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Indian Journal of Ophthalmology Apr 2023Dry eye disease (DED) is a commonly occurring, multifactorial disease characterized by reduced tear film stability and hyperosmolarity at the ocular surface, leading to... (Review)
Review
Dry eye disease (DED) is a commonly occurring, multifactorial disease characterized by reduced tear film stability and hyperosmolarity at the ocular surface, leading to discomfort and visual compromise. DED is driven by chronic inflammation and its pathogenesis involves multiple ocular surface structures such as the cornea, conjunctiva, lacrimal glands, and meibomian glands. The tear film secretion and its composition are regulated by the ocular surface in orchestration with the environment and bodily cues. Thus, any dysregulation in ocular surface homeostasis causes an increase in tear break-up time (TBUT), osmolarity changes, and reduction in tear film volume, all of which are indicators of DED. Tear film abnormalities are perpetuated by underlying inflammatory signaling and secretion of inflammatory factors, leading to the recruitment of immune cells and clinical pathology. Tear-soluble factors such as cytokines and chemokines are the best surrogate markers of disease severity and can also drive the altered profile of ocular surface cells contributing to the disease. Soluble factors can thus help in disease classification and planning treatment strategies. Our analysis suggests increased levels of cytokines namely interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-9, IL-12, IL-17A, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α); chemokines (CCL2, CCL3, CCL4, CXCL8); MMP-9, FGF, VEGF-A; soluble receptors (sICAM-1, sTNFR1), neurotrophic factors (NGF, substance P, serotonin) and IL1RA and reduced levels of IL-7, IL-17F, CXCL1, CXCL10, EGF and lactoferrin in DED. Due to the non-invasive sample collection and ease of quantitively measuring soluble factors, tears are one of the best-studied biological samples to molecularly stratify DED patients and monitor their response to therapy. In this review, we evaluate and summarize the soluble factors profiles in DED patients from the studies conducted over the past decade and across various patient groups and etiologies. The use of biomarker testing in clinical settings will aid in the advancement of personalized medicine and represents the next step in managing DED.
Topics: Humans; Dry Eye Syndromes; Tears; Cytokines; Chemokines; Biomarkers; Lacrimal Apparatus
PubMed: 37026250
DOI: 10.4103/IJO.IJO_2981_22 -
Nature Reviews. Clinical Oncology Sep 2023Oncogenesis is associated with intestinal dysbiosis, and stool shotgun metagenomic sequencing in individuals with this condition might constitute a non-invasive approach... (Meta-Analysis)
Meta-Analysis Review
Oncogenesis is associated with intestinal dysbiosis, and stool shotgun metagenomic sequencing in individuals with this condition might constitute a non-invasive approach for the early diagnosis of several cancer types. The prognostic relevance of antibiotic intake and gut microbiota composition urged investigators to develop tools for the detection of intestinal dysbiosis to enable patient stratification and microbiota-centred clinical interventions. Moreover, since the advent of immune-checkpoint inhibitors (ICIs) in oncology, the identification of biomarkers for predicting their efficacy before starting treatment has been an unmet medical need. Many previous studies addressing this question, including a meta-analysis described herein, have led to the description of Gut OncoMicrobiome Signatures (GOMS). In this Review, we discuss how patients with cancer across various subtypes share several GOMS with individuals with seemingly unrelated chronic inflammatory disorders who, in turn, tend to have GOMS different from those of healthy individuals. We discuss findings from the aforementioned meta-analysis of GOMS patterns associated with clinical benefit from or resistance to ICIs across different cancer types (in 808 patients), with a focus on metabolic and immunological surrogate markers of intestinal dysbiosis, and propose practical guidelines to incorporate GOMS in decision-making for prospective clinical trials in immuno-oncology.
Topics: Humans; Dysbiosis; Prospective Studies; Neoplasms; Biomarkers; Immunotherapy
PubMed: 37365438
DOI: 10.1038/s41571-023-00785-8 -
Abdominal Radiology (New York) Mar 2022Liver fibrosis (LF) is the wound healing response to chronic liver injury. LF is the endpoint of chronic liver disease (CLD) regardless of etiology and the single most... (Review)
Review
Liver fibrosis (LF) is the wound healing response to chronic liver injury. LF is the endpoint of chronic liver disease (CLD) regardless of etiology and the single most important determinant of long-term liver-related clinical outcomes. Quantification of LF is important for staging, to evaluate response to treatment and to predict outcomes. LF is traditionally staged by liver biopsy. However, liver biopsy is invasive and suffers from sampling errors when biopsy size is inadequate; therefore, non-invasive tests (NITs) have found important roles in clinical care. NITs include simple laboratory-based serum tests, panels of serum tests, and imaging biomarkers. NITs are validated against the liver biopsy and will be used in the future for evaluation of nearly all CLDs with invasive liver biopsy reserved for some cases. Both serum tests and some imaging biomarkers such as elastography are currently used clinically as surrogate markers for LF. Several other imaging biomarkers are still considered research and awaiting clinical application in the future. As the evaluation of imaging biomarkers will likely become the norm in the future, understanding pathogenesis of LF is important. Knowledge of properties measured by imaging biomarkers and its correlation with LF is important to understand the application of NITs by abdominal radiologists. In this review, we present a brief overview of pathogenesis of LF, spatiotemporal evolution of LF in different CLD, and severity assessment with liver biopsy. This will be followed by a brief discussion on properties measured by imaging biomarkers and their relationship to the LF.
Topics: Biomarkers; Biopsy; Elasticity Imaging Techniques; Humans; Liver; Liver Cirrhosis; Liver Diseases
PubMed: 35022806
DOI: 10.1007/s00261-021-03396-y -
Frontiers in Endocrinology 2023
Topics: Humans; Prediabetic State; Endocrine System
PubMed: 37664837
DOI: 10.3389/fendo.2023.1268552 -
Nutrients Feb 2021Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is... (Randomized Controlled Trial)
Randomized Controlled Trial
Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is sparse. We examined VD effects on anti-Müllerian hormone (AMH) and other endocrine markers in PCOS and non-PCOS women. This is a post hoc analysis of a single-center, double-blind RCT conducted between December 2011 and October 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. We included 180 PCOS women and 150 non-PCOS women with serum 25-hydroxyvitamin D (25(OH)D) concentrations <75 nmol/L in the trial. We randomized subjects to receive 20,000 IU of VD3/week (119 PCOS, 99 non-PCOS women) or placebo (61 PCOS, 51 non-PCOS women) for 24 weeks. Outcome measures were AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, dehydroepiandrosterone sulfate, and androstenedione. In PCOS women, we observed a significant treatment effect on FSH (mean treatment effect 0.94, 95% confidence interval [CI] 0.087 to 1.799, = 0.031) and LH/FSH ratio (mean treatment effect -0.335, 95% CI -0.621 to 0.050, = 0.022), whereas no significant effect was observed in non-PCOS women. In PCOS women, VD treatment for 24 weeks had a significant effect on FSH and LH/FSH ratio but no effect on AMH levels.
Topics: Adult; Anti-Mullerian Hormone; Austria; Biomarkers; Dietary Supplements; Double-Blind Method; Female; Fertility; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Polycystic Ovary Syndrome; Time Factors; Vitamin D
PubMed: 33562394
DOI: 10.3390/nu13020547 -
The Pan African Medical Journal 2023
Topics: Child; Humans; Adiposity; Blood Pressure; Obesity; Hypertension; Biomarkers; Body Mass Index; Risk Factors
PubMed: 38465005
DOI: 10.11604/pamj.2023.46.114.42371 -
JAMA Dermatology Dec 2019Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always...
IMPORTANCE
Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking.
OBJECTIVE
To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children's hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018.
MAIN OUTCOMES AND MEASURES
Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry.
RESULTS
A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was -15.2 (0.91) and normal was -19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) -2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and TH2 (IL-33 and IL-4R) and TH17/TH22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools).
CONCLUSIONS AND RELEVANCE
In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.
Topics: Age of Onset; Biomarkers; Biopsy; Child, Preschool; Cross-Sectional Studies; Dermatitis, Atopic; Feasibility Studies; Female; Filaggrin Proteins; Humans; Immunohistochemistry; Infant; Infant, Newborn; Male; Real-Time Polymerase Chain Reaction; Severity of Illness Index; Skin; Water Loss, Insensible
PubMed: 31596431
DOI: 10.1001/jamadermatol.2019.2983 -
Current Opinion in Critical Care Feb 2023Critical care medicine revolves around syndromes, such as acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury. Few interventions have shown to be... (Review)
Review
PURPOSE OF REVIEW
Critical care medicine revolves around syndromes, such as acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury. Few interventions have shown to be effective in large clinical trials, likely because of between-patient heterogeneity. Translational evidence suggests that more homogeneous biological subgroups can be identified and that differential treatment effects exist. Integrating biological considerations into clinical trial design is therefore an important frontier of critical care research.
RECENT FINDINGS
The pathophysiology of critical care syndromes involves a multiplicity of processes, which emphasizes the difficulty of integrating biology into clinical trial design. Biological assessment can be integrated into clinical trials using predictive enrichment at trial inclusion, time-dependent variation to better understand treatment effects and biological markers as surrogate outcomes.
SUMMARY
Integrating our knowledge on biological heterogeneity into clinical trial design, which has revolutionized other medical fields, could serve as a solution to implement personalized treatment in critical care syndromes. Changing the trial design by using predictive enrichment, incorporation of the evaluation of time-dependent changes and biological markers as surrogate outcomes may improve the likelihood of detecting a beneficial effect from targeted therapeutic interventions and the opportunity to test multiple lines of treatment per patient.
Topics: Humans; Clinical Trials as Topic; Respiratory Distress Syndrome; Biomarkers; Critical Care; Biology
PubMed: 36580371
DOI: 10.1097/MCC.0000000000001007 -
Liver International : Official Journal... Aug 2023Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment... (Review)
Review
Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds.
Topics: Humans; Hepatitis D, Chronic; Treatment Outcome; Longitudinal Studies; Biomarkers; Hepatitis B, Chronic; Hepatitis B virus; Antiviral Agents
PubMed: 36196680
DOI: 10.1111/liv.15447 -
The American Journal of Gastroenterology Jul 2020In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do...
Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.
INTRODUCTION
In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined.
METHODS
The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated.
RESULTS
There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN.
DISCUSSION
Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
Topics: Alkaline Phosphatase; Bilirubin; Biomarkers; Cholagogues and Choleretics; Cholangitis; Female; Humans; Male; Middle Aged; Prognosis; Reference Values; Survival Rate; Ursodeoxycholic Acid
PubMed: 32618657
DOI: 10.14309/ajg.0000000000000557