WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol Apolipo-protein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation

https://science.sciencemag.org/content/sci/240/4852/622.full.pdf

Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.

The concentrations of bile salt, lecithin, and cholesterol were determined on each of 66 samples of gall bladder bile from patients with cholesterol gallstones and 25 samples of normal gall bladder bile. When these three constituents were plotted simultaneously on triangular coordinates, a complete separation of the normal and "abnormal" bile was achieved. This separation was the result of an increase in the quantity of cholesterol relative to the amounts of bile salts and lecithin contained in the bile from patients with cholesterol gallstones. An in vitro model system was constructed (on triangular coordinates) that allows prediction of the maximum amount of cholesterol that can be solubilized in solutions containing varying proportions of bile salt and lecithin. When the bile data were compared with the solubility of cholesterol derived from the model system, normal biles were found to be less than saturated with cholesterol, whereas biles from patients with cholesterol gallstones were saturated and in some cases contained insoluble cholesterol in the form of microcrystals. It is suggested that the physical state of bile (i.e., the presence or absence of insoluble cholesterol) is determined by the relative concentrations of bile salt, lecithin, and cholesterol, and the other biliary constituents do not appear to significantly effect the solubility of cholesterol in bile.

/pdf/the-physicochemical-basis-of-cholesterol-gallstone-formation-22vnz3wr3t.pdf

The physicochemical basis of cholesterol gallstone formation in man

The Physical Chemistry of Lipids

The hydrated synthetic lecithins, dimyristoyl and dipalmitoyllecithins, undergo two thermal transitions, a broad low enthalpy "pretransition" prior to the sharp first-order "chain-melting" transition. Both phospholipids exhibit the same temperature-dependent structural changes associated with the thermal pretransition. At low temperatures, below the pretransition, a one-dimensional lamellar lattice is observed. The hydrocarbon chains are fully extended and tilted with respect to the plane of the lipid bilayer. The hydrocarbon chain packing displays a temperature dependence and the angle of tilt of the hydrocarbon chains decreases with increasing temperature, reaching a minimum value of 30 degrees at the pretransition temperature of both lecithins. The pretransition is associated with a structural transformation from a one-dimensional lamellar to a two-dimensional monoclinic lattice consisting of lipid lamellae distorted by a periodic ripple. The hydrocarbon chains remain tilted in the temperature range intermediate between the pretransition and chain-melting transition. The cell parameters of this two-dimensional lattice exhibit a compositional dependence. The a parameter (proportional to the lamellar repeat distance) increases with increasing water content, while the b parameter (a measure of the ripple periodicity) decreases with increasing water content. At the chain-melting transition, the hydrocarbon chains of the phospholipid melt and assume a liquid-like conformation and the lattice reverts to one-dimensional lamellar. These structural changes observed for dimyristoyl- and dipalmitoyllecithins may be a common feature of all synthetic lecithins exhibiting a thermal pretransition. The appearance of the pretransition and accompanying two-dimensional may arise from specific interactions between the choline moiety of the polar head group and the structured water matrix surrounding it.

Nature of the Thermal pretransition of synthetic phospholipids: dimyristolyl- and dipalmitoyllecithin.

Lipid Digestion and Absorption

We determined the maximum solubilities of cholesterol in aqueous conjugated bile salt-egg lecithin-cholesterol systems as a function of several physical-chemical variables including those of physiological importance employing phase equilibria techniques. Equilibration rates are influenced by time and the method of sample preparation in that metastable supersaturation is readily induced at high bile salt: lecithin ratios, and equilibrium saturation by dissolution is achieved sluggisly at low bile salt:lecithin ratios. Equilibrium values for cholesterol saturation vary with the bile salt species, bile salt: lecithin ratio, temperature, ionic strength, and, in particular, with the total concentration of biliary lipids. Within physiological bile salt:lecithin ratios at 37 degreesC the influence of bile salt type and ionic strength is small, whereas the effects of bile salt:lecithin ratio and the total lipid concentration are major factors. We plotted on triangular coordinates a family of cholesterol solubility curves for each total lipid concentration (0.30--30 g/dl) and computed fifth-degree polynomial equations for each curve. With both the curves and the polynomial equations the "per cent cholesterol saturation" of fasting gallbladder and hepatic biles from patients with and without gallstones was calculated and both methods gave similar values. These results deomonstrate that by employing cholesterol saturation values appropriate to the total lipid concentration (range 0.2--24.9 g/dl) of individual biles, all cholesterol stone patients have supersaturated gallbladder biles, (mean, 132% [normal weight individuals], and 199% [morbidly obese individuals]). With controls and pigment stone patients the mean values were 95 and 98%, respectively, and in both approximately 50% of biles were supersaturated. Fasting hepatic biles were significantly more supersaturated than gallbladder biles (means 228--273%). Cholesterol monohydrate crystals were found in the majority of gallbladder (83%) and hepatic (58%) biles of cholesterol gallstone patients but were not observed in pigment stone patients or controls. We conclude that of the several factors in addition to the bile salt:lecithin ratios which can influence the cholesterol saturation of bile the total lipid concentration is the predominant determinant physiologically. Our results demonstrate that (a) metastable supersaturation is frequent in both normal and abnormal biles, (b) cholesterol gallstone patients have supersaturated gallbladder and hepatic biles without exception, and (c) the predominant driving force for cholesterol precipitation appears to be the absolute degree of cholesterol supersaturation.

/pdf/the-physical-chemistry-of-cholesterol-solubility-in-bile-2lr8h16mdd.pdf

Donald Small

Papers

The physicochemical basis of cholesterol gallstone formation in man

The Physical Chemistry of Lipids

Nature of the Thermal pretransition of synthetic phospholipids: dimyristolyl- and dipalmitoyllecithin.

Lipid Digestion and Absorption

The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man.