Comparison of Interstitial Lung Disease Between Antineutrophil Cytoplasmic Antibodies Positive and Negative Patients: A Retrospective Cohort Study.

OBJECTIVE: Positive antineutrophil cytoplasmic antibodies (ANCAs) may occur in the setting of interstitial lung disease (ILD), with or without ANCA-associated vasculitis (AAV). We aim to compare the characteristics and clinical course of patients with ILD and positive ANCA (ANCA-ILD) to those with negative ANCA. METHODS: We performed a single-center retrospective cohort study from 2018 to 2021. All patients with ILD and ANCA testing were included. Patient characteristics (symptoms, dyspnea scale, and systemic AAV), test results (pulmonary high-resolution computed tomography and pulmonary function tests), and adverse events were collected from electronic medical records. Descriptive statistics and the Fisher exact test were used to compare the outcomes of patients with ANCA-ILD to those with ILD and negative ANCA. RESULTS: A total of 265 patients with ILD were included. The mean follow-up duration was 69.3 months, 26 patients (9.8%) were ANCA positive, and 69.2% of those with ANCA-ILD had another autoantibody. AAV occurred in 17 patients (65.4%) with ANCA-ILD. In 29.4% of patients, AAV developed following ILD diagnosis. Usual interstitial pneumonia was the most common radiologic pattern in patients with ANCA-ILD. There was no association between ANCA status and the evolution of dyspnea, diffusing capacity of the lungs for carbon monoxide, and lung imaging. Forced vital capacity improved over time in 42% of patients with ANCA-ILD and in 17% of patients with negative ANCA (P = 0.006). Hospitalization occurred in 46.2% of patients with ANCA-ILD and in 21.8% of patients with negative ANCA (P = 0.006). Both groups had similar mortality rates. CONCLUSION: Routine ANCA testing should be considered in patients with ILD. Patients with ANCA-ILD are at risk for AAV. More research is required to better understand and manage patients with ANCA-ILD.

Serine deprivation enhances antineoplastic activity of biguanides.

Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth-inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism.

Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and modulators of AKT signaling. The contrasting metabolic features revealed by our strategy could be used to metabolically target CLL lymphocyte subsets creating new therapeutic windows for this disease for mTORC1 or AMPK inhibitors. Indeed, we report that Metformin, a drug used to treat diabetes was selectively cytotoxic to Dasatinib sensitive samples. Ultimately, we suggest that a similar strategy could be applied to other cancer types by using Dasatinib and/or relevant tyrosine kinase inhibitors.