Cigarette smoking and gemcitabine-induced neutropenia in advanced solid tumors.

BACKGROUND: Chemotherapy-associated neutropenia has been reported to be a pharmacodynamic marker of response in some advanced solid tumors. Factors that accelerate drug clearance lead to lower plasma concentrations and toxicity, including neutropenia. Smoking accelerates the metabolism of several drugs, including chemotherapy. We sought to study the effects of smoking on gemcitabine-induced neutropenia in this retrospective study. METHODS: Smoking status and neutropenia along with other clinical parameters were recorded in 151 patients receiving first-line gemcitabine-based chemotherapy for advanced solid tumors. RESULTS: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary cancer (15.2%). Logistic regression showed that never smokers had increased neutropenia versus current smokers (odds ratio: 3.5; 95% confidence interval, CI: 1.1-11.4). A 5-unit increase in pack-years reduced the odds of having higher neutropenia toxicity by 6.3% (95% CI 12 to 1%; p = 0.036). CONCLUSION: Smokers had less neutropenia than nonsmokers, a finding that was more pronounced with increasing pack-years. This pharmacodynamic marker of gemcitabine-induced neutropenia may result in less efficacy of gemcitabine. Future prospective trials should correlate smoking, metabolizing phenotype, neutropenia, and response to gemcitabine therapy.

Enrichment and site mapping of O-linked N-acetylglucosamine by a combination of chemical/enzymatic tagging, photochemical cleavage, and electron transfer dissociation mass spectrometry.

Numerous cellular processes are regulated by the reversible addition of either phosphate or O-linked beta-N-acetylglucosamine (O-GlcNAc) to nuclear and cytoplasmic proteins. Although sensitive methods exist for the enrichment and identification of protein phosphorylation sites, those for the enrichment of O-GlcNAc-containing peptides are lacking. Reported here is highly efficient methodology for the enrichment and characterization of O-GlcNAc sites from complex samples. In this method, O-GlcNAc-modified peptides are tagged with a novel biotinylation reagent, enriched by affinity chromatography, released from the solid support by photochemical cleavage, and analyzed by electron transfer dissociation mass spectrometry. Using this strategy, eight O-GlcNAc sites were mapped from a tau-enriched sample from rat brain. Sites of GlcNAcylation were characterized on important neuronal proteins such as tau, synucleins, and methyl CpG-binding protein 2.

Acute limb ischemia as sole initial manifestation of SARS-CoV-2 infection.

We present the case of a patient with acute upper limb ischemia as the sole initial manifestation of severe acute respiratory syndrome associated with coronavirus disease 2 infection, without concomitant respiratory symptoms or pneumonia. Viral infection presumably precipitated the patient's thromboembolic event, causing multifocal vascular occlusions. This case illustrates that coronavirus disease-19 must be considered in the differential diagnosis of patients presenting with signs or symptoms of coagulopathy, even in the absence of respiratory symptoms. We believe that an awareness of the variety of clinical presentations in patients with coronavirus disease-19, particularly extrapulmonary manifestations, is critical for optimal patient management as well as implementation of appropriate infection prevention measures.

Synthesis of pterocellin A.

The first total synthesis of pterocellin A (1) was achieved in 10 linear steps from commercially available kojic acid (6) and 2-bromo-3-pyridinol (11) in a convergent sequence. The key constructive steps are a directed lithiation to couple two pyridines and an intramolecular nucleophilic aromatic substitution to form 1. [structure: see text]

Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer.

INTRODUCTION: Cigarette smoke associated polycyclic aromatic hydrocarbons can induce key drug-metabolizing enzymes of cytochrome P450 and isoforms of the glucuronyl transferases families. These enzymes metabolize several systemic therapies for lung cancer. Induction of these enzymes may lead to accelerated clearance with resultant impact on systemic therapy efficacy and toxicity in smokers compared with nonsmokers. This article reviews published literature regarding the influence of smoking as it relates to alteration of metabolism of systemic therapy in lung cancer. METHODS: A structured search of the National Library of Medicine's PubMed/MEDLINE identified relevant articles. Data were abstracted and analyzed to summarize the findings. RESULTS: Studies that analyzed pharmacokinetic data were prospective. Smokers receiving erlotinib exhibited rapid clearance, requiring a higher dose to reach equivalent systemic exposure compared with nonsmokers. Smokers receiving irinotecan also demonstrated increased clearance and lower systemic exposure. There was no difference in clearance of paclitaxel or docetaxel in smokers. Chemotherapy-associated neutropenia was worse in nonsmokers compared with smokers in patients treated with paclitaxel, docetaxel, irinotecan, and gemcitabine. CONCLUSIONS: Systemic therapy for lung cancer has a narrow therapeutic index such that small changes in plasma concentrations or exposure in smokers may result in suboptimal therapy and poor outcomes. Smoking cessation must be emphasized at each clinical visit. However, prospective trials should take into consideration the effects of smoking history on drug pharmacokinetics and efficacy. The metabolizing enzyme phenotype in smokers may require individualized dose algorithms for specific agents.