It is a challenge to precisely classify plasma proteomic profiles into their clinical status based solely on their patterns even though distinct patterns of plasma proteomic profiles are regarded as ...potential to be a biomarker because the profiles have large within-subject variances.
The present study proposes a rank-based weighted CBR classifier (RWCBR). We hypothesized that a CBR classifier is advantageous when individual patterns are specific and do not follow the general patterns like proteomic profiles, and robust feature weights can enhance the performance of the CBR classifier. To validate RWCBR, we conducted numerical experiments, which predict the clinical status of the 70 subjects using plasma proteomic profiles by comparing the performances to previous approaches.
According to the numerical experiment, SVM maintained the highest minimum values of Precision and Recall, but RWCBR showed highest average value in all information indices, and it maintained the smallest standard deviation in F-1 score and G-measure.
RWCBR approach showed potential as a robust classifier in predicting the clinical status of the subjects for plasma proteomic profiles.
Targeted cancer therapies offer great clinical promise, but treatment resistance is common, and basic research aimed at overcoming this challenge is limited by reduced genomic and biologic complexity ...in artificially induced rodent tumors compared with their human counterparts. Animal models that more faithfully recapitulate genotype-specific human pathology could improve the predictive value of these investigations. Here, a newly identified animal model for oncogenic BRAF-driven cancers is described. With 20,000 new cases in the United States each year, canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares significant histologic, biologic, and clinical phenotypes with human muscle invasive bladder cancer. In order to identify somatic drivers of canine InvTCC, the complete transcriptome for multiple tumors was determined by RNAseq. All tumors harbored a somatic mutation that is homologous to the human BRAF(V600E) mutation, and an identical mutation was present in 87% of 62 additional canine InvTCC tumors. The mutation was also detectable in the urine sediments of all dogs tested with mutation-positive tumors. Functional experiments suggest that, like human tumors, canine activating BRAF mutations potently stimulate the MAPK pathway. Cell lines with the mutation have elevated levels of phosphorylated MEK, compared with a line with wild-type BRAF. This effect can be diminished through application of the BRAF(V600E) inhibitor vemurafenib. These findings set the stage for canine InvTCC as a powerful system to evaluate BRAF-targeted therapies, as well as therapies designed to overcome resistance, which could enhance treatment of both human and canine cancers
This study demonstrates the activating BRAF mutation (V600E), which is found in multiple human cancers, is a driver of canine InvTCC, and highlights a urine-based test for quick diagnosis.
Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage ...with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes.
Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion.
This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.
Abstract Aim Dysfunction of circulating endothelial progenitor cells (EPCs) has been shown to affect the development of microvascular diseases in diabetes patients. The aim of this study was to ...elucidate the development and mechanical dysfunction of EPCs in type 2 diabetes (T2D). Methods The colony-forming capacity of EPCs and differentiation potential of bone marrow (BM) c-Kit(+)/Sca-I(+) lineage-negative mononuclear cells (KSL) were examined in T2D mice, db/db mice and KKAy mice, using EPC colony-forming assay (EPC-CFA). Results T2D mice had fewer BM stem/progenitor cells, and proliferation of KSL was lowest in the BM of db/db mice. In T2D mice, the frequency of large colony-forming units (CFUs) derived from BM-KSL was highly reduced, indicating dysfunction of differentiation into mature EPCs. Only a small number of BM-derived progenitors CD34(+) KSL cells, which contribute to the supply of EPCs for postnatal neovascularization, was also found. Furthermore, in terms of their plasticity to transdifferentiate into various cell types, BM-KSL exhibited a greater potential to differentiate into granulocyte macrophages (GMs) than into other cell types. Conclusion T2D affected EPC colony formation and differentiation of stem cells to mature EPCs or haematopoietic cells. These data suggest opposing regulatory mechanisms for differentiation into mature EPCs and GMs in T2D mice.
En coup de sabre (ECDS) and Parry‐Romberg syndrome (PRS) are variants of linear morphea on the head and neck that can be associated with neurologic manifestations. Intracranial abnormalities on ...computed tomography (CT) and magnetic resonance imaging (MRI) are present in a significant proportion of individuals with these conditions. We describe 32 children from our institution with ECDS or PRS; neuroimaging was performed in 21 cases. We also review 51 additional cases from the literature. Nineteen percent of the children at our institution with ECDS or PRS had intracranial abnormalities on MRI, half of whom were asymptomatic. Hyperintensities on T2‐weighted sequences were the most common finding, present in all children with intracranial abnormalities on MRI. Seizures (13%) and headaches (9%) were the most common neurologic symptom. Neurologic symptoms were not correlated with neuroimaging abnormalities, with two asymptomatic children having marked MRI findings and only two of nine symptomatic children having an abnormal MRI. Similarly the severity of the superficial disease did not predict neurologic involvement; a child with subtle skin involvement had striking MRI findings and seizures, whereas another with a bony defect had no brain parenchymal involvement. Neurologic symptoms and neuroimaging abnormalities are found in a surprisingly substantial percentage of children with ECDS and PRS. Early recognition of neurologic involvement is necessary because it affects treatment choices. Because clinical predictors of intracranial abnormalities are poor, strong consideration should be given to obtaining an MRI before treatment initiation to assist in management decisions and establish a baseline examination.
This study aimed to detect signals of adverse drug reactions (ADRs) associated with biological disease-modifying antirheumatic drugs (DMARDs) and targeted therapies in rheumatoid arthritis (RA) and ...ankylosing spondylitis (AS) patients. Utilizing the KOrean College of Rheumatology BIOlogics & Targeted Therapy Registry (KOBIO) data, we calculated relative risks, excluded previously reported drug-ADR pairs, and externally validated remaining pairs using US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and single centre's electronic health records (EHR) data. Analyzing data from 2279 RA and 1940 AS patients, we identified 35 significant drug-ADR pairs in RA and 26 in AS, previously unreported in drug labels. Among the novel drug-ADR pairs from KOBIO, 15 were also significant in the FAERS data. Additionally, 2 significant drug-laboratory abnormality pairs were found in RA using CDM MetaLAB analysis. Our findings contribute to the identification of 14 novel drug-ADR signals, expanding our understanding of potential adverse effects related to biological DMARDs and targeted therapies in RA and AS. These results emphasize the importance of ongoing pharmacovigilance for patient safety and optimal therapeutic interventions.
Background and purpose
Previous studies have revealed that the predictors of short‐ and long‐term stroke recurrence are different. We designed a comprehensive stroke recurrence (CSR) model, composed ...of demographic, clinical and radiological findings, to predict long‐term ischaemic stroke recurrences.
Methods
We retrospectively collected the derivation cohort from consecutive patients with first‐ever ischaemic stroke within 7 days of symptom onset. Univariate and multivariable Cox regression analysis were used to evaluate the association between 2‐year recurrence and demographic, clinical and neuroradiological factors. The CSR score was calculated by adding the integer value of independent predictors that was derived from the β‐coefficient in the multivariable analysis. To qualify the model, we analyzed the receiver operating characteristics curve. We assessed internal validation with bootstrap methods and assessed external validation with another independent cohort.
Results
A total of 958 patients were enrolled, and 63 patients had recurrent strokes during the follow‐up periods. The rate of stroke recurrence was 7.0% at 2 years. In the multivariable analysis, multiple stage lesions, isolated cortical lesions on diffusion‐weighted imaging, severe white matter hyperintensities, multiple lacunar infarctions and relevant arterial stenosis were independently associated with stroke recurrence. The CSR model showed good discrimination area under the curve (AUC), 0.81 (0.74–0.88), which was consistent with internal AUC, 0.75 (0.66–0.85) and external AUC, 0.80 (0.69–0.90) validation.
Conclusions
Abnormal neuroimaging findings, rather than cardiovascular risk factors, are predictive of long‐term ischaemic stroke recurrence. Causative mechanism of stroke and underlying hostile brain milieu seem to be associated with long‐term stroke recurrence.
This paper is concerned with the problem of stability analysis for neural networks with time-varying delays. By constructing a newly augmented Lyapunov functional and some novel techniques, ...delay-dependent criteria to guarantee the asymptotic stability of the concerned networks are derived in terms of linear matrix inequalities (LMIs). The improvement of feasible region of the proposed criteria comparing with the previous works is shown by two numerical examples.
Summary
The aim of this study was to evaluate the impact of insulin resistance on the persistence of a protective level of anti‐HBs (hepatitis B surface antigen) in a nondiabetic general population. ...A cohort study was designed comprising of 38 473 Korean men and women with anti‐HBs at concentrations ≥10 mIU/mL, who underwent a health examination. Insulin resistance was assessed with a homoeostasis model assessment of insulin resistance (HOMA‐IR). A decline in anti‐HBs to <10 mIU/L during the follow‐up was considered to be a loss of protective anti‐HBs. Cox‐proportional hazard models were used to estimate the adjusted hazard ratios and 95% confidence intervals for anti‐HBs loss across quintiles of HOMA‐IR and insulin. We identified 20 826 incidents of loss of anti‐HBs antibody during 180 522 person‐years of follow‐up (incident rate 11.5 per 100 person‐years). Increasing HOMA‐IR was positively associated with incident loss of anti‐HBs. The multivariable‐adjusted hazard ratios (95% confidence intervals) for incident loss of anti‐HBs comparing quintiles 2–5 vs quintile 1 of HOMA‐IR were 1.09 (1.04–1.14), 1.14 (1.09–1.19), 1.14 (1.09–1.19) and 1.21 (1.16–1.27), respectively. These associations were stronger in younger individuals under the age of 35 than in people 35 years of age or older (P for interaction = 0.004). The association was also more evident in subjects with higher titres (≥100 mIU/mL) of anti‐HBs than in those with low titres (P for interaction < 0.001). Insulin resistance was associated with an increased risk for loss of vaccine‐acquired anti‐HBs in a large sample of a nondiabetic, general population, indicating a possible role of insulin resistance in vaccine‐induced immunity.
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