In recent years, a variety of low molecular weight antibiotics have been isolated from diverse animal species. These agents, which include peptides, lipids, and alkaloids, exhibit antibiotic activity against environmental microbes and are thought to play a role in innate immunity. We report here the discovery of a broad-spectrum steroidal antibiotic isolated from tissues of the dogfish shark Squalus acanthias. This water-soluble antibiotic, which we have named squalamine, exhibits potent bactericidal activity against both Gram-negative and Gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. The chemical structure of the antibiotic 313-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane}-7a,24'-dihydroxy-Sacholestane 24-sulfate has been determined by fast atom bombardment mass spectroscopy and NMR. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. The discovery of squalamine in the shark implicates a steroid as a potential host-defense agent in vertebrates and provides insights into the chemical design of a family of broad-spectrum antibiotics.Animals must defend themselves against environmental microbes if they are to survive. Multiple mechanisms of host defense against microbes have been described such as the array of humoral and cellular responses of the classical vertebrate immune system and less-specific physical and chemical barriers. Over the past several years, an increasing number of low molecular weight antibiotic substances, believed to play a role in defense against environmental microbes, have been isolated from diverse species of animals. These molecules include peptides (1-3), lipids (4, 5), and alkaloids (6-8).In the course of our studies exploring the diversity of antibiotics from animal sources, we have surveyed tissues from a number of animal species (9, 10). We focused our search for antibiotic substances on the gastrointestinal tract of various animals after the recent discovery of peptide antibiotics in the gut of frogs (11), pigs (12, 13), mice (14), and humans (34). In the course of our survey, we discovered that stomach extracts of the shark Squalus acanthias exhibited potent antimicrobial activity, prompting efforts to purify and identify the responsible molecule.In this report we describe the isolation, structural determination, and characterization of a water-soluble cationic steroid from the shark that exhibits potent antimicrobial activity against fungi, protozoa, and both Gram-negative and Gram-positive bacteria. This molecule is shown to be an unusual adduct of spermidine with an anionic bile salt intermediate that, to our knowledge, is without precedent in vertebrates. We have named the aminosterol "squalamine," derived from the genus Squalus and its chemical structure as an amine. MATERIALS AND METHODSPurification of Squlamine. Squalus acanthias sharks were captured off the New England coast. The shark stomach tissue (400 g) was frozen immediately after dissectio...

Purpose: Molecular subtyping for pancreatic cancer has made substantial progress in recent years, facilitating the optimization of existing therapeutic approaches to improve clinical outcomes in pancreatic cancer. With advances in treatment combinations and choices, it is becoming increasingly important to determine ways to place patients on the best therapies upfront. While various molecular subtyping systems for pancreatic cancer have been proposed, consensus regarding proposed subtypes, as well as their relative clinical utility, remains largely unknown and presents a natural barrier to wider clinical adoption. Methods:We assess three major subtype classification schemas in the context of results from two clinical trials and by meta-analysis of publicly available expression data to assess statistical criteria of subtype robustness and overall clinical relevance. We then developed a Single Sample Classifier (SSC) using penalized logistic regression based on the most robust and replicable schema.

SummaryWe assessed the efficacy of a comprehensive programme for stopping smoking in 210 smokers scheduled for surgery, before admission and 3 months after attending a pre-operative clinic. Participants were randomly allocated to receive an intervention incorporating nicotine replacement therapy for patients smoking more than 10 cigarettes per day ('dependent smokers'), or to a control group to receive usual care. Dependent smokers allocated to the intervention group were more likely to report abstinence before surgery than those allocated to receive usual-care (63 (73%) vs. 29 (56%), respectively; OR 2.2 (95% CI 1.0-4.8)), and 3 months after attendance (16 (18%) vs. 3 (5%), respectively; OR = 3.9 (95% CI 1.0-21.7).

No abstract

Pack shape and pack opening affect ever-smokers' perceptions of the packs and the cigarettes they contain. This means that they have the potential to create appeal and differentiate products and thus should be regulated.