Citations

Abstract Lung fibroblasts are key regulators of tissue homeostasis and extracellular matrix (ECM) remodeling, and their aberrant activation drives the progressive parenchymal scarring characteristic of idiopathic pulmonary fibrosis (IPF), a fatal disease with limited therapeutic options. Despite their central pathogenic role, lung fibroblasts are difficult to isolate due to their embedded position within the ECM, and standard in vitro culture conditions may lead to the loss of their native functional and transcriptional characteristics, hampering the study of fibroblast behavior in disease. The transcriptional heterogeneity of lung fibroblast subtypes and the extent to which culture-induced alterations diverge from native tissue signatures remain poorly understood. Here, we integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics of lung tissue from IPF patients and age-matched healthy donors with transcriptomic profiling of cultured fibroblasts collected at passages 1 and 6 after isolation using three optimized protocols: whole lung cell suspension (WLCS), negative fraction enrichment, and outgrowth. Tissue-based analysis identified six transcriptionally distinct mesenchymal subtypes: alveolar, adventitial, inflammatory, peribronchial, CTHRC1+ and smooth muscle cell (SMC). The fibroblast subtype CTHRC1+ represented the most transcriptionally activated pro-fibrotic subtype, showing the greatest upregulation of ECM biosynthesis genes, a prominent role in intercellular communication, and preferential enrichment within fibroblastic foci in IPF lung tissue. Pseudotime trajectory analysis supported a directional transcriptional continuum from alveolar and inflammatory fibroblasts toward the CTHRC1+ state, driven by coordinated activation of pro-fibrotic transcription factors, including RUNX2, CREB3L1, and SCX. In vitro culture progressively reshaped fibroblast transcriptional identity relative to native tissue, with increased collagen and matrix metalloproteinase (MMP) expression during passaging, loss of distinct CTHRC1+ fibroblasts, and gain of alveolar fibroblasts displaying pro-fibrotic activation across all isolation protocols. These findings provide a high-resolution transcriptional map of lung fibroblast heterogeneity in IPF and highlight critical limitations of standard in vitro culture systems for recapitulating native fibroblast diversity, with important implications for the development and evaluation of fibroblast-targeted therapeutic strategies in IPF.

A systematic clinical approach is required for the diagnosis and management of renal and ureteral stones. The presenting symptoms, past medical history, medications, and physical examination all provide clues to the diagnosis of urinary stones. In the acute setting, noncontrast helical computerized tomography has emerged as the first line imaging test for renal colic. More traditional imaging tests are also important in the management of stone disease. After making the diagnosis of a urinary stone, the urologist should discuss the advantages and disadvantages of all treatment options with the patient. For most stone patients today, many equally effective treatment approaches can exist for the same problem. To help direct surgical management, guidelines for stone management have been devised. With technologic advances, stone treatment has improved and complications have decreased. While patient care has been significantly impacted by use of effective endourologic techniques, patients should complete imaging tests following surgery to assure a stone-free state. In addition, recurrent stone formers should complete a medical stone evaluation to identify treatable causes of their stones.

Epidural and dorsal root stimulation have emerged as promising therapies to restore function after spinal cord injury. However, how each modality uniquely or jointly engages spinal circuits remains unclear. To address this, we analyzed leg electromyography (EMG) responses to epidural stimulation (ES) and dorsal root ganglia stimulation (DRGS) delivered to the lumbosacral cord in the same individuals.

Purpose: To determine the incidence of secondary IOL implantation in a cohort of children randomized to aphakia after unilateral congenital cataract surgery. Setting: Twelve clinical sites in the United States. Design: Randomized clinical trial. Data regarding secondary IOL implantation was collected retrospectively when patients were age 10½ years. Methods: We calculated the cumulative incidence of secondary IOL implantation in participants in the Infant Aphakia Treatment Study (IATS) who were randomized to aphakia to age 4½ years and were followed at age 10½ years. Results: Twenty-two (43%, 95% CI 29%,58%) of the 51 participants left aphakic to age 4½ years who had better than light perception vision at age 4½ years received a secondary IOL by age 10½. More than half (59%) of these were implanted by age 6 (Median 64.5 months, IQR 60,80). Secondary IOLs were implanted in children with good visual acuity (<20/40), as well as those with poor visual outcomes (>20/200) (39% and 44% respectively). Children who received a secondary IOL did not report less contact lens wear than those remaining aphakic (average of 94% of waking hours versus 90%, respectively). However, the proportion of children receiving a secondary IOL varied substantially by study center. Conclusions: Many children with unilateral congenital cataract who are initially left aphakic remain aphakic throughout the elementary school years. Practice patterns and family preference seem to be important drivers of the decision to implant a secondary IOL in these children.

Abstract Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R ⁻ , drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 ⁺ and CD8 ⁺ T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 ⁺ T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 ⁺ T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive ‘viral-induced precursors’ (VIPs) and Timer-negative KLRG1 ⁺ ‘viral-induced terminal effectors’ (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 ⁺ T cell reprogramming, and durable regression of distant lesions in patients.

Organ transplantation has become an established treatment option for end-stage organ disease. Both living and end-of-life (so called deceased) organ donation narrow the gap between supply and demand for transplantable organs. Advances in human biology prove that death occurs as a gradual process over time and not as a single discrete event. Declaring death with either neurological criteria (heart-beating organ donation) or circulatory criteria (non-heart-beating organ donation) enables the procurement of transplantable organs before human death is complete, namely, from the incipiently dying donor. Thus, surgical procurement of organs from the incipiently dying donor is the proximate cause of death, raising new questions on end-of-life organ donation. It is imperative to first and foremost care for the patient as a dying person. International Muslim scholars should reevaluate previous Islamic rulings and provide guidance about current practice of end-of-life organ donation.

Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 overexpression. Historically, treatment options for TNBC have been limited, because of the absence of actionable targets. The addition of immune checkpoint inhibitors to chemotherapy improved outcomes for a subset of patients with metastatic PD-L1–positive disease; however, a critical need for more effective therapies remains. Antibody-drug conjugates (ADCs) have been a promising advance in the management of advanced TNBC and are reshaping the landscape as they move earlier into the treatment algorithm. A greater understanding of the molecular heterogeneity of TNBC has enabled the pursuit of more targeted and personalized therapeutic strategies. Despite this, TNBC continues to have the least favorable outcomes compared with other breast cancer subtypes. This review highlights current evidence and future challenges in advanced TNBC, including optimizing therapeutic sequencing and the ongoing need for predictive biomarkers and novel agents.

PURPOSE Since 2012, several states have implemented mandatory paid sick leave (PSL) policies. PSL can provide patients time and income continuity to undergo screening and/or timely diagnostic workup for new cancer-related symptoms and complete lengthy and expensive cancer treatment courses. This study aimed to examine the association between mandatory PSL policies and cancer stage at diagnosis and overall survival (OS). METHODS Adults age 18-64 years diagnosed with cancer were identified from the Surveillance, Epidemiology, and End Results program registries between 2010 and 2019. Difference-in-differences (DID) analyses were used to compare absolute changes in stage I and stage IV diagnoses and 1-year OS before and after policy implementation in states that enacted mandatory PSL relative to states that did not enact such policies. RESULTS A total of 1,052,307 patients with cancer were included. In adjusted DID analyses, there were a 0.83 (95% CI = –1.49 to –0.16, P = .014) PP decrease in stage IV diagnoses and a 0.63 (95% CI = 0.10 to 1.17, P = .021) PP increase in 1-year OS associated with implementation of mandatory PSL policies. In exploratory analyses, males and individuals with lung cancer experienced the greatest shifts in policy-associated changes in stage at diagnosis and OS. CONCLUSION PSL policy implementation is associated with decreased late-stage diagnoses and improved OS in patients with cancer. Policies that improve opportunities to receive medical care may facilitate earlier cancer detection and ultimately contribute to better patient outcomes.