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The New England Journal of Medicine Sep 2023Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established.
METHODS
In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed.
RESULTS
Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.
CONCLUSIONS
In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).
Topics: Humans; Biopsy; Double-Blind Method; Fibroblast Growth Factors; Fibrosis; Gastrointestinal Agents; Injections, Subcutaneous; Non-alcoholic Fatty Liver Disease; Treatment Outcome
PubMed: 37356033
DOI: 10.1056/NEJMoa2304286 -
The Journal of Clinical and Aesthetic... Dec 2023Direct immunofluorescence (DIF) is a valuable diagnostic tool in the dermatology clinic. The proper use of a biopsy for DIF is dependent on several factors, including...
Direct immunofluorescence (DIF) is a valuable diagnostic tool in the dermatology clinic. The proper use of a biopsy for DIF is dependent on several factors, including appropriate clinical indication, correct clinical site selection, and proper specimen handling and transport. Improper use of DIF can lead to false negatives, decreased diagnostic yield, and poor resource utilization. This article provides instruction on the appropriate indications and biopsy site selection for DIF. Three examples of skin diseases in which DIF would be particular useful when making a diagnosis are provided.
PubMed: 38464740
DOI: No ID Found -
European Heart Journal Sep 2023This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.
BACKGROUND AND AIMS
This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.
METHODS AND RESULTS
Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration.
CONCLUSION
Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.
Topics: Humans; Female; Middle Aged; Aged; Atrial Fibrillation; Electrophysiologic Techniques, Cardiac; Heart Atria; Heart Rate; Fibrosis; Atrial Remodeling; Catheter Ablation
PubMed: 37350738
DOI: 10.1093/eurheartj/ehad396 -
Cancers Jul 2023The aim of this study was to determine the false negative rates of prebiopsy magnetic resonance imaging (MRI) and MRI-ultrasound (US) 12-core systematic prostate biopsy...
BACKGROUND
The aim of this study was to determine the false negative rates of prebiopsy magnetic resonance imaging (MRI) and MRI-ultrasound (US) 12-core systematic prostate biopsy (PBx) by analyzing radical prostatectomy specimens.
METHODS
This retrospective study included 3600 prostate cancer (PCa) patients who underwent robot-assisted laparoscopic radical prostatectomy. Based on comparison of lobe-specific data on final pathology with preoperative biopsy and imaging data, the study population was subdivided into group I-contralateral (CL) benign PBx ( = 983), group II-CL and/or bilateral (BL) non-suspicious mpMRI ( = 2223) and group III-CL benign PBx + non-suspicious mpMRI ( = 688). This population was studied for the presence of PCa, clinically significant PCa (csPCa), extracapsular extension (ECE) (pathological stage pT3), positive frozen section and final positive surgical margin (PSM) in the CL lobe. Descriptive statistics were performed.
RESULTS
In subgroups I, II and III, PCa was respectively detected in 21.5%, 37.7% and 19.5% of cases, and csPCa in 11.3%, 16.3% and 10.3% of cases. CL pT3 disease was seen in 4.5%, 4% and 5.5%, and CL surgical margins and/or frozen section analysis were positive in 6%, 7% and 5% of cases in subgroups I, II and III, respectively.
CONCLUSIONS
There are still significant rates of false negatives in the standard care diagnostics of PCa. Further strategies are required to improve the accuracy of diagnosis and determination of tumor location.
PubMed: 37444597
DOI: 10.3390/cancers15133487 -
Hepatology (Baltimore, Md.) Nov 2023HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our...
BACKGROUND AND AIMS
HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing.
APPROACH AND RESULTS
We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S 3 picowell-based and the 10× Chromium reverse-emulsion droplet-based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S 3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences.
CONCLUSIONS
The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.
Topics: Animals; Humans; Hepatitis B, Chronic; Biopsy, Fine-Needle; Hepatitis B virus; Liver; CD8-Positive T-Lymphocytes; Biomarkers; Sequence Analysis, RNA
PubMed: 37158243
DOI: 10.1097/HEP.0000000000000438 -
Nature Medicine Oct 2023There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis...
There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; Liver Cirrhosis; Fibrosis; Biomarkers; Biopsy
PubMed: 37679433
DOI: 10.1038/s41591-023-02539-6 -
The Journal of Clinical Investigation Jun 2023Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or...
Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.
Topics: Humans; Podocytes; alpha-Synuclein; Fabry Disease; alpha-Galactosidase; Kidney; Trihexosylceramides
PubMed: 37014703
DOI: 10.1172/JCI157782 -
Frontiers in Immunology 2023The skin is the body's largest organ. It serves as a barrier to pathogen entry and the first site of immune defense. In the event of a skin injury, a cascade of events... (Review)
Review
The skin is the body's largest organ. It serves as a barrier to pathogen entry and the first site of immune defense. In the event of a skin injury, a cascade of events including inflammation, new tissue formation and tissue remodeling contributes to wound repair. Skin-resident and recruited immune cells work together with non-immune cells to clear invading pathogens and debris, and guide the regeneration of damaged host tissues. Disruption to the wound repair process can lead to chronic inflammation and non-healing wounds. This, in turn, can promote skin tumorigenesis. Tumors appropriate the wound healing response as a way of enhancing their survival and growth. Here we review the role of resident and skin-infiltrating immune cells in wound repair and discuss their functions in regulating both inflammation and development of skin cancers.
Topics: Humans; Wound Healing; Skin; Inflammation; Carcinogenesis
PubMed: 37398649
DOI: 10.3389/fimmu.2023.1060258