Michael L. Gross

Bio: Michael L. Gross is an academic researcher from Washington University in St. Louis. The author has contributed to research in topics: Mass spectrometry & Fast atom bombardment. The author has an hindex of 82, co-authored 701 publications receiving 27140 citations. Previous affiliations of Michael L. Gross include Cornell University & Eppley Institute for Research in Cancer and Allied Diseases.

Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators

Abstract: Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon–DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)-1(α,β)-N7Gua at 59–213 μmol/mol DNA–phosphate whereas the level of stable adducts was 0.1 μmol/mol DNA–phosphate. In female Sprague–Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 μmol 4-OHE2-1(α,β)-N7Gua/molDNA–phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87–440 μmol of 4-OHE1(E2)-1(α, β)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 μmol of adduct/mol DNA–phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

Proteins under pressure

Abstract: Oceans not only cover the major part of the earth’s surface but also reach into depths exceeding the height of the Mt Everest They are populated down to the deepest levels (≈11800 m), which means that a significant proportion of the global biosphere is exposed to pressures of up to 120 MPa Although this fact has been known for more than a century, the ecology of the ‘abyss’ is still in its infancy Only recently, barophilic adaptation, ie the requirement of elevated pressure for viability, has been firmly established In non-adapted organisms, increased pressure leads to morphological anomalies or growth inhibition, and ultimately to cell death The detailed molecular mechanism of the underlying ‘metabolic dislocation’ is unresolved

A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

Abstract: Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Ionic Liquids as Matrixes for Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

Abstract: Room-temperature ionic liquids are useful as solvents for organic synthesis, electrochemical studies, and separations. We wished to examine whether their high solubalizing power, negligible vapor pressure, and broad liquid temperature range are advantageous if they are used as matrixes for UV-MALDI. Several different ionic matrixes were synthesized and tested, using peptides, proteins, and poly(ethylene glycol) (PEG-2000). All ionic liquids tested have excellent solubilizing properties and vacuum stability compared to other commonly used liquid and solid matrixes. However, they varied widely in their ability to produce analyte gas-phase ions. Certain ionic matrixes, however, produce homogeneous solutions of greater vacuum stability, higher ion peak intensity, and equivalent or lower detection limits than currently used solid matrixes. Clearly, ionic liquids and their more amorphous solid analogues merit further investigation as MALDI matrixes.

Space charge effects in Fourier transform mass spectrometry. Mass calibration.

Abstract: Developpement d'une nouvelle relation entre la masse ionique et la frequence cyclotron efficace, pour des ions stockes dans une cellule cubique et detectes par spectrometrie de masse a transformee de Fourier

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Dietary polyphenols and the prevention of diseases

Abstract: Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

A systematic nomenclature for carbohydrate fragmentations in FAB-MS/MS spectra of glycoconjugates

Abstract: A summary of the ion types observed in the Fast Atom Bombardment Mass Spectrometry (FAB-MS) and collision induced decomposition (CID) MS/MS spectra of glycoconjugates (glycosphingolipids, glycopeptides, glycosides and carbohydrates) is presented. The variety of product ion types that arise by cleavages within the carbohydrate moieties has prompted us to introduce a systematic nomenclature to designate these ions. The proposed nomenclature has been developed primarily for FAB-MS, but can be used as well for other ionization techniques [field desorption (FD), direct chemical ionization (DCI), laser desorption/Fourier transform (LD/FT), etc.], and is applicable to spectra recorded in either the positive or negative ion mode during both MS and MS/MS experiments. Ai, Bi and Ci labels are used to designate fragments containing a terminal (nonreducing end) sugar unit, whereas Xj, Yj and Zj represent ions still containing the aglycone (or the reducing sugar unit). Subscripts indicate the position relative to the termini analogous to the system used in peptides, and superscripts indicate cleavages within carbohydrate rings. FAB-MS/MS spectra of a native glycosphingolipid and glycopeptide, and a permethylated ganglioside are shown as illustrations.