Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma.
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ABSTRACT:
SUBMITTER: Dobre EG
PROVIDER: S-EPMC8467841 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials.
| S-EPMC5997834 | biostudies-other
Project description:Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.
| S-EPMC9325258 | biostudies-literature
Project description:Personalized cancer vaccines (PCVs) are receiving attention as an avenue for cancer immunotherapy. PCVs employ immunogenic peptide epitopes capable of stimulating the immune system to destroy cancer cells with great specificity. Challenges associated with effective delivery of these peptides include poor solubility of hydrophobic sequences, rapid clearance, and poor immunogenicity, among others. The incorporation of peptides into nanoparticles has the potential to overcome these challenges, but the broad range of functionalities found in amino acids presents a challenge to conjugation due to possible interferences and lack of reaction specificity. Herein, a facile and versatile approach to generating nanosized PCVs under mild nonstringent conditions is reported. Following a simple two-step semibatch synthetic approach, amphiphilic hyperbranched polymer-peptide conjugates were prepared by the conjugation of melanoma antigen peptides, either TRP2 (hydrophobic) or MUT30 (hydrophilic), to an alkyne functionalized core via strain-promoted azide-alkyne click chemistry. Self-assembly of the amphiphiles gave spherical nanovaccines (by transmission electron microscopy) with sizes in the range of 10-30 nm (by dynamic light scattering). Fluorescently labeled nanovaccines were prepared to investigate the cellular uptake by antigen presenting cells (dendritic cells), and uptake was confirmed by flow cytometry and microscopy. The TRP2 nanovaccine was taken up the most followed by MUT30 nanoparticles and, finally, nanoparticles without peptide. The nanovaccines showed good biocompatibility against B16-F10 cells, yet the TRP2 peptide showed signs of toxicity, possibly due to its hydrophobicity. A test for immunogenicity revealed that the nanovaccines were poorly immunogenic, implying the need for an adjuvant when administered in vivo. Treatment of mice with melanoma tumors showed that in combination with adjuvant, CpG, groups with the peptide nanovaccines slowed tumor growth and improved survival (up to 24 days, TRP2) compared to the untreated group (14 days).
| S-EPMC5687982 | biostudies-literature
Project description:Protein kinases are mutated or otherwise rendered constitutively active in numerous cancers where they are attractive therapeutic targets with well over a dozen kinase inhibitors now being used in therapy. While fluorescent sensors have capacity to measure changes in kinase activity, surprisingly they have not been utilized for biomarker studies. A first-generation peptide sensor for ERK based on the Sox fluorophore is described. This sensor called ERK-sensor-D1 possesses high activity toward ERK and more than 10-fold discrimination over other MAPKs. The sensor can rapidly quantify ERK activity in cell lysates and monitor ERK pathway engagement by BRAF and MEK inhibitors in cultured melanoma cell lines. The dynamic range of the sensor assay allows ERK activities that have potential for profound clinical consequences to be rapidly distinguished.
| S-EPMC4291693 | biostudies-literature
Project description:BackgroundStroke is a worldwide cause of disability; 40% of stroke survivors sustain cognitive impairments, most of them following inpatient rehabilitation at specialized clinical centers. Web-based cognitive rehabilitation tasks are extensively used in clinical settings. The impact of task execution depends on the ratio between the skills of the treated patient and the challenges imposed by the task itself. Thus, treatment personalization requires a trade-off between patients' skills and task difficulties, which is still an open issue. In this study, we propose Elo ratings to support clinicians in tasks assignations and representing patients' skills to optimize rehabilitation outcomes.ObjectiveThis study aims to stratify patients with ischemic stroke at an early stage of rehabilitation into three levels according to their Elo rating; to show the relationships between the Elo rating levels, task difficulty levels, and rehabilitation outcomes; and to determine if the Elo rating obtained at early stages of rehabilitation is a significant predictor of rehabilitation outcomes.MethodsThe PlayerRatings R library was used to obtain the Elo rating for each patient. Working memory was assessed using the DIGITS subtest of the Barcelona test, and the Rey Auditory Verbal Memory Test (RAVLT) was used to assess verbal memory. Three subtests of RAVLT were used: RAVLT learning (RAVLT075), free-recall memory (RAVLT015), and recognition (RAVLT015R). Memory predictors were identified using forward stepwise selection to add covariates to the models, which were evaluated by assessing discrimination using the area under the receiver operating characteristic curve (AUC) for logistic regressions and adjusted R2 for linear regressions.ResultsThree Elo levels (low, middle, and high) with the same number of patients (n=96) in each Elo group were obtained using the 50 initial task executions (from a total of 38,177) for N=288 adult patients consecutively admitted for inpatient rehabilitation in a clinical setting. The mid-Elo level showed the highest proportions of patients that improved in all four memory items: 56% (54/96) of them improved in DIGITS, 67% (64/96) in RAVLT075, 58% (56/96) in RAVLT015, and 53% (51/96) in RAVLT015R (P<.001). The proportions of patients from the mid-Elo level that performed tasks at difficulty levels 1, 2, and 3 were 32.1% (3997/12,449), 31.% (3997/12,449), and 36.9% (4595/12,449), respectively (P<.001), showing the highest match between skills (represented by Elo level) and task difficulties, considering the set of 38,177 task executions. Elo ratings were significant predictors in three of the four models and quasi-significant in the fourth. When predicting RAVLT075 and DIGITS at discharge, we obtained R2=0.54 and 0.43, respectively; meanwhile, we obtained AUC=0.73 (95% CI 0.64-0.82) and AUC=0.81 (95% CI 0.72-0.89) in RAVLT075 and DIGITS improvement predictions, respectively.ConclusionsElo ratings can support clinicians in early rehabilitation stages in identifying cognitive profiles to be used for assigning task difficulty levels.
| S-EPMC8663500 | biostudies-literature
Project description: Not available
| S-EPMC6585365 | biostudies-literature
Project description:AimsSarcopenia is characterized by a gradual loss of skeletal muscle mass and strength with increased adverse outcomes. Recently, large-scale epidemiological studies have demonstrated a relationship between several chronic disorders and ocular pathological conditions using an oculomics approach. We hypothesized that sarcopenia can be predicted through eye examinations, without invasive tests or radiologic evaluations in the context of predictive, preventive, and personalized medicine (PPPM/3PM).MethodsWe analyzed data from the Korean National Health and Nutrition Examination Survey (KNHANES). The training set (80%, randomly selected from 2008 to 2010) data were used to construct the machine learning models. Internal (20%, randomly selected from 2008 to 2010) and external (from the KNHANES 2011) validation sets were used to assess the ability to predict sarcopenia. We included 8092 participants in the final dataset. Machine learning models (XGBoost) were trained on ophthalmological examinations and demographic factors to detect sarcopenia.ResultsIn the exploratory analysis, decreased levator function (odds ratio [OR], 1.41; P value <0.001), cataracts (OR, 1.31; P value = 0.013), and age-related macular degeneration (OR, 1.38; P value = 0.026) were associated with an increased risk of sarcopenia in men. In women, an increased risk of sarcopenia was associated with blepharoptosis (OR, 1.23; P value = 0.038) and cataracts (OR, 1.29; P value = 0.010). The XGBoost technique showed areas under the receiver operating characteristic curves (AUCs) of 0.746 and 0.762 in men and women, respectively. The external validation achieved AUCs of 0.751 and 0.785 for men and women, respectively. For practical and fast hands-on experience with the predictive model for practitioners who may be willing to test the whole idea of sarcopenia prediction based on oculomics data, we developed a simple web-based calculator application (https://knhanesoculomics.github.io/sarcopenia) to predict the risk of sarcopenia and facilitate screening, based on the model established in this study.ConclusionSarcopenia is treatable before the vicious cycle of sarcopenia-related deterioration begins. Therefore, early identification of individuals at a high risk of sarcopenia is essential in the context of PPPM. Our oculomics-based approach provides an effective strategy for sarcopenia prediction. The proposed method shows promise in significantly increasing the number of patients diagnosed with sarcopenia, potentially facilitating earlier intervention. Through patient oculometric monitoring, various pathological factors related to sarcopenia can be simultaneously analyzed, and doctors can provide personalized medical services according to each cause. Further studies are needed to confirm whether such a prediction algorithm can be used in real-world clinical settings to improve the diagnosis of sarcopenia.Supplementary informationThe online version contains supplementary material available at 10.1007/s13167-022-00292-3.
| S-EPMC9437169 | biostudies-literature
Project description:ObjectiveAlthough most patients diagnosed with early-stage cutaneous melanoma (CM) have excellent outcomes, because of the large number diagnosed each year, many will experience recurrence or death. Prognostic testing for CM using the 31-gene expression profile (31-GEP) test can benefit patients by helping guide risk-appropriate treatment and surveillance plans. We sought to evaluate patients' attitudes toward prognostic testing with the 31-GEP and assess whether patients experience decision regret about having 31-GEP testing.MethodsA 43-question survey was distributed by the Melanoma Research Foundation in June-August 2021 to CM patients enrolled in their database. Patients were asked questions regarding their decision to undergo 31-GEP testing and the extent to which they experienced decision regret using a validated set of Decision Regret Scale questions.ResultsWe analyzed responses from patients diagnosed in 2014 or later (n = 120). Of these, 28 had received 31-GEP testing. Most respondents (n = 108, 90%) desired prognostic information when diagnosed. Of those who received 31-GEP testing, most felt the results were useful (n = 22 out of 24) and had regret scores significantly less than neutral regret, regardless of their test results (Class 1: p < 0.001; Class 2: p = 0.036). Further, decision regret scores were not significantly different between patients who received a Class 1 31-GEP result and those who received a Class 2 result (mean Class 1 = 1.39 and mean Class 2 = 1.90, p = 0.058).ConclusionsMost newly diagnosed CM patients desired prognostic information about their tumors. Patients who received 31-GEP testing felt it was useful and did not regret their decision to undergo 31-GEP testing.
| S-EPMC9883557 | biostudies-literature
Project description: Not available
| S-EPMC6580667 | biostudies-literature
Project description:Until recently, treatment options for patients with metastatic melanoma were very limited. This landscape has evolved dramatically since the discovery of activating mutations in the BRAF gene in ~45% of cutaneous melanomas. Vemurafenib, dabrafenib, and trametinib have all received regulatory approval for the treatment of metastatic melanoma patients with a BRAFV600 mutation. Based on the necessity to document the presence of a BRAFV600 mutation to prescribe these agents, molecular testing is now the standard of care in this disease. However, the options and rationale for testing are evolving rapidly due to an improved understanding of the molecular drivers and heterogeneity of melanoma. Such testing may identify rational combinatorial approaches to prevent or overcome resistance for the approved BRAF inhibitors. In addition, new clinical strategies have been identified for a number of other molecular changes that are detected in this disease, including somatic changes in NRAS, PTEN, CDKN2A, and c-KIT, among others. This review summarizes the current understanding of the genetic landscape of mutations in melanoma, their associations with clinicopathological features, and their implications for clinical testing and treatment.
| S-EPMC4306428 | biostudies-literature