RESUMO
BACKGROUND/PURPOSE: Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation. METHODS: We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment. RESULTS: Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (- 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL. CONCLUSION: Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation.
Assuntos
Gota , Polietilenoglicóis , Urato Oxidase , Ácido Úrico , Humanos , Estudos Retrospectivos , Gota/tratamento farmacológico , Biomarcadores , RimRESUMO
OBJECTIVE: Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis. METHODS: Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features. RESULTS: We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions. INTERPRETATION: Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Linfócitos T CD8-Positivos , Sistema Nervoso Central , BiomarcadoresRESUMO
BACKGROUND: This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients. METHODS: A total of 120 plasma samples from 40 patients with HER2 + BrCa were prospectively collected at three treatment times of neoadjuvant therapy (NAT) with TCbHP regimen. Serum metabolites were analyzed based on LC-MS and GC-MS data. Random forest was used to establish predictive models based on pre-therapeutic differentially expressed metabolites. Time series analysis was used to obtain potential monitors for treatment response. Transcriptome analysis was performed in nine available pretherapeutic specimens of core needle biopsies. Integrated analyses of metabolomics and transcriptomics were also performed in these nine patients. qRT-PCR was used to detect altered genes in trastuzumab-sensitive and trastuzumab-resistant cell lines. RESULTS: Twenty-one patients achieved pCR, and 19 patients achieved non-pCR. There were significant differences in plasma metabolic profiles before and during treatment. A total of 100 differential metabolites were identified between pCR patients and non-pCR patients at baseline; these metabolites were markedly enriched in 40 metabolic pathways. The area under the curve (AUC) values for discriminating the pCR and non-PCR groups from the NAT of the single potential metabolite [sophorose, N-(2-acetamido) iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] or combined panel of these metabolites were greater than 0.910. Eighteen metabolites exhibited potential for monitoring efficacy. Several validated genes might be associated with trastuzumab resistance. Thirty-nine altered pathways were found to be abnormally expressed at both the transcriptional and metabolic levels. CONCLUSION: Serum-metabolomics could be used as a powerful tool for exploring informative biomarkers for predicting or monitoring treatment efficacy. Metabolomics integrated with transcriptomics analysis could assist in obtaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia Neoadjuvante , Metabolômica , Trastuzumab , BiomarcadoresRESUMO
MicroRNAs (miRNAs) have essential roles in the etiology of breast cancer and are regarded as possible markers in this malignancy. In order to find new markers for breast cancer, the current study has measured expression level of four miRNAs, namely miR-125a, miR-106b, miR-96 and miR-92a-3p in the paired breast samples. Expression levels of miR-125a and miR-106b were higher in tumoral tissues compared with control tissues (Expression ratios (95% CI)â¯=â¯4.01 (1.96-8.19) and 3.9 (1.95-7.81); P valuesâ¯=â¯0.0005 and 0.0003, respectively). miR-106b and miR-125a differentiated between malignant and non-malignant tissues with AUC values of 0.7 and 0.67, respectively. We detected association between expression of miR-106b and clinical stage (Pâ¯=â¯0.03), in a way that its expression was the lowest in the advanced stages. Finally, significant relationships were found between miR-96 and miR-125a in both tumoral and non-tumoral specimens (ρâ¯=â¯0.76 and 0.69, respectively). This nonparametric measure of rank correlation also showed relationship between miR-106b and miR-96 in both sets of samples (ρâ¯=â¯0.63 and 0.61, respectively). Cumulatively, the assessed miRNAs, particularly miR-125a and miR-106b are putative targets for further expression and functional assays in breast cancer.
Assuntos
Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores , Regulação Neoplásica da Expressão Gênica/genética , Proliferação de CélulasRESUMO
Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-ß (Aß) ("A"), tau pathology ("T"), and neurodegeneration ("N"). Diagnostic cut-offs for Aß1-42, the Aß1-42/Aß1-40 ratio, tau and hyperphosphorylated-tau concentrations in cerebrospinal fluid have been defined and may support AD clinical diagnosis. Blood-based biomarkers of the AT(N) categories have been described in the AD continuum. Cross-sectional and longitudinal studies have shown that the combination of blood biomarkers tracking neuroaxonal injury (neurofilament light chain) and neuroinflammatory pathways (glial fibrillary acidic protein) enhance sensitivity and specificity of AD clinical diagnosis and improve the prediction of AD onset. However, no international accepted cut-offs have been identified for these blood biomarkers. A kit for blood Aß1-42/Aß1-40 is commercially available in the U.S.; however, it does not provide a diagnosis, but simply estimates the risk of developing AD. Although blood-based AD biomarkers have a great potential in the diagnostic work-up of AD, they are not ready for the routine clinical use.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau , Estudos Transversais , Peptídeos beta-Amiloides , Biomarcadores/líquido cefalorraquidianoRESUMO
BACKGROUND: Undiagnosed tuberculosis remains a major threat for people living with HIV. Multiple blood transcriptomic biomarkers have shown promise for tuberculosis diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) tuberculosis screening. METHODS: We enrolled consecutive adults (age ≥18 years) referred to start ART at a community health centre in Cape Town, South Africa, irrespective of symptoms. Sputa were obtained (using induction if required) for two liquid cultures. Whole-blood RNA samples underwent transcriptional profiling using a custom Nanostring gene panel. We measured the diagnostic accuracy of seven candidate RNA signatures (one single gene biomarker [BATF2] and six multigene biomarkers) for the reference standard of Mycobacterium tuberculosis culture status, using area under the receiver-operating characteristic curve (AUROC) analysis, and sensitivity and specificity at prespecified thresholds (two standard scores above the mean of healthy controls; Z2). Clinical utility was assessed by calculating net benefit in decision curve analysis. We compared performance with C-reactive protein (CRP; threshold ≥5 mg/L), WHO four-symptom screen (W4SS), and the WHO target product profile for tuberculosis triage tests. FINDINGS: A total of 707 people living with HIV (407 [58%] female and 300 [42%] male) were included, with median CD4 count 306 cells per mm3 (IQR 184-486). Of 676 participants with available sputum culture results, 89 (13%) had culture-confirmed tuberculosis. The seven RNA signatures were moderately to highly correlated (Spearman rank coefficients 0·42-0·93) and discriminated tuberculosis culture positivity with similar AUROCs (0·73-0·80), but none statistically better than CRP (AUROC 0·78, 95% CI 0·72-0·83). Diagnostic accuracy was similar across CD4 count strata, but lower among participants with negative W4SS (AUROCs 0·56-0·65) compared with positive (AUROCs 0·75-0·84). The RNA biomarker with the highest AUROC point estimate was a four-gene signature (Suliman4; AUROC 0·80, 95% CI 0·75-0·86), with sensitivity 83% (95% CI 74-90) and specificity 59% (55-63) at the Z2 threshold. In decision curve analysis, Suliman4 and CRP had similar clinical utility to guide confirmatory tuberculosis testing, but both had higher net benefit than W4SS. In exploratory analyses, an approach combining CRP (≥5 mg/L) and Suliman4 (≥Z2) had sensitivity of 80% (70-87), specificity of 70% (66-74), and higher net benefit than either biomarker alone. INTERPRETATION: RNA biomarkers showed better clinical utility to guide confirmatory tuberculosis testing for people living with HIV before ART initiation than symptom-based screening, but their performance did not exceed that of CRP and fell short of WHO recommended targets. Interferon-independent approaches might be required to improve accuracy of host-response biomarkers to support tuberculosis screening before ART initiation. FUNDING: South African Medical Research Council, European and Developing Countries Clinical Trials Partnership 2, National Institutes of Health National Institute of Allergy and Infectious Diseases, The Wellcome Trust, National Institute for Health and Care Research, Royal College of Physicians London.
Assuntos
Infecções por HIV , Mycobacterium tuberculosis , Tuberculose , Adulto , Humanos , Masculino , Feminino , Adolescente , África do Sul , Tuberculose/diagnóstico , Sensibilidade e Especificidade , Infecções por HIV/tratamento farmacológico , Biomarcadores , RNA/uso terapêutico , Mycobacterium tuberculosis/genéticaRESUMO
The high global prevalence of hepatitis B and hepatitis C and the poor prognosis of hepatitis B and hepatitis C-associated hepatocellular carcinoma (HCC), necessitates the early diagnosis and treatment of the disease. Recent studies show that cell-to-cell communication via extracellular vesicles (EVs) is involved in the HCC progression. The objective of the following study was to explore the role of EVs in the progression of viral-induced HCC and investigate their potential for the early diagnosis of cancer. First, the mRNA derived from EVs of HCC patients was compared to the mRNA derived from EVs from the healthy controls. Expression analysis of ANGPTL3, SH3BGRL3, and IFITM3 genes from the EVs was done. Afterward, to confirm whether hepatocytes can uptake EVs, HuH7 cells were exposed to EVs, and the expression analysis of downstream target genes (AKT, TNF-α, and MMP-9) in Huh7 cells was done. Transcriptional analysis showed that in the EVs from HCC patients, the expression levels of ANGPTL3, SH3BGRL3, and IFITM3 were significantly increased by 2.62-, 4.3-, and 9.03-folds, respectively. The downstream targets, AKT, TNF-α, and MMP-9, also showed a considerable change of 4.1-, 1.46-, and 5.05-folds, respectively, in Huh7 cells exposed to HCC EVs. In conclusion, the following study corroborates the role of EVs in HCC progression. Furthermore, the significant alteration in mRNA levels of the selected genes demonstrates their potential to be used as possible biomarkers for the early diagnosis of HCC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Vesículas Extracelulares , Hepatite B , Hepatite C , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt , Fator de Necrose Tumoral alfa/metabolismo , Hepatite C/genética , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , RNA Mensageiro/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína 3 Semelhante a AngiopoietinaRESUMO
BACKGROUND: Technological devices such as smartphones, wearables and virtual assistants enable health data collection, serving as digital alternatives to conventional biomarkers. We aimed to provide a systematic overview of emerging literature on 'digital biomarkers,' covering definitions, features and citations in biomedical research. METHODS: We analysed all articles in PubMed that used 'digital biomarker(s)' in title or abstract, considering any study involving humans and any review, editorial, perspective or opinion-based articles up to 8 March 2023. We systematically extracted characteristics of publications and research studies, and any definitions and features of 'digital biomarkers' mentioned. We described the most influential literature on digital biomarkers and their definitions using thematic categorisations of definitions considering the Food and Drug Administration Biomarkers, EndpointS and other Tools framework (ie, data type, data collection method, purpose of biomarker), analysing structural similarity of definitions by performing text and citation analyses. RESULTS: We identified 415 articles using 'digital biomarker' between 2014 and 2023 (median 2021). The majority (283 articles; 68%) were primary research. Notably, 287 articles (69%) did not provide a definition of digital biomarkers. Among the 128 articles with definitions, there were 127 different ones. Of these, 78 considered data collection, 56 data type, 50 purpose and 23 included all three components. Those 128 articles with a definition had a median of 6 citations, with the top 10 each presenting distinct definitions. CONCLUSIONS: The definitions of digital biomarkers vary significantly, indicating a lack of consensus in this emerging field. Our overview highlights key defining characteristics, which could guide the development of a more harmonised accepted definition.
Assuntos
Pesquisa Biomédica , Humanos , BiomarcadoresRESUMO
BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.
Assuntos
Lúpus Eritematoso Sistêmico , Reumatologia , Humanos , Feminino , Estados Unidos , Masculino , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Autoanticorpos , Biomarcadores , CinesinasRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.
Assuntos
Interferon Tipo I , Lúpus Eritematoso Sistêmico , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Redes Reguladoras de Genes , Interferon Tipo I/genética , BiomarcadoresRESUMO
INTRODUCTION: Traditionally associated with undernutrition, increasing evidence suggests micronutrient deficiencies can coexist with overnutrition. Therefore, this work aimed to systematically review the associations between iron, zinc and vitamin A (VA) status and weight status (both underweight and overweight) in children and young people. METHODS: Ovid Medline, Ovid Embase, Scopus and Cochrane databases were systematically searched for observational studies assessing micronutrient status (blood, serum or plasma levels of iron, zinc or VA biomarkers) and weight status (body mass index or other anthropometric measurement) in humans under 25 years of any ethnicity and gender. Risk of bias assessment was conducted using the American Dietetic Association Quality Criteria Checklist. Where possible, random effects restricted maximum likelihood meta-analyses were performed. RESULTS: After screening, 83 observational studies involving 190 443 participants from 44 countries were identified, with many studies having reported on more than one micronutrient and/or weight status indicator. Iron was the most investigated micronutrient, with 46, 28 and 27 studies reporting data for iron, zinc and VA status, respectively. Synthesising 16 records of OR from seven eligible studies, overnutrition (overweight and obesity) increased odds of iron deficiency (ID) (OR (95% CI): 1.51 (1.20 to 1.82), p<0.0001, I2=40.7%). Odds appeared to be higher for children living with obesity (1.88 (1.33 to 2.43), p<0.0001, I2=20.6%) in comparison to those with overweight (1.31 (0.98 to 1.64), p<0.0001, I2=40.5%), although between group differences were not significant (p=0.08). CONCLUSIONS: Overnutrition is associated with increased risk of ID, but not zinc or VA deficiencies, with an inverted U-shaped relationship observed between iron status and bodyweight. Our results highlight significant heterogeneity in the reporting of micronutrient biomarkers and how deficiencies were defined. Inflammation status was rarely adequately accounted for, and the burden of ID may well be under-recognised, particularly in children and young people living with overnutrition. PROSPERO REGISTRATION NUMBER: CRD42020221523.
Assuntos
Anemia Ferropriva , Hipernutrição , Deficiência de Vitamina A , Criança , Humanos , Adolescente , Ferro , Deficiência de Vitamina A/epidemiologia , Zinco , Sobrepeso/complicações , Anemia Ferropriva/etiologia , Anemia Ferropriva/prevenção & controle , Micronutrientes , Hipernutrição/epidemiologia , Hipernutrição/complicações , Vitamina A , Obesidade/complicações , Fatores de Risco , BiomarcadoresRESUMO
Purpose: Nonanterior uveitis frequently involves the retinal vasculature; however, no molecular markers associated with the retinal vascular disease are currently known. In this study, we aimed to identify serum biomarker signatures associated with retinal vascular involvement in noninfectious pediatric uveitis. Methods: We performed a 384-plex targeted proteomic analysis of serum samples of 154 noninfectious pediatric uveitis patients diagnosed with nonanterior uveitis (n = 74), idiopathic chronic anterior uveitis (iCAU, n = 36), or juvenile idiopathic arthritis-associated uveitis (JIA-U, n = 44), as well as 22 noninflammatory pediatric controls. Data on retinal vascular involvement (i.e., papillitis, cystoid macular edema, retinal vasculitis, or retinal capillary leakage on optical coherence tomography and/or fluorescein angiography) were used to stratify cases in the nonanterior uveitis group. Results: In the analysis of nonanterior uveitis, we identified nine proteins significantly associated with retinal vascular involvement, including F13B, MYOM3, and PTPN9. These proteins were enriched through pathway enrichment analysis for the coagulation cascade. Comparing cases and controls, we identified 63 differentially expressed proteins, notably proteins involved in platelet biology and complement cascades, which could be primarily attributed to differences in serum proteomes between anterior uveitis and nonanterior uveitis groups. Conclusions: Serum proteins related to the coagulation and complement cascade are associated with retinal vascular involvement in pediatric uveitis patients. Our results indicate involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future. Translational Relevance: Our targeted proteomics analysis in serum of pediatric uveitis patients indicates involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future.
Assuntos
Doenças Retinianas , Uveíte Anterior , Uveíte , Humanos , Criança , Proteômica , Uveíte/diagnóstico , Uveíte Anterior/diagnóstico , BiomarcadoresRESUMO
Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).
Assuntos
Antineoplásicos , Vacinas Anticâncer , Neoplasias , Humanos , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Neoplasias/prevenção & controle , BiomarcadoresRESUMO
PURPOSE OF REVIEW: The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies. RECENT FINDINGS: Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy. SUMMARY: MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.
Assuntos
Preservação de Órgãos , Neoplasias da Bexiga Urinária , Humanos , Qualidade de Vida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Biomarcadores , MúsculosRESUMO
AIMS: In patients with ulcerative colitis (UC), no biomarker is available to help the physician to choose the most suitable biotherapy. The primary objective of this pilot study was to assess the feasibility of identification of α4ß7- and TNF-expressing cells, to predict the response to vedolizumab using confocal laser endoscopy (CLE). METHODS: Patients with moderate-to-severe UC, naïve of biotherapy, received vedolizumab. Clinical evaluation was performed at each infusion. Endoscopic evaluation was performed before inclusion and at week 22. Fresh colonic biopsies were stained using FITC-labelled vedolizumab and Alexa fluor-labelled adalimumab and ex vivo dual-band CLE images were acquired. Blood samples were collected to measure trough concentrations of vedolizumab and to determine absolute counts of T and B cells subpopulations, NK cells and monocytes. RESULTS: Nineteen patients were enrolled in the study and received at least one dose of vedolizumab. Clinical remission and endoscopic improvement were observed in 58% of whom 5 patients (45%) had an endoscopic subscore of 0. In terms of clinical response and remission, endoscopic improvement and histologic response, FITC-conjugated vedolizumab staining tended to be higher in responder patients compared to non-responders at week 22. A threshold value of 6 positive FITC-vedolizumab staining areas detected by CLE seemed informative to discriminate the responders and non-responders. The results were similar in terms of clinical remission and endoscopic improvement with a sensitivity of 78% and a specificity of 85% (p = 0.05). Trough concentrations and blood immune cells were not associated with responses to vedolizumab. CONCLUSION: This pilot study demonstrate that dual-band CLE is feasible to detect α4ß7- and TNF-expressing cells. Positive α4ß7 staining seems to be associated with clinical and endoscopic remission in UC patients treated by anti-α4ß7-integrin, subject to validation by larger-scale studies. Clinical-trial.gov: NCT02878083.
Assuntos
Anticorpos Monoclonais Humanizados , Colite Ulcerativa , Humanos , Projetos Piloto , Fluoresceína-5-Isotiocianato , Biomarcadores , Endoscopia Gastrointestinal , Fármacos Gastrointestinais/uso terapêutico , Resultado do Tratamento , Indução de RemissãoRESUMO
There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Antígeno B7-H1 , Biomarcadores , Fatores Imunológicos , Imunoterapia , Biomarcadores TumoraisRESUMO
Sugars from sugar-sweetened beverages (SSBs) are an important risk factor for tooth decay. The study goal was to determine if there was variation in added sugar intake across communities and between and within households. In this cross-sectional study, intakes of total sugar, added sugar, and sugar-sweetened beverages (SSBs) were estimated for 282 Alaska Native children ages 0-10 years from 131 households in three Yukon-Kuskokwim (YK) Delta communities using biomarker equations based on hair carbon and nitrogen isotope ratios previously developed for the Yup'ik population. ANOVA was used to assess associations between each predictor (community and household) and outcome (estimated total sugars, added sugars, and SSB intake). Between- and within-household variation was estimated using a linear mixed-effects model with a random intercept for households with three or more children. There was no significant difference in mean estimated total sugar (p = 0.29), added sugar (p = 0.24), or SSB intake (p = 0.40) across communities. Significant variations were observed between and within households, with within-household variation amounting to 59% of the between-household variation. Added sugar intake in Alaska Native children from the three study communities is higher than the recommended maximum, and the variation is greater within households than between households.
Assuntos
Criança , Humanos , Estudos Transversais , Açúcares , Cabelo , Biomarcadores , Bebidas/análiseRESUMO
Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.
Assuntos
Doenças Autoimunes , Doença de Hashimoto , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , Fenótipo , Proteína C-Reativa , Doenças Autoimunes/genética , Biomarcadores , Estudo de Associação Genômica AmplaRESUMO
Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients' lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71-0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-ß signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.
Assuntos
Osteoartrite , Humanos , Estudos Retrospectivos , Osteoartrite/diagnóstico , Osteoartrite/genética , Osteoartrite/tratamento farmacológico , Biomarcadores , Anti-Inflamatórios não Esteroides/uso terapêutico , Aprendizado de Máquina , Proteínas de Ligação ao CálcioRESUMO
Metabolic reprogramming plays an important role in kidney cancer. We aim to investigate the causal effect of 249 metabolic biomarkers on kidney cancer from population-based data. This study extracts data from previous genome wide association studies with large sample size. The primary endpoint is random-effect inverse variance weighted (IVW). After completing 249 times of two-sample Mendelian randomization analysis, those significant metabolites are included for further sensitivity analysis. According to a strict Bonferrion-corrected level (P < 2e-04), we only find two metabolites that are causally associated with renal cancer. They are lactate (OR:3.25, 95% CI: 1.84-5.76, P = 5.08e-05) and phospholipids to total lipids ratio in large LDL (low density lipoprotein) (OR: 0.63, 95% CI: 0.50-0.80, P = 1.39e-04). The results are stable through all the sensitivity analysis. The results emphasize the central role of lactate in kidney tumorigenesis and provide novel insights into possible mechanism how phospholipids could affect kidney tumorigenesis.