Target For Treatment Research Articles

Study on miR-29a inhibiting papillary thyroid carcinoma by downregulating TAGLN2

ObjectiveThis study aims to explore the possible mechanism of miR-29a inhibiting papillary thyroid carcinoma (PTC) through the downregulation of TAGLN2. The paper expects to find novel targets for PTC treatment and prognosis improvement, and is also of great significance in enhancing the overall therapeutic level of PTC and improving life quality of patients. MethodsChanges in PTC cell growth, migration, and invasive ability were respectively detected using MTS assays, wound healing experiments, and Matrigel matrix invasion assays. Expressions of E-cadherin, N-cadherin, vimentin, and MMP2 were determined by Western blotting. Differences in protein expressions between groups were compared. Overexpression and knockdown of TAGLN2 were performed in K1 cells, and the expression levels of PI3K/AKT pathway protein in K1 cells were detected by Western blotting. ResultmiR-29a significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of K1 cells. Overexpression of miR-29a played an important role in improving the malignant phenotype of PTC by regulating the expression of actin-binding protein TAGLN2. Overexpression of TAGLN2 can counteract the inhibitory effect of miR-29a on K1 cells. TAGLN2 can activate the PI3K/AKT signaling pathway, indicating that it may promote the progress of EMT by activating PI3K/AKT. ConclusionThe miR-29a/TAGLN2 axis may affect the malignant phenotype of K1 cells by regulating downstream PI3K/AKT signaling pathways, thus providing a new target for the treatment of PTC.

Current Concepts in the Molecular Mechanisms and Management of Diabetic Neuropathy by Pharmacotherapeutics and Natural Compounds.

One of the most crippling effects of diabetes mellitus is diabetic neuropathy, which can cause discomfort, loss of movement, and even amputation. Diabetic neuropathy manifests in a variety of ways, ranging from pain to death. Diagnosing diabetic neuropathy can be challenging since it often goes unnoticed for many years following the onset of diabetes. In addition to oxidative stress in neurons, hyperglycemia activates a number of metabolic pathways that are important sources of damage and possible targets for treatment in diabetic neuropathy. Downstream metabolic cascades caused by prolonged hyperglycemia include activation of protein kinase C, increased production of advanced glycation end products, excessive release of cytokines, increased oxidative stress, and injury to peripheral nerves. Despite the fact that these metabolic anomalies are considered the main cause of diabetes-related microvascular issues, the diverse mechanistic processes of neuropathy are characterized by organ-specific histological and biochemical features. Although the symptoms of diabetic neuropathy can be treated, there are few options to correct the underlying problem. Diabetic neuropathy exerts a tremendous financial, psychological, and physical burden on society, emphasizing the need for efficient and focused treatment. The major goal of this review is to shed light on the multiple mechanisms and pathways that contribute to the onset of diabetic neuropathy and to provide readers with a comprehensive understanding of emerging therapeutic strategies to postpone or reverse various forms of diabetic neuropathy. The article discusses available medications and provides the latest guidelines for the treatment of pain and distal symmetric polyneuropathy, including diabetic autonomic neuropathy, which may help the patients control pain well and assess alternatives for treatment that might be more successful in preventing or delaying the course of a disease.

AQP4-AS1 Can Regulate the Expression of Ferroptosis-Related Regulator ALOX15 through Competitive Binding with miR-4476 in Lung Adenocarcinoma.

Background The AQP4-AS1/miR-4476-ALOX15 regulatory axis was discovered in previous studies. We aimed to investigate the regulatory mechanism of the ferroptosis-related regulator ALOX15 by AQP4-AS1 and miR-4476 in lung adenocarcinoma (LUAD) and find new targets for clinical treatment. Methods After bioinformatics analysis, we contained one ferroptosis-related gene (FRG), namely ALOX15. MicroRNAs (miRNAs) and long noncoding RNAs were predicted by miRWalk. Furthermore, we constructed overexpressed LUAD cell lines. Real-time quantitative polymerase chain reaction and western blot were used to determine the expression of mRNA and protein, respectively. Cell Counting Kit-8 (CCK-8) and EdU assay were used to detect the cell proliferation. Double luciferase assay was used to detect the binding relationship between AQP4-AS1 and miR-4464. Results ALOX15 was the most significantly downregulated FRG compared with normal tissues. Furthermore, protein-protein interaction network analysis indicated that the AQP4-AS1-miR-4476-ALOX15 regulatory axis might be involved in the occurrence and development of LUAD and there might be direct interaction between AQP4-AS1 and miR-4476, and miR-4476 and ALOX15. Furthermore, AQP4-AS1 and ALOX15 were significantly downregulated in the LUAD tissue and cell lines, whereas miR-4476 showed the opposite results ( p < 0.001). AQP4-AS1 overexpression improved the ALOX15 expression in LUAD cell lines. CCK-8 and EdU assay revealed that overexpression of AQP4-AS1 and ALOX15 inhibited the LUAD cell proliferation. Double luciferase assay results indicated that there was a combination between AQP4-AS1 and miRNA-4476. In addition, we found that overexpressed AQP4-AS1 activates the ferroptosis in LUAD cell lines. Conclusions AQP4-AS1 can regulate the expression of ALOX15 through competitive binding with miR-4476, further activate ferroptosis and inhibit the proliferation of LUAD cells.

MiR‑1343‑3p inhibits autophagy by directly targeting ATG7 in multiple myeloma cells.

Multiple myeloma (MM) is the second most common type of hematological malignancy globally. Despite application of several new drugs, such as daratumumab, bortezomib/lenalidomide/dexamethasone, in combination with hematopoietic stem cell transplantation, overall prognosis remains poor and the pathological mechanism of MM is still unknown. The present study used TargetScan to predict autophagy-related 7 (ATG7) as a candidate target gene of microRNA (miR)-1343-3p and confirmed the interaction between miR-1343-3p and the ATG7 3' untranslated region (3'UTR) using a dual-luciferase reporter assay. In U266 and RPMI-8226 MM cell lines, miR-1343-3p mimic transfection decreased mRNA and protein levels of ATG7, while miR-1343-3p inhibition increased ATG7 expression levels using reverse transcription-qPCR and western blot analysis. miR-1343-3p mimic transfection inhibited U266 and RPMI-8226 cell survival. Finally, miR-1343-3p regulated ATG7 and autophagy in MM cells using western blot analysis. The present findings suggested that miR-1343-3p may regulate ATG7 and autophagy by directly targeting the 3'UTR of ATG7. To the best of our knowledge, there are no direct data showing the roles of miR-1343-3p in development of MM; however, miR-1343-3p may be considered a potential target for MM treatment.

Triggering receptor expressed on myeloid cells-1 aggravates obliterative bronchiolitis via enhancing the proinflammatory phenotype of macrophages

BackgroundTriggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays an important role in innate immune system. However, whether and how TREM-1 contributes to obliterative bronchiolitis (OB) progression remains unclear. MethodsA murine orthotopic tracheal transplantation model was constructed to mimic the pathogenesis of OB. qPCR and immunoblotting were used to measure TREM-1 expression. RNA sequencing was used to investigate the impact of TREM-1 on proinflammatory phenotype of macrophages. Trem-1 knockout mice and Nlrp3 knockout mice were generated to investigate the role of the TREM-1/NLRP3 pathway in the proinflammatory phenotype of macrophages. The infiltration of immune cells within the grafts was quantified using immunofluorescence staining. Flow cytometry was used to detect the proportion of different immune cells in mice spleen and the expression levels of iNOS and co-stimulatory molecules in macrophages. ResultsThe expression of TREM-1 was upregulated in the mouse OB model. Genetic ablation or pharmacological inhibition of TREM-1 ameliorated OB, whereas the stimulation of TREM-1 using anti-TREM-1 agonistic antibody exacerbated OB. Moreover, Trem-1 ablation reduced the infiltration of iNOS+ macrophages and limited the T cell responses. In vitro studies revealed that Trem-1 deletion impaired the proinflammatory function and antigen presentation ability of macrophages. Additionally, Trem-1 knockout inhibited the activation of NLRP3 signaling pathway. NLRP3 overexpression restored the proinflammatory phenotype of Trem-1 knockout macrophages. ConclusionsThese findings indicated that TREM-1 could promote the proinflammatory phenotype of macrophages through NLRP3 inflammasome activation, thereby exacerbating OB progression. These findings indicated that TREM-1 may serve as a therapeutic target for OB treatment.

Molecular Dynamics of a N-Cyclohexyl-1,2,4-Oxadiazole Derivative as a Reversible Cruzain Inhibitor in Trypanosoma cruzi.

Chagas disease kills around 10,000 people yearly, primarily in Latin America, where it is prevalent. Current treatment has limited chronic effectiveness, is unsafe, and has substantial side effects. As a result, the use of oxadiazole derivatives and similar heterocyclic compounds as bioisosteres are well known, and they are prospective candidates in the hunt for novel anti-Trypanosoma cruzi chemicals. Recent research has revealed that the cysteine protease cruzain from T. cruzi is a validated target for disease treatment. Thus, using a molecular dynamics simulation, the current study attempted to determine if a significant interaction occurred between the enzyme cruzain and its ligand. Interactions with the catalytic site and other critical locations were observed. Also, the RMSD values suggested that the molecule under research had stable interactions with its target. Finally, the findings indicate that the investigated molecule 2b can interfere enzymatic activity of cruzain, indicating that it might be a promising antichagasic drug.

Retinoic acid receptor responder 2 and lipid metabolic reprogramming: A new insight into brain metastasis.

The brain is a common metastatic site for carcinoma, and metabolic reprogramming is crucial for organ-tropic metastatic formation. Li et al. found RARRES2 deficiency affected lipid metabolic reprogramming through PTEN-mTOR-SREBP1 pathway and promoted BCBrM. Other studies revealed that lipid metabolic reprogramming is part of metabolic adaptation to central nervous system. Overall, there is an intricate connection between lipid metabolism and brain metastases, and disrupting this connection may be a potential therapeutic target for BCBrM treatment.

Development and biopharmaceutical evaluation of aqueous micelle based corticosteroid formulations for topical treatment of oral lichen planus.

The dearth of approved products to treat oral lichen planus (OLP) compels off-label use of dermatological corticosteroid formulations not optimized for indications in the oral cavity. The aims of this study were to develop aqueous micelle based formulations of triamcinolone acetonide (TA) and fluocinonide (FLU), using D-tocopheryl polyethylene glycol succinate, and to investigate corticosteroid delivery to the epithelium-lamina propria junction region - the anatomical target for OLP treatment - in comparison to that from marketed products. Total mucosal deposition of TA after application of Kenacort® A Orabase® (0.1 % TA) and micellar hydrogel (0.1 %) was 242.1 ± 68.5 and 5936.7 ± 1269.6 ng/cm2, respectively. For FLU, deposition after application of Novoter (0.05 % FLU) and micellar hydrogel (0.05 %) was 617.1 ± 126.5 and 2580.0 ± 285.5 ng/cm2, respectively. A buccal biodistribution study showed that application of micelle hydrogels under occlusion for 30 min delivered 117.0 ± 15.6 ng/cm2 and 225.6 ± 36.7 ng/cm2, of TA and FLU, respectively, to the epithelium-lamina propria junction region. In contrast, the amounts deposited after applying Kenacort® A Orabase® and Novoter, were < LOQ. The results demonstrated that TPGS-based micelles improved mucosal bioavailability of TA and FLU in the epithelium-lamina propria junction region and might serve to improve topical OLP therapy.

LGALS3 regulates endothelial-to-mesenchymal transition via PI3K/AKT signaling pathway in silica-induced pulmonary fibrosis

Silicosis is a progressive and chronic occupational lung disease characterized by lung inflammation, silicotic nodule formation, and diffuse pulmonary fibrosis(Jin et al. 2024). Emerging evidence indicates that endothelial-mesenchymal transition (EndoMT) plays a crucial role in the development of silicosis. Herein, we conducted a SiO2-induced EndoMT model and established a mouse model with pulmonary fibrosis by silica. We identified that SiO2 effectively increased the expression of mesenchymal markers while decreasing the levels of endothelial markers in endothelial cells. It’s further demonstrated that SiO2 induced the PI3K/Akt signaling pathway activation via LGALS3 synthesis. Next, interfering LGALS3 blocked the process of EndoMT by inhibiting the activity of PI3K/AKT signaling. In vivo, the administration of a specific PI3K inhibitor LY294002 significantly alleviated silica-induced pulmonary fibrosis. Collectively, these results identified that the LGALS3/PI3K/AKT pathway provided a rationale target for the clinical treatment and intervention of silicosis.

Identification of the Roles of Coagulation-related Signature and its Key Factor RABIF in Hepatoma Cell Malignancy.

Hepatoma is a high morbidity and mortality cancer, and coagulation is a potential oncogenic mechanism for hepatoma development. In this study, we aimed to reveal the role of coagulation in hepatoma. We applied the LASSO to construct a coagulation-related risk score (CRS) and a clinical nomogram with independent validation. The heterogeneity of various aspects, including functional enrichment, SNV, CN, immunocyte infiltration, immune pathways, immune checkpoint, and genomic instability indexes, was evaluated. Besides, the prognostic value of the CRS genes was tested. We selected the critical risky gene related to coagulation from the LASSO coefficients, for which we applied transwell and clone formation assays to confirm its roles in hepatoma cell migration and clone formation ability, respectively. The CRS and the nomogram predicted patients' survival with good accuracy in both two datasets. The high-CRS group was associated with higher cell cycle, DNA repair, TP53 mutation rates, amplification, and lower deletion rates at chromosome 1. For immunocyte infiltration, we noticed increased Treg infiltration and globally upregulated immune checkpoints and genomic instability indexes. Additionally, every single CRS gene affected the patient's survival. Finally, we observed that RABIF was the riskiest gene in the CRS. Its knockdown suppressed hepatoma cell migration and clone formation capability, which could be rescued by RABIF overexpression. We built a robust CRS with great potential as a prognosis and immunotherapeutic indicator. Importantly, we identified RABIF as an oncogene, promoting hepatoma cell migration and clone formation, revealing underlying pathological mechanisms, and providing novel therapeutic targets for hepatoma treatment.

Transcription factor PRRX1-activated ANXA6 facilitates EGFR-PKCα complex formation and enhances cisplatin sensitivity in bladder cancer

BackgroundTumor resistance to cisplatin represents a major clinical challenge, particularly in bladder cancer (BC). ANXA6 is a member of annexin family, and its role in cisplatin resistance remains unclear. This study explores ANXA6's role in promoting cisplatin sensitivity. MethodsBioinformatics analyses and clinical specimen verifications assessed the correlation between ANXA6 and cisplatin treatment. A series of assays, including CCK-8, clone formation assay, flow cytometry assays for reactive oxygen species (ROS) and apoptosis, and comet assays, were used to confirm ANXA6's role in enhancing cisplatin sensitivity and re-sensitizing resistant BC cells. Mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments elucidated ANXA6's role in enhancing PKCα/EGFR complex formation and inhibiting the EGFR pathway. ChIP-PCR and dual-luciferase assays determined PRRX1's regulatory role on ANXA6 transcription. Finally, the impact of ANXA6 in vivo was evaluated using xenograft models. ResultsBioinformatics analyses showed a significant correlation between ANXA6 expression and cisplatin sensitivity. In vitro and in vivo experiments confirmed that ANXA6 was a new target for cisplatin treatment. ANXA6 overexpression not only enhanced cell viability inhibition, DNA damage and apoptosis caused by cisplatin, but also re-sensitized cisplatin-resistant cells. Mechanistically, ANXA6 promotes PKCα/EGFR complex formation, inhibiting EGFR phosphorylation and downstream AKT and ERK1/2. Moreover, PRRX1 was identified as a transcription factor promoting ANXA6 expression, thereby augmenting the cytotoxic effects of cisplatin. ConclusionOur study reveals the mechanism by which ANXA6 enhances cisplatin sensitivity and re-sensitizes resistant cells. The roles of PRRX1 and ANXA6 in cisplatin resistance offer new therapeutic targets to overcome cisplatin resistance in clinical practice.

GSDMB interacts with IGF2BP1 to suppress colorectal cancer progression by modulating DUSP6-ERK pathway

There is growing evidence that the protein family of Gasdermins (GSDMs) play an essential role during the progression of colorectal cancer (CRC). However, it is not completely clear that how GSDMB, abundantly expressed in epithelial cells of gastrointestinal tract, regulates the tumorigenesis of CRC. A wealth of evidence linking GSDMB to the pathogenesis of cancer has come from genome-wide association studies. Here, we provide evidence that aberrantly upregulated GSDMB is responsible for suppressing the CRC progression by using in vitro cell and intestinal organoid, as well as in vivo GSDMB transgenic mice models. Mechanistically, GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which directly binds to and recognizes the 3′-UTR of dual specificity phosphatase 6 (DUSP6) mRNA, enhances the translation of DUSP6 protein and inhibits downstream ERK phosphorylation, thereby facilitating cell death and restraining cell proliferation. Our results suggest that GSDMB has potential as a novel therapeutic target for CRC treatment.

The Prognostic Value and Clinical Significance of lncRNA SNHG5 Expression in Patients with Multiple Malignancies: A Bioinformatic and Meta-analysis.

Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA SNHG5) has been identified as both a promising target for treatment and a predictor of prognosis in diverse types of cancer. The objective of this study was to assess whether lncRNA SNHG5 expression can be utilized as a prognostic biomarker for human cancer. To ensure a thorough search of the literature for relevant English studies published before July 2023, several databases were searched, including PubMed, Web of Science, ProQuest, Cochrane Library, and Google Scholar. The study evaluated the impact of lncRNA SNHG5 on the overall survival (OS) of cancer by calculating the pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs). To further confirm the accuracy of the findings, the study investigated the expression profile and prognostic significance of lncRNA SNHG5 through the use of GenomicScape, OncoLnc, Kaplan-Meier plotter, and GEPIA databases. In this study, 995 patients were examined across a total of fourteen original studies. The findings indicated that there was a significant relationship between heightened lncRNA SNHG5 expression and reduced OS, as evidenced by both univariate and multivariate analyses (HR = 1.89; 95% CI, 1.44-2.49; p < 0.001; HR = 3.97; 95% CI, 1.80-8.73; p < 0.001, respectively). Pooled OR analysis showed a significant association between over-expression of lncRNA SNHG5 with advanced histological grade (OR = 0.28; 95% CI, 0.11-0.71; p = 0.007), present lymph node metastasis (LNM; OR = 4.28; 95% CI, 2.47-7.43; p < 0.001), and smoking history (OR = 0.27; 95% CI, 0.15-0.49; p < 0.001). Bioinformatic databases confirmed that elevated SNHG5 expression was significantly linked to poor prognosis in cancer patients, including colorectal cancer (CRC), acute myeloid leukemia (AML), and esophageal adenocarcinoma (ESAD), and a longer OS in patients with uterine corpus endometrial carcinoma (UCEC). These results suggest that lncRNA SNHG5 may serve as an adverse prognostic biomarker in several human cancers. Further investigations are needed to better understand the underlying mechanisms that link lncRNA SNHG5 to multiple malignancies.

Impact of Therapeutic Inertia on Patient-Reported Outcomes in Moderate-to-Severe Atopic Dermatitis: A 12-Month Longitudinal Study from the TARGET-DERM AD Registry

Background: Therapeutic inertia, the delay or reluctance to modify treatment when goals are unmet, is a significant challenge in managing chronic diseases, including atopic dermatitis (AD). This inertia can lead to suboptimal disease control and affect patient outcomes. Objectives: This study evaluates the effect of therapeutic inertia on patient-reported outcomes (PROs) in moderate-to-severe AD patients undergoing systemic treatment over 3 to 12 months. Methods: We analyzed longitudinal data from the TARGET-DERM AD registry, which includes 3,457 patients with moderate-to-severe AD from 39 centers across the U.S. and Canada. Eligible patients had documented patient-reported outcomes (PROs) at the initiation of systemic therapy and at subsequent 3-month intervals up to 12 months of follow-up. We assessed the proportion of patients not meeting treatment targets based on expert consensus. Patients had a validated Investigator Global Assessment (vIGA-AD) score of 3 or more at initiation of either an advanced systemic therapy (AST) such as biologics or JAK inhibitors or a conventional systemic therapy (CST) such as cyclosporine, methotrexate, or prednisone. PROs were evaluated at 3-month intervals up to 12 months, assessing achievement against the predefined treatment targets. PRO measures included Worst-Itch (PROMIS Itch-Severity), POEM, PO-SCORAD, NRS-sleep, and NRS-pain with specific moderate and optimal target levels established for each. Itch-Severity (range: 0–10; moderate target: ≥4-point reduction, optimal target: score ≤1), POEM (range: 0-28; moderate target: ≥4-point reduction, optimal target: score ≤2), PO-SCORAD (range: 0-103; moderate target: score ≤24; optimal target: score ≤10), NRS-sleep and NRS-pain (range: 0-10; moderate target: reduction ≥3-points; optimal target: score ≤1). Results: Out of 2107 patients with moderate-to-severe AD, 445 qualifying participants were included (63.8% adult, 62.0% female, 45.4% Non-Hispanic White, mean age of 31 years). Most patients (88.8%) initiated AST, with dupilumab being the most common (86.5%). At 6 months, significant proportions of AST-treated patients failed to reach moderate and optimal targets for itch (67% and 79%, respectively), POEM (46% and 69%), and NRS-sleep (59% and 47%). By 12 months, these figures were similar, with 66% and 88% failing to meet itch targets, 53% and 73% failing to meet POEM targets, and 62% and 45% failing to meet NRS-sleep targets, respectively. A similar pattern was observed for other PROs. CST-treated patients exhibited similar trends. Conclusions: The study highlights the profound impact of therapeutic inertia on the quality of life of patients with moderate-to-severe AD. Despite systemic therapy, a considerable proportion failed to meet treatment targets over a 12-month period, underscoring the need for more proactive and responsive treatment strategies in AD management.

Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids

AbstractAutism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechanism underlying ASD progression. Here, it is generated induced pluripotent stem cell (iPSC)‐derived cerebral organoids from normocephalic individuals with ASD in a prospective birth cohort with a shared clinical diagnosis. Multiple cell lines and time series scRNA‐seq combined with a histomorphological analysis revealed premature neural differentiation of neural stem cells (NSCs) and decreased expression of Fatty acid binding protein 7 (FABP7) in ASD organoids. It is subsequently revealed alterations in the phosphorylation levels of Mitogen‐Activated Protein Kinase Kinase 1/2 (MEK1/2), which are downstream of FABP7, and the regulation of the FABP7/MEK pathway reversed improper neural differentiation in the ASD organoids. Moreover, both Fabp7‐knockdown and MEK2‐overexpressing mice exhibited repetitive stereotyped behaviors and social defects relevant to autism. This study reveals the role of the FABP7/MEK pathway in abnormal NSC differentiation in normocephalic individuals with ASD, which might provide a promising therapeutic target for ASD treatment.

Characteristic alterations of gut microbiota and serum metabolites in patients with chronic tinnitus: a multi-omics analysis

ABSTRACT Chronic tinnitus is a central nervous system disorder. Currently, the effects of gut microbiota on tinnitus remain unexplored. To explore the connection between gut microbiota and tinnitus, we conducted 16S rRNA sequencing of fecal microbiota and serum metabolomic analysis in a cohort of 70 patients with tinnitus and 30 healthy volunteers. We used the weighted gene co-expression network method to analyze the relationship between the gut microbiota and the serum metabolites. The random forest technique was utilized to select metabolites and gut taxa to construct predictive models. A pronounced gut dysbiosis in the tinnitus group, characterized by reduced bacterial diversity, an increased Firmicutes/Bacteroidetes ratio, and some opportunistic bacteria including Aeromonas and Acinetobacter were enriched. In contrast, some beneficial gut probiotics decreased, including Lactobacillales and Lactobacillaceae. In serum metabolomic analysis, serum metabolic disturbances in tinnitus patients and these differential metabolites were enriched in pathways of neuroinflammation, neurotransmitter activity, and synaptic function. The predictive models exhibited great diagnostic performance, achieving 0.94 (95% CI: 0.85–0.98) and 0.96 (95% CI: 0.86–0.99) in the test set. Our study suggests that changes in gut microbiota could potentially influence the occurrence and chronicity of tinnitus, and exert regulatory effects through changes in serum metabolites. Overall, this research provides new perceptions into the potential role of gut microbiota and serum metabolite in the pathogenesis of tinnitus, and proposes the “gut-brain-ear” concept as a pathomechanism underlying tinnitus, with significant clinical diagnostic implications and therapeutic potential. IMPORTANCE Tinnitus affects millions of people worldwide. Severe cases may lead to sleep disorders, anxiety, and depression, subsequently impacting patients’ lives and increasing societal healthcare expenditures. However, tinnitus mechanisms are poorly understood, and effective therapeutic interventions are currently lacking. We discovered the gut microbiota and serum metabolomics changes in patients with tinnitus, and provided the potential pathological mechanisms of dysregulated gut flora in chronic tinnitus. We proposed the innovative concept of the “gut-brain-ear axis,” which underscores the exploration of gut microbiota impact on susceptibility to chronic tinnitus through serum metabolic profile modulation. We also reveal novel biomarkers associated with chronic tinnitus, offering a new conceptual framework for further investigations into the susceptibility of patients, potential treatment targets for tinnitus, and assessing patient prognosis. Subsequently, gut microbiota and serum metabolites can be used as molecular markers to assess the susceptibility and prognosis of tinnitus.Furthermore, fecal transplantation may be used to treat tinnitus.

Why Do Optimal Targets for Itch and Skin Clearance Matter in Atopic Dermatitis Treatment? Insights from TARGET-DERM AD Registry

Introduction/Background: Atopic dermatitis (AD) patients undergoing treatment may only experience partial improvement in itch and skin lesions, often leading to suboptimal outcomes. The Aiming High in Eczema/Atopic Dermatitis (AHEAD) treat-to-target recommendations emphasize the importance of achieving optimal treatment targets, such as complete or near-complete itch relief and skin clearance. However, there is limited evidence on the impact of achieving these higher efficacy targets on patient-reported outcomes and quality of life in AD. Objectives: To evaluate the independent and combined effects of achieving optimal treatment targets for itch and skin clearance on patient-reported outcomes (PROs) in AD, based on the AHEAD treat-to-target recommendations. Method: A cross-sectional analysis was conducted on adult participants in TARGET-DERM AD, a longitudinal study with over 4,000 participants across 52 U.S. and Canadian clinical-practice sites (2019-2024). Itch severity was measured using the PROMIS Itch-Severity question (NRS-Itch, 0–10 scale), with scores of 0/1 indicating no or minimal itch. Skin severity was assessed using the validated Investigator Global Assessment (vIGA-AD), where 0/1 represents clear or almost clear skin. Associations between itch and skin severity with optimal patient outcomes including POEM 0–2 (clear/almost-clear disease), DLQI 0/1 (minimal/no impact on quality of life), NRS-Sleep 0/1, and NRS-Pain 0/1 were evaluated. Logistic regression models examined the main and interaction effects of itch and skin severity. Results: Among 1,920 patients (58.6% female; 54.5% Non-Hispanic White; 93.8% US; mean age 45 years), optimal DLQI, POEM, NRS-Sleep, and NRS-Pain occurred most frequently among those achieving the optimal treatment targets for itch (WI-NRS 0/1; 52.1%, 53.7%, 57.3%, and 83.1%, respectively) and skin clearance (vIGA-AD 0/1; 44.7%, 44.3%, 44.7%, and 74.3%, respectively). Compared to partial improvement, the adjusted odds ratios (aOR) of optimal PROs were greatest for participants with complete or near-complete resolution of both itch and skin lesions (DLQI 0/1: 20.0; POEM 0-2: 41.7; Sleep-NRS: 16.1; Pain-NRS: 6.0). Conclusions: Achieving optimal treatment targets for both itch and skin lesions markedly enhances patient-reported outcomes in AD. The results of this real-world study support treat-to-optimal targets to assess therapeutic effectiveness and optimize patient outcomes.

Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis and Inadequate Response to Dupilumab: Efficacy and Safety Results from the Phase 3b/4 LEVEL UP Study

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4 and interleukin-13 signaling, are both approved treatments for moderate-to-severe AD. LEVEL UP is a phase 3b/4 efficacy assessor blinded monotherapy study comparing UPA to DUPI for treatment of moderate-to-severe AD in adults and adolescents over a 16-week period (Period 1). Patients not achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) from baseline at Week 16 entered an additional 16-week extension phase (Period 2). In Period 2, patients either continued/escalated to UPA 30 mg (UPA/UPA 30) or switched from DUPI to UPA 15 mg (DUPI/UPA), with the potential to escalate to 30 mg based on clinical response. Efficacy for skin and itch outcomes in Period 2 were assessed using observed case analysis while on treatment, without statistical comparisons. Here we report efficacy and safety results for the DUPI/UPA switch group. A total of 355 patients who did not achieve EASI 75 at Week 16 entered Period 2 of the study (DUPI/UPA, N=208). At Week 32, response rates in the DUPI/UPA group were: 79.6%, 58.7%, and 19.9% achieving EASI 75, EASI 90, and EASI 100, respectively; 60.2% achieving WP-NRS improvement ≥4 among those with baseline WP-NRS ≥4; 37.0% achieving WP-NRS 0/1 among those with baseline WP-NRS &gt;1; and 26.8% simultaneously achieving EASI 90 and WP-NRS 0/1 by Week 32. Clinically meaningful outcomes were also observed at an earlier visit (Week 20). No new safety signals through Week 32 were identified compared to the established safety profile of UPA. Most patients with an inadequate response to DUPI at Week 16 experienced clinically meaningful improvements in skin clearance and itch at 4 weeks post-switch to UPA, with additional patients achieving these outcomes by 16 weeks post-switch. These findings suggest that switching from DUPI to UPA is an effective treatment strategy for patients who do not meet moderate or optimal treatment targets with DUPI.

Persistent Inadequate Disease Control and Therapeutic Inertia in Moderate-to-Severe Atopic Dermatitis: A 12-month Longitudinal Analysis of Real-world Outcomes from the TARGET-DERM AD registry

Background: Therapeutic inertia refers to the delay or failure in treatment escalation in patients not achieving adequate disease control; it is a challenge in the management of moderate-to-severe atopic dermatitis (AD). Despite the availability of conventional (CST) and advanced systemic therapies (AST) utilized for the treatment of moderate to severe AD, many patients do not achieve treatment success. However, the extent of this inadequacy in real-world clinical practice remains underexplored. Objectives: This study evaluates the occurrence of therapeutic inertia and the proportion of patients with moderate-to-severe AD who continue to show inadequate response after receiving systemic therapies for a duration from 3 to 12 months Methods: We conducted a longitudinal analysis of patients with moderate-to-severe AD (vIGA-AD≥3) from the TARGET-DERM AD registry, including 3,457 participants from 39 centers in the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and after 3 months up to 12 months of follow up. We assessed clinician- and patient-reported outcomes to identify the proportion of patients not meeting treatment targets based on expert consensus. An inadequate response was defined as not achieving a validated Investigator Global Assessment (vIGA-AD) score ≤2, a 50% improvement in Body Surface Area (BSA), and a ≥4-point reduction in the Worst Pruritus Numeric Rating Scale (WP-NRS). An optimal response was defined as a vIGA-AD score ≤1 (clear or almost clear skin), BSA ≤2%, and WP-NRS itch score of 0/1 (complete or almost complete skin resolution). Results: Out of 2,107 patients with moderate-to-severe AD, 445 met the inclusion criteria. The majority were adults (63.8%), female (62.0%), and Non-Hispanic White (45.4%), with an average age of 31 years. Most patients (88.8%) initiated treatment with AST, with dupilumab being the most common (86.5%). The mean vIGA-AD was 3.3 for AST and 3.6 for CST at initiation (P&lt;0.01). At 6 months, 37% and 67% of AST-treated patients had inadequate responses in terms of skin clearance and itch outcomes, respectively, while 82% and 79% did not achieve optimal responses. At 12 months, these figures were approximately 30% and 66% for inadequate responses and 85% and 88% for not achieving optimal responses, respectively. CST-treated patients showed a similar trend. Conclusions: The study reveals that a significant portion of moderate-to-severe AD patients fail to achieve adequate disease control with systemic therapies over 12 months, indicating substantial presence of therapeutic inertia. These findings suggest a need for more proactive management strategies in AD treatment.

Long-Term Maintenance of Optimal Treatment Targets for Skin and Itch Outcomes With Upadacitinib in Moderate-to-Severe Atopic Dermatitis: 140-Week Results From the Phase 3 Measure Up 1 and 2 Studies

Introduction: Despite undergoing prolonged systemic therapy, many patients with moderate-to-severe atopic dermatitis (AD) do not achieve optimal targets for skin and itch outcomes as defined by Aiming High in Eczema/AD (AHEAD) recommendations (eg, ≥90% improvement from baseline in Eczema Area and Severity Index [EASI 90] and Worst Pruritus Numerical Rating Scale [WP-NRS] score of 0/1 [no/minimal itch]). We evaluated long-term maintenance of optimal treatment targets with upadacitinib, an oral selective JAK inhibitor approved for moderate-to-severe AD in adolescents and adults. Methods: This 140-week interim analysis included adolescents and adults with moderate-to-severe AD who were randomized at baseline to upadacitinib 15 mg (UPA15) or 30 mg (UPA30) in the ongoing, phase 3, double-blind Measure Up 1 and 2 studies. Assessments included the proportion of patients (at the population level) who maintained EASI 90, WP-NRS 0/1, or simultaneous achievement of EASI 90 + WP-NRS 0/1 responses from week 16 (end of the placebo-controlled period) onwards. Data are reported as observed cases with no imputation for missing data. Results: Among patients who achieved EASI 90 at week 16 (UPA15, n=298; UPA30, n=384), EASI 90 was maintained by 79.8% (UPA15) and 83.7% (UPA30) at week 52, 76.7% (UPA15) and 83.0% (UPA30) at week 100, and 74.0% (UPA15) and 84.2% (UPA30) at week 140. Of patients achieving WP-NRS 0/1 at week 16 (UPA15, n=193; UPA30, n=281), WP-NRS 0/1 was maintained by 69.4% (UPA15) and 72.0% (UPA30) at week 52, 65.6% (UPA15) and 68.4% (UPA30) at week 100, and 62.3% (UPA15) and 66.0% (UPA30) at week 140. Of patients simultaneously achieving EASI 90 + WP-NRS 0/1 at week 16 (UPA15, n=156; UPA30, n=243), maintenance was achieved by 68.1% (UPA15) and 70.8% (UPA30) at week 52, 62.7% (UPA15) and 66.5% (UPA30) at week 100, and 58.7% (UPA15) and 64.4% (UPA30) at week 140. Among patients who did not maintain optimal outcomes, most still achieved clinically meaningful responses. Conclusion: Most patients maintained optimal skin and itch outcomes through 140 weeks of upadacitinib treatment, demonstrating its potential to provide sustained long-term disease control in atopic dermatitis.