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Corrigendum To Effects Of Dialysate Potassium Concentration Of 3.0 Mmol/L With Sodium Zirconium Cyclosilicate On Dialysis-Free Days Versus Dialysate Potassium Concentration Of 2.0 Mmol/L Alone On Rates Of Cardiac Arrhythmias In Hemodialysis Patients With Hyperkalemia. Kidney International 2025;107:169-179
No full textThe Perk/ATF4 Pathway Is Required for Metabolic Reprogramming and Progressive Lung Fibrosis
No full textAsbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis individuals had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/- Lyz2-cre mice was reduced to control levels. PERK increased activating transcription factor 4 (Atf4) expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a therapeutic target to reverse established fibrosis
Gut Dysbiosis Patterns in Cvid Patients With Noninfectious Complications Observed in a Germ-Free Mouse Model Through Fecal Microbiota Transplantation
No full textPatients with common variable immunodeficiency (CVID) who develop noninfectious complications (NIC) have worse clinical outcomes than those with infections only (INF). While gut microbiome aberrations have been linked to NIC, reductionist animal models that accurately recapitulate CVID are lacking. Our aim in this study was to uncover potential microbiome roles in the development of NIC in CVID. We performed whole-genome shotgun sequencing on fecal samples from CVID patients with NIC, INF, and their household controls. We also performed fecal microbiota transplants from CVID patients to germ-free mice. We found potentially pathogenic microbe
Peripheral Extracellular Vesicles for Diagnosis and Prognosis of Resectable Lung Cancer: The LUCEx Study Protocol
No full textBackground/Objectives: Lung cancer is the primary cause of cancer-related deaths. Most patients are typically diagnosed at advanced stages. Low-dose computed tomography (LDCT) has been proven to reduce lung cancer mortality, but screening programs using LDCT are associated with a high number of false positives and unnecessary thoracotomies. It is therefore imperative that a certain diagnosis is refined, especially in cases of solitary pulmonary nodules that are difficult to technically access for an accurate preoperative diagnosis. Extracellular vesicles (EVs) involved in intercellular communication may be an innovative biomarker for diagnosis and therapeutic strategies in lung cancer, regarding their ability to carry tumor-specific cargo. The aim of the LUCEx study is to determine if extracellular vesicle cargoes from both lung tissue and blood could provide complementary information to screen lung cancer patients and enable personalized follow-up after the surgery.
Methods: The LUCEx study is a prospective study aiming to recruit 600 patients with lung cancer and 50 control subjects (false positives) undergoing surgery after diagnostic imaging for suspected pulmonary nodules using computed tomography (CT) scans. These patients will undergo curative surgery at the Department of Thoracic Surgery of the Miguel Servet Hospital in Zaragoza, Spain, and will be followed-up for at least 5 years. At baseline, samples from both tumor distal lung tissue and preoperative peripheral blood will be collected and processed to compare the quantity and content of EVs, particularly their micro-RNA (miRNA) cargo. At the third and fifth years of follow-up, CT scans, functional respiratory tests, and blood extractions will be performed.
Discussion: Extracellular vesicles and their miRNA have emerged as promising tools for the diagnosis and prognosis of several diseases, including cancer. The LUCEx study, based on an observational clinical cohort, aims to understand the role of these vesicles and their translational potential as complementary tools for imaging diagnosis and prognosis
Dual Targeting of Orphan Nuclear Receptors NR4A1 and NR4A2 for Nonhormonal Endometriosis Therapy
No full textPrevious studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3\u27-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell growth, survival, and migration and also some of the same genes in endometriotic epithelial and stromal cells. For example, DIM-3,5 compounds downregulate ERβ in stromal but not epithelial endometriotic cells, and this response is NR4A1- and not NR4A2-dependent. Among the EMT-related markers, claudin-1 is induced by DIM-3,5 ligands and after knockdown of NR4A1 or NR4A2 in both epithelial and stromal cells. Most of the EMT markers are downregulated by DIM-3,5 ligands and are coregulated by NR4A1 and NR4A2. In vivo studies showed that DIM-3,5-Cl2 significantly reduced the growth of endometriotic lesions in a mouse model without inducing cytotoxicity during treatment. Thus, DIM-3,5 derivatives simultaneously suppress NR4A1- and NR4A2-dependent endometriosis progression effectively and represent a promising nonhormonal therapeutic strategy to replace current hormone-based treatments that can be associated with adverse effects
Author Correction: Generation of a Tree Shrew Breast Cancer Model Using Lentivirus Expressing PIK3CA-H1047R
No full textDysregulated Mitochondrial Energy Metabolism Drives the Progression of Mucosal Field Effects to Invasive Bladder Cancer
No full textMultiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. The mutational landscape emerged on a background of disorganized urothelial differentiation, activated epithelial-mesenchymal transition, and enhanced immune infiltration with T-cell exhaustion. Complex dysregulation of mitochondrial energy metabolism with downregulation of oxidative phosphorylation emerged as the leading mechanism driving the progression of mucosal field effects to invasive cancer. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
Author Correction: Orthogonal and Multiplexable Genetic Perturbations With an Engineered Prime Editor and a Diverse RNA Array
No full textCorrection to: Nature Communications 10.1038/s41467-024-55134-9, published online 30 December 2024 In the version of the article initially published, there were errors in Fig. 3d, where in the x-axis labels now reading “GPP-shRNA1, GPP-shRNA2, GPP-shRNA3…,” the second and third labels were duplicates of the first. The figure is amended in the HTML and PDF versions of the article
Stress, Employment Changes, and Psychological Distress Among Caregivers of Patients With Head and Neck Cancer
No full textImportance: Patients undergoing external beam radiation therapy (EBRT) for head and neck cancer (HNC) often experience adverse effects that require substantial caregiving. The burdens of caregiving can impact caregiver employment and mental health over time, yet this topic remains underexplored.
Objective: To examine the associations between caregiving for patients with HNC who undergo EBRT and caregiver stress, employment status, and psychological distress.
Design, setting, and participants: This was a secondary analysis of data from a longitudinal survey study that surveyed caregivers at baseline (ie, at initiation of EBRT) and at 4-month and 12-month follow-ups. The study was conducted at 2 comprehensive cancer centers in Houston, Texas, and New York, New York, and included patients with HNC who had undergone EBRT and their caregivers. Data were collected from September 1, 2009, to August 31, 2014, and were analyzed from June 1, 2024, to August 31, 2024.
Main outcomes and measures: The primary outcomes included caregiver employment status and psychological distress level, the latter of which was measured using the Brief Symptom Inventory-18 (BSI-18) for general distress and the Impact of Event Scale-Revised (IES-R) for cancer-specific distress.
Results: The study included 188 caregivers, 159 (84.6%) of whom were female; the mean (SD) age for all caregivers was 54.6 (10.4) years. At baseline, 53 caregivers (28.2%) met BSI-18 criteria for general distress, and 85 (45.2%) met IES-R criteria for cancer-specific distress. By the 12-month follow-up, these rates decreased to 16 of 112 (14.3%) and 30 of 112 (26.8%), respectively. Caregivers were 40% less likely to be employed full-time at the 4-month follow-up (odds ratio, 0.60 [95% CI, 0.48-0.75]), and this reduction persisted with a 41% lower likelihood of full-time employment at the 12-month follow-up (odds ratio, 0.59 [95% CI, 0.47-0.74]). Caregivers who reduced their work hours or exited the workforce during the entire study period (n = 48 [25.5%]) reported higher levels of general distress (β = 4.02 [95% CI, 0.65-7.39]). Furthermore, greater role captivity (β = 5.37 [95% CI, 2.12-8.63]) and lower caregiving competence (β = -3.84 [95% CI, -6.21 to -1.47]) were associated with elevated levels of both general distress and cancer-specific distress.
Conclusions and relevance: The findings of this survey study suggest that caregiving for patients with HNC undergoing EBRT may be associated with lower employment rates and poorer mental health among caregivers. Integrating caregivers into multidisciplinary HNC care to identify those at risk and connecting them to timely employment-based interventions such as flexible work arrangements and caregiver leave, as well as community-based support services such as counseling and social network-building, could help alleviate the dual burden of employment strain and psychological distress, benefiting both caregivers and patients