Daily Respiratory Research Analysis
Analyzed 196 papers and selected 3 impactful papers.
Summary
Analyzed 196 papers and selected 3 impactful articles.
Selected Articles
1. Clinical outcomes with perioperative nivolumab by nodal status in patients with stage III resectable NSCLC: phase 3 CheckMate 77T exploratory analysis.
In this exploratory analysis of the phase 3 CheckMate 77T trial, perioperative nivolumab plus chemotherapy significantly improved 1-year event-free survival and pathologic complete response in stage III N2 NSCLC compared with chemotherapy alone. Benefits extended to multistation N2 disease, with higher rates of nodal downstaging and more frequent simple lobectomy.
Impact: These results support perioperative chemoimmunotherapy as a standard approach in resectable stage III N2 NSCLC and challenge the assumption that N2 status confers uniformly poor prognosis under modern immunotherapy.
Clinical Implications: For resectable stage III N2 NSCLC, integrating nivolumab with neoadjuvant chemotherapy followed by adjuvant nivolumab can improve EFS and pCR and may facilitate less extensive surgery. Multidisciplinary teams should consider perioperative immunotherapy irrespective of multistation N2 involvement.
Key Findings
- In N2 disease, 1-year EFS was 70% with nivolumab vs 45% with placebo (HR 0.46, 95% CI 0.30–0.70).
- Pathologic complete response increased to 22.0% with nivolumab vs 5.6% with placebo.
- In multistation N2, 1-year EFS 71% vs 46% (HR 0.43) and pCR 29.0% vs 2.7%.
- Higher rates of nodal downstaging and more simple lobectomies occurred with nivolumab; no new safety signals.
Methodological Strengths
- Randomized phase 3 backbone with prospectively collected outcomes
- Consistent benefit across N2 subgroups including multistation disease
Limitations
- Exploratory subgroup analysis without multiplicity adjustment
- Not powered specifically for nodal-status stratified comparisons
Future Directions: Prospective stratification by nodal burden and biomarker-integrated perioperative strategies (e.g., ctDNA MRD guidance) should be tested to optimize duration and selection for adjuvant nivolumab.
Individuals with non-small-cell lung cancer (NSCLC) with metastases to the ipsilateral mediastinum or subcarinal lymph nodes (N2 disease) have poor long-term survival. This exploratory analysis from the randomized phase 3 CheckMate 77T study assessed clinical outcomes by nodal status in individuals with stage III NSCLC who received neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab (nivolumab) versus neoadjuvant chemotherapy followed by surgery and adjuvant placebo (placebo). Here we show that among patients with N2 disease, nivolumab versus placebo improved event-free survival (1-year rate, 70% versus 45%; hazard ratio, 0.46 (95% confidence interval, 0.30-0.70)) and pathological complete response rate (22.0% versus 5.6%); 77% versus 73% had definitive surgery, of whom 84% versus 74% received a simple lobectomy. Furthermore, nivolumab improved outcomes versus placebo in patients with multistation N2 NSCLC (1-year event-free survival rate: 71% versus 46%; hazard ratio, 0.43 (0.21-0.88); pathological complete response rate, 29.0% versus 2.7%). In the N2 subgroup with definitive surgery, 67% and 59% of patients had nodal downstaging after surgery (57% versus 44% downstaged to node-negative disease). Median EFS in randomized patients with stage III non-N2 NSCLC was not reached with nivolumab and 17.0 months with placebo (1-year EFS rate, 74% versus 62%; hazard ratio, 0.60 (0.33-1.08)). No new safety signals were identified. These findings support perioperative nivolumab plus neoadjuvant chemotherapy as an efficacious treatment for stage III N2 disease and suggest that N2 status may not predict poor prognosis in resectable NSCLC treated with perioperative immunotherapy. ClinicalTrials.gov identifier: NCT04025879 .
2. The OAS-RNase L pathway: Insights from experiments of nature.
Human genetic “experiments of nature” indicate that the OAS–RNase L pathway primarily protects against SARS-CoV-2 by restraining phagocyte-driven post-viral inflammation, rather than by blocking early airway replication. This reframes the pathway’s function from a purely antiviral effector to a regulator of maladaptive inflammation.
Impact: It challenges the canonical view of OAS–RNase L as an antiviral-only effector and highlights therapeutic opportunities targeting post-viral hyperinflammation in COVID-19 and related respiratory diseases.
Clinical Implications: Prioritizes therapies that modulate innate immune-driven post-viral inflammation (e.g., targeting phagocyte pathways) over purely antiviral strategies in late COVID-19 phases; informs biomarker selection and timing for immunomodulation.
Key Findings
- Human OAS1/OAS2/RNase L inborn errors implicate the pathway in controlling post-viral inflammation rather than early replication in the respiratory tract.
- RNase L impacts host and viral ssRNA, linking to translational arrest, interferon signaling, and apoptosis.
- Genetic evidence integrates with gain-of-function observations to position OAS–RNase L as a regulator of phagocyte-driven inflammation in COVID-19.
Methodological Strengths
- Synthesis of convergent human genetic evidence from inborn errors across OAS1/OAS2/RNase L.
- Mechanistic framing integrates molecular biology of RNase L with clinical COVID-19 phenotypes.
Limitations
- Narrative synthesis without a formal systematic methodology may introduce selection bias.
- Translational gaps remain regarding optimal therapeutic targets and timing in clinical settings.
Future Directions: Define biomarkers and interventional windows to modulate phagocyte-driven post-viral inflammation; test OAS–RNase L–targeted or downstream pathway therapies in clinical trials.
The 2'-5' oligoadenylate synthetases (OASs) are type I interferon-inducible enzymes that, with ribonuclease L (RNase L), have been studied in the context of their coupled action as antiviral effectors. RNase L degrades host and viral ssRNA, affecting diverse cellular processes including translational arrest, interferon response, and apoptosis, all of which are thought to restrict viral replication. Recent studies of recessive inborn errors of human OAS1, OAS2, and RNase L, however, revealed that for SARS-CoV-2 infection, the main protective action of this pathway in natura may be through restricting phagocyte-driven postviral inflammation rather than restricting early viral replication in the respiratory tract. This finding is consistent with the identification of gain-of-function
3. Tight junction protein claudin-1 is a novel internalization factor for swine enteric coronaviruses infection.
Claudin-1 is identified as a host internalization factor that binds SeCoV S1/RBD, enhances viral entry, and is necessary for efficient infection in vitro and in vivo. Remarkably, claudin-1 also binds SARS-CoV-2 S1, suggesting a conserved host interaction across coronavirus genera.
Impact: Revealing claudin-1 as a conserved internalization factor reshapes understanding of coronavirus entry beyond canonical receptors and opens a new therapeutic target class at epithelial tight junctions.
Clinical Implications: Although conducted in porcine systems, targeting claudin-1 or its spike interactions could inform broad antiviral strategies and barrier-protective approaches, with translational exploration warranted for human coronaviruses.
Key Findings
- Claudin-1 expression is upregulated in TGEV-infected piglet jejunum and correlates with viral N protein levels.
- Gain- and loss-of-function studies show claudin-1 enhances susceptibility to TGEV, PEDV, and PDCoV; knockout reduces infection.
- Claudin-1 specifically interacts with SeCoV S1/RBD and promotes internalization; it also binds SARS-CoV-2 S1.
- In vivo induction of claudin-1 in piglets increases intestinal PDCoV infection.
Methodological Strengths
- Multisystem validation (overexpression/knockout cell lines and in vivo piglet induction).
- Biochemical interaction mapping between claudin-1 and spike S1/RBD across coronaviruses.
Limitations
- Porcine-focused models may limit direct extrapolation to human respiratory epithelia.
- Functional binding to SARS-CoV-2 S1 is shown, but full entry/replication dependence in human tissues remains untested.
Future Directions: Define claudin-1’s role in human coronavirus entry and pathogenesis, resolve structural interfaces for drug design, and test barrier-targeted antivirals in relevant organoid and in vivo models.
UNLABELLED: Swine enteric coronaviruses (SeCoVs), including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine deltacoronavirus (PDCoV), have been reported to use aminopeptidase N (APN) as a cellular receptor. However, APN alone cannot effectively explain the infection of both APN-positive and APN-negative enterocytes by PEDV and TGEV, nor the wide host range of PDCoV, suggesting the involvement of other host factors. In this study, we demonstrate that TGEV infection in piglets upregulates claudin-1 expression not only in infected cells but also in uninfected cells. Claudin-1 levels correlated strongly with TGEV N protein levels in the jejunum of infected piglets. Functional studies revealed that claudin-1 overexpression enhanced cellular susceptibility to TGEV, PEDV, and PDCoV, whereas its knockout significantly attenuated infection. Mechanistically, claudin-1 specifically interacts with the S1 or receptor-binding domain (RBD) of SeCoVs and promotes viral internalization. Furthermore, induction of claudin-1 in piglets promotes PDCoV infection in the intestine. Notably, claudin-1 also binds to the S1 protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, our results identify claudin-1 as a novel internalization factor for porcine enteric coronaviruses, playing a critical role in facilitating infection within the digestive tract, and highlight its potential as a target for future clinical interventions. IMPORTANCE: We observed a downregulation in the expression of the majority of tight junction proteins in intestinal tissues infected with transmissible gastroenteritis virus (TGEV). However, unexpectedly, claudin-1 exhibited a significant upregulation in intestinal epithelial cells. This intriguing finding prompted us to delve deeper into the potential role of claudin-1 in facilitating virus invasion of epithelial cells. Utilizing overexpression and knockout cell lines, we demonstrate that claudin-1 is an internalization factor for swine enteric coronaviruses (SeCoVs), including TGEV, porcine epidemic diarrhea virus (PEDV), and porcine deltacoronavirus (PDCoV). Notably, claudin-1 interacts with the S1 protein of TGEV, PEDV, PDCoV, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spanning across alpha, beta, and delta coronaviruses. Our findings provide deeper insights into the infection mechanisms and pathogenesis of SeCoVs and SARS-CoV-2.