Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition.

Patterns of Failure in Metastatic NSCLC Treated With First Line Pembrolizumab and Use of Local Therapy in Patients With Oligoprogression.

Introduction: The patterns of failure (POF) for metastatic non-small-cell lung cancer (mNSCLC) treated with immunotherapy are not well established.

Methods: We conducted a retrospective cohort study of mNSCLC that received first-line pembrolizumab with or without chemotherapy at a single academic center from 2015 to 2021. We defined POF with 2 classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination.

Outcomes in Patients With Non-small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy.

Background: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited.

Patients And Methods: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology.

Influence of Mutation on Survival in Patients With Advanced -Mutant Non-Small-Cell Lung Cancer.

Purpose: mutation (MT) in epidermal growth factor receptor () -MT non-small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly established.

Patients And Methods: We performed an analysis of patients with stage IV MT NSCLC with available gene sequencing data. Associations between baseline characteristics; molecular profile, including MT; and survival outcomes were assessed.

Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss.

Mitochondrial membrane potential loss has severe bioenergetic consequences and contributes to many human diseases including myocardial infarction, stroke, cancer, and neurodegeneration. However, despite its prominence and importance in cellular energy production, the basic mechanism whereby the mitochondrial membrane potential is established remains unclear. Our studies elucidate that complex II-driven electron flow is the primary means by which the mitochondrial membrane is polarized under hypoxic conditions and that lack of the complex II substrate succinate resulted in reversible membrane potential loss that could be restored rapidly by succinate supplementation.

Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis.

Nitric oxide (NO) and other reactive nitrogen species target multiple sites in the mitochondria to influence cellular bioenergetics and survival. Kinetic imaging studies revealed that NO from either activated macrophages or donor compounds rapidly diffuses to the mitochondria, causing a dose-dependent progressive increase in NO-dependent DAF fluorescence, which corresponded to mitochondrial membrane potential loss and initiated alterations in cellular bioenergetics that ultimately led to necrotic cell death. Cellular dysfunction is mediated by an elevated 3-nitrotyrosine signature of the mitochondrial complex I subunit NDUFB8, which is vital for normal mitochondrial function as evidenced by selective knockdown via siRNA.

Expression of nitric oxide synthases and endogenous NO metabolism in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), a multifactorial disease of preterm neonates of complex etiology, is a significant problem within very low birth weight infants. Nitric oxide (NO) has been implicated in both the pathogenesis and as a potential therapeutic of this disease. At this time, there is little direct evidence of the changes in NO production and metabolism that occur within BPD in humans.

Immunohistochemical detection of S-nitrosylated proteins.

Accumulating evidence shows that S-nitrosothiols, formed by the addition of nitric oxide (NO) to a cysteine thiol, S-nitrosylation, are involved in basal cellular regulation. It has been proposed that SNO formation/removal may be disrupted in a variety of pathophysiological conditions. Two types of methodology are presently available to identify specific S-nitrosylated proteins: (1) derivatization and (2) post-purification chemical detection.