 129 miRNAs were increased and decreased in RA patients and healthy controls, respectively. There were 10 candidate plasma exosomal miRNAs selected for the next identification. Compared with the healthy controls, eight plasma exosomal miRNAs (let-7a-5p, let-7b-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-128-3p, and miR-25-3p) were significantly elevated in RA patients, but miR-144-3p and miR-15a-5p expression exhibited no significant changes. The let-7a-5p and miR-25-3p levels were linked to the rheumatoid factor-positive phenotype in RA patients. For the eight miRNAs, the area under the subject work characteristic curve (AUC) is 0.641 to 0.843, and their combination had a high diagnostic accuracy for RA (AUC = 0.916). Our study illustrates that novel exosomal miRNAs in the plasma may represent potential noninvasive biomarkers for RA.

Comprehensive Analysis of SLC35A2 in Pan-Cancer and Validation of Its Role in Breast Cancer.

Elucidation of the oncogenic role of SLC35A2 in human tumors and the potential function and clinical significance in breast cancer. Pan-cancer analysis was performed via various bioinformatics tools to explain the pathogenic role of SLC35A2. A prognostic nomogram was also developed based on the SLC35A2 expression and clinicopathological characteristics in breast cancer patients. In addition, the role of SLC35A2 was validated in breast cancer by in vivo and in vitro experiments. SLC35A2 expression is increased in 27 tumor types, and its high expression is substantially correlated with poor prognosis in patients with a variety of cancers. Receiver operating characteristic (ROC) curves showed that SLC35A2 expression levels could accurately distinguish most tumor tissues from normal tissues. High SLC35A2 expression was linked to increased immune infiltration in myeloid-derived suppressor cells (MDSC), as well as immune checkpoints, ferroptosis-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI). SLC35A2 may be involved in tumorigenesis by regulating the glycosylation process. Furthermore, multivariate Cox analysis showed that SLC35A2 was an independent prognostic factor for breast cancer. And the nomogram model had good predictive accuracy for the prognosis of breast cancer patients. Meanwhile, cellular experiments demonstrated that knockdown of SLC35A2 could significantly inhibit the proliferation, migration and invasion of breast cancer cells, while increasing the protein level of E-cadherin and decreasing N-cadherin. A nude mouse xenograft model showed that inhibition of SLA35A2 expression could significantly inhibit tumor growth. SLC35A2 has good diagnostic and prognostic values in multiple cancers and is closely related to tumor immune infiltration. In addition, SLA35A2 as an oncogene in breast cancer may be involved in the progression of epithelial mesenchymal transition (EMT).

Incidental scan findings in cardiac amyloid scintigraphy

When interpreting amyloid scintigraphy the nuclear cardiology physician should be aware of incidental image findings that may interfere with scan interpretation and may be of potential clinical significance. As for other nuclear cardiac imaging it is important to inspect the entire field of view of the planar and SPECT images. Correlation with the patient’s history and physical examination is crucial in interpretation of these incidental findings.

Characterizing Foveal Hypoplasia Using Optical Coherence Tomography Angiography: Evaluation of Microvascular Abnormalities and Clinical Significance.

This study aimed to evaluate foveal avascular zone (FAZ) features and macular flow density (FD) in various retinal layers in a cohort of patients with foveal hypoplasia (FH) using optical coherence tomography angiography (OCTA), in order to characterize microvascular abnormalities and explore their potential clinical significance. FAZ parameters and FD, as well as retinal thickness and volume values were analyzed and compared between patients with FH and an age- and gender-matched control cohort. Correlations between disease severity and visual acuity (VA), as well as between disease severity and FAZ features were evaluated. A total of 19 eyes with FH and 19 control eyes were included. The study group showed significantly higher FD values in the foveal sectors of the superficial and deep capillary plexus compared to controls. FAZ area, perimeter, and acircularity index (ACI) were noticeably altered in eyes with FH; however, they did not correlate with disease severity. Visual acuity was negatively correlated with disease severity. The results of this study provide evidence of altered microvasculature architecture specifically in the foveal sectors of patients with FH. The higher FD values in the foveal sectors of FH patients suggest a potential compensatory response of the retinal microvasculature. FAZ parameters and FD values of the foveal sectors could be used as part of an OCTA-based grading system in FH patients.