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Clayton Werner posted an update a month ago
Patients may experience swelling in unexpected areas, which proves resistant to treatments focused on MCs. Genetic variations have facilitated the understanding of key pathways in the etiology of urticaria and non-atopic angioedema, which has driven the development of treatments tailored to specific biological pathways. This paper examines the current knowledge of genetic causes, both inherited and acquired, for these conditions, noting important clinical distinctions, and evaluating the benefits and limitations of biomarkers in their differential diagnosis.
Chronic spontaneous urticaria (CSU) patients have omalizumab as their only approved biological treatment option, but a strongly correlated biomarker for anticipating its clinical response has not been sufficiently characterized.
Our research focused on identifying the association between patients’ initial serum IgE levels and the impact of omalizumab in managing CSU.
Using a systematic methodology, pertinent studies were retrieved from PubMed, Web of Science, Scopus, and the Cochrane Library, covering the duration from initial publication until August 23, 2022. The research protocol was formally registered with PROSPERO, reference CRD42022355592. No limitations were imposed on the language used. Meta-analysis employed a random-effects model.
The meta-analytic review comprised ten interventional studies, including one randomized controlled trial; this encompassed 866 patients with CSU. A combined analysis showed a statistically significant elevation in serum total IgE levels among complete responders (CRs) versus non-responders (NRs) (mean difference 56509 IU/mL; 95% confidence interval 24230-88789). A similar significant increase was observed in partial responders (PRs) relative to non-responders (NRs) (MD 62688 IU/mL; 95% CI 32949-92427 IU/mL). No statistically meaningful difference in IgE levels was detected between complete and partial responders. A comparison of mean total IgE levels across CRs, PRs, and NRs revealed values of 163154 IU/mL, 179926 IU/mL, and 51535 IU/mL, respectively. Furthermore, serum total IgE levels in early complete remissions were substantially elevated compared to those in late complete remissions (MD 55194 IU/mL; 95% CI 13402-96986). All findings’ robustness was confirmed through sensitivity analyses, utilizing the leave-one-out approach.
A comprehensive meta-analysis and systematic review of data reveals a strong association between pretreatment serum IgE levels and omalizumab treatment efficacy in patients with chronic spontaneous urticaria.
Omalizumab’s efficacy in chronic spontaneous urticaria patients, as determined by this meta-analysis and systematic review, is significantly influenced by pre-treatment total serum immunoglobulin E levels.
Despite cost variations, the quantity of esophageal biopsy bottles necessary for assessing eosinophilic esophagitis (EoE) remains ambiguous.
Analyze the difference in clinical outcomes between patients having one and two esophageal biopsies to ascertain the presence of eosinophilic esophagitis.
Data from a retrospective study of adults undergoing esophagogastroduodenoscopy (EGD) for esophageal symptoms between January 2015 and June 2021, exhibited 15 eosinophils per high-power field (eos/hpf). In patients with one bottle (1 bottle-EoE), biopsies were obtained from either the entire esophagus or its proximal portion. Patients who received two esophageal specimen bottles had biopsies taken from both the distal and proximal esophageal areas. These biopsies were subsequently sorted into two groups, those with 15 eosinophils per high-power field (hpf) in both bottles (2-bottle Dif-EoE) and those with 15 eosinophils/hpf only in the distal esophageal bottle (2-bottle Lim-EoE). The primary outcomes from the follow-up EGD procedure were the Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) assessed endoscopic findings, and the presence of 15 eosinophils per high-powered field.
Eosinophilic esophageal disease was observed in 85 patients, categorized as follows: 49 exhibiting double-bottle Dif-EoE, 18 exhibiting double-bottle Lim-EoE, and 18 displaying single-bottle EoE. Within a median follow-up timeframe of 33 to 56 months, patients with 1 bottle EoE experienced a greater prevalence of dysphagia (p=0.029), yet no differences were found in EREFS (p=0.014) or the presence of 15 eosinophils per high-power field (p=0.039). Patients with Dif-EoE who received two bottles of medication exhibited a considerably greater rate of topical steroid treatment (163% vs. 0% vs. 0%, p=0039), compared to other patient groups.
The identical endoscopic and histologic results were noted in patients with EoE, based on the number of bottles (one or two) used for esophageal biopsies.
The endoscopic and histologic responses were alike in patients who had one or two bottles of esophageal biopsy material analyzed to evaluate for EoE.
Hepatocyte apoptosis dysregulation is a common thread in various types of long-term liver disorders. TGF-1, a pro-apoptotic factor extensively studied in the liver, interacts with a receptor complex involving TGF-receptor I and II, and is coupled with the activity of Smad transcription factors. Foxo1, a key player among the forkhead box O (Foxo) transcription factors, is instrumental in governing hepatic glucose production and apoptosis. This study investigated how TGF-1 signaling might interact with Foxo1 in the process of controlling apoptosis in hepatocytes. Our research, leveraging hepatocytes isolated from wild-type and liver-specific Foxo1 knockout mice, showed TGF-1 to induce hepatocyte apoptosis via a Foxo1-dependent mechanism. We confirmed TGF-1’s ability to activate protein kinase A, specifically through the TGF-receptor I-Smad3 pathway, resulting in Foxo1 phosphorylation at Ser273 and the induction of hepatocyte apoptosis. Excessively, Smad3 expression in the mouse liver amplified phosphorylated Foxo1 at Serine 273, the total amount of Foxo1, and the pro-apoptotic Foxo1 downstream gene Bim, ultimately triggering hepatocyte apoptosis. beta-nicotinamide0 Employing hepatocytes from Foxo1-S273A/A knock-in mice, which lack Foxo1-S273 phosphorylation, we further elucidated the crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-1. By merging our observations, we identified a novel role for TGF-1 protein kinase AFoxo1 signaling cascades in the regulation of hepatocyte survival.
Organoids, representing a novel in vitro approach, are used to scrutinize intercellular crosstalk amongst different cell types in disease pathophysiology. In seeking to better understand the processes that cause primary sclerosing cholangitis (PSC) to progress, we developed scaffold-free three-dimensional cholangiocyte organoids (3D-CHOs) based on primary liver cells obtained from normal and PSC patients. Samples of human livers, sourced from both healthy donors and patients with PSC, were utilized to isolate primary cholangiocytes (EpCam+/cytokeratin-19+), liver endothelial cells (CD31+), and hepatic stellate cells (HSCs, characterized by CD31-/CD68-/desmin+/vitamin A+). Cholangiocytes, hepatic stellate cells (HSCs), and liver endothelial cells were employed to create 3D-CHOs, which remained viable for up to a month. The isolated primary cell lines and 3D-CHOs were subject to further analysis by means of immunofluorescence, RT-qPCR, and transmission electron microscopy. Transcriptional signatures indicative of PSC phenotypes in 3D-CHOs encompassed cholangiocytes (SOX9, CFTR, EpCAM, AE, SCT, and SCTR), fibrosis (ACTA2, COL1A1, DESMIN, and TGF1), angiogenesis (PECAM, VEGF, CDH5, and vWF), and inflammation (IL-6 and TNF-). Confocal immunofluorescence studies demonstrated a precise location of neurokinin-1 receptor within both cytokeratin-19-positive cholangiocytes and desmin-positive hepatic stellate cells, a result of the cholangiocytes’ neuroendocrine phenotype formation and the subsequent expression of neuromodulators. Patients with PSC, when examined using 3D-CHOs, demonstrated the hallmarks of PSC, marked by elevated neurokinin-1 receptor and tachykinin precursor 1, and reduced membrane metalloendopeptidase. In contrast to 2D cell culture, scaffold-free 3D multicellular CHO models provided a superior in vitro representation of PSC in vivo phenotypes, enabling potential applications in PSC disease-related studies.
The body’s response to tissue damage, including the orchestration of inflammation and repair, is critical for homeostasis. Aberrant accumulation of extracellular matrix proteins, prominently collagen, defines tissue fibrosis, a pathological response to injury. Wnt antagonism is epitomized by Dickkopf1 (DKK1). DKK1’s involvement in the bleomycin (BLM)-induced lung injury and fibrosis model is still a subject of investigation. BLM-induced lung injury, in a murine model, led to a marked increase in DKK1 protein expression in the lungs, a finding that aligns with the elevated DKK1 levels observed in lung tissues from human pulmonary fibrosis patients. Elevated DKK1 levels were demonstrably linked to the simultaneous processes of immune cell infiltration and collagen deposition. Remarkably, the lowered levels of DKK1 in Dkk1 hypomorphic doubleridge (Dkk1d/d) mice prevented BLM-induced lung inflammation and fibrosis. Reduced immune cell infiltration, collagen deposition, and expression of the profibrotic cytokine transforming growth factor-1 (TGF-1), as well as the myofibroblast marker -smooth muscle actin (-SMA) associated with extracellular matrix protein generation, occurred in Dkk1d/d mice. Subsequent to BLM-induced lung damage, the authors’ findings, consistent with prior data, highlighted the substantial reduction in lung inflammation and fibrosis phenotypes upon local DKK1 antibody administration. The results, analyzed together, paint a picture of DKK1 as a pro-inflammatory and profibrotic agent, furthering inflammation and fibrosis in the context of BLM-induced lung injury. This designates DKK1 as an alluring target for dysregulated pulmonary inflammation and subsequent tissue repair.