The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths.

The detection of a population of submillimeter-bright, strongly lensed galaxies.

Gravitational lensing is a powerful astrophysical and cosmological probe and is particularly valuable at submillimeter wavelengths for the study of the statistical and individual properties of dusty star-forming galaxies. However, the identification of gravitational lenses is often time-intensive, involving the sifting of large volumes of imaging or spectroscopic data to find few candidates. We used early data from the Herschel Astrophysical Terahertz Large Area Survey to demonstrate that wide-area submillimeter surveys can simply and easily detect strong gravitational lensing events, with close to 100% efficiency.

Old galaxies in the young Universe.

More than half of all stars in the local Universe are found in massive spheroidal galaxies, which are characterized by old stellar populations with little or no current star formation. In present models, such galaxies appear rather late in the history of the Universe as the culmination of a hierarchical merging process, in which larger galaxies are assembled through mergers of smaller precursor galaxies. But observations have not yet established how, or even when, the massive spheroidals formed, nor if their seemingly sudden appearance when the Universe was about half its present age (at redshift z approximately 1) results from a real evolutionary effect (such as a peak of mergers) or from the observational difficulty of identifying them at earlier epochs.

New mono- and bis-intercalating compounds between DNA base pairs.

With the aim to obtain new bis-intercalating agents in DNA a series of compounds was prepared linking two identical tricyclic moieties (two 4,5'-8-trimethylpsoralen (TMP)) or different (one TMP and one pyrido[3,2-b]quinoline) through a hydrocarburic aminated flexible chai. Bis-psoralen-amines as well as psoralen-pyrydoquinolin-amines were obtained. For comparison the corresponding mono-psoralen-amines were also prepared condensing a TMP moiety with various hydrocarburic aminated chains.

Treatment of Early Stage Hodgkin's Disease According to Risk Factors.

Between January 1981 and December 1987, 95 patients with stage IA (34 patients), IIA (42 patients) and stage IIB (19 patients) Hodgkin's disease (HD) were evaluated in our institution. Thirty patients defined as "high risk" because of either bulky mediastinal disease, systemic symptoms or both were treated with combined modality therapy (CMT). The remaining 65 patients considered as "standard risk" because they presented at diagnosis without any known adverse prognostic factor, received radiotherapy (RT) only.

Present aspects concerning the molecular mechanisms of photochemotherapy with psoralens.

The various photophysical and photochemical events that can be produced by psoralens after their excitation by UV-A radiation are reviewed, with particular reference to their possible significance for induction of photobiological effects. A close correlation has been found between the covalent photoaddition of furocoumarins to the pyrimidine bases of DNA and the inhibition of DNA synthesis inside living cells; this fact underlines the importance of this photoaddition for the antiproliferative effects exerted by furocoumarins. A good correlation has also been found between the formation of cross-linkages in DNA and the induction of erythema on skin; monofunctional furocoumarins, like methyl-angelicin derivatives, are unable to induce erythema, although they have very strong antiproliferative properties.

Chemical basis of the photosensitizing activity of angelicins.

Angelicins are a group of compounds that show marked photobiologic activity on various substrates; some of them have been proposed as potential agents for the photochemotherapy of skin diseases. A good correlation exists between the photosensitizing activity of these compounds and their capacity to induce monofunctional lesions to DNA; therefore, we believe the chemical nature of these photolesions, we isolated from the products of hydrolysis of the photocombinations between 5 angelicins (angelicin, 4-methyl, 5-methyl, 5'-methyl, and 5,5'-dimethylangelicin) and DNA, the corresponding new fluorescent monoadducts between the 4',5'-double bond of the furocoumarins and the 5,6-double bond of thymine.

In vitro photoreactions of selected psoralens and methylangelicins with DNA, RNA, and proteins.

This paper presents an overview of the photophysical and photochemical properties of some furocoumarin derivatives and their interactions and photoreactions with DNA, RNA, and proteins, as well as their ability to produce singlet oxygen. The relevance of these properties in the induction of photobiologic effects is also discussed.

A study of the relationship between photosensitizing and therapeutic activity of 4,5',8-trimethylpsoralen, and its major metabolite 4,8-dimethyl, 5'-carboxypsoralen.

The molecular basis for the clinically observed differences in the skin photosensitizing activity and therapeutic effectiveness of the topically applied and orally administered drug trimethylpsoralen (TMP) was investigated. TMP, when tested topically, is a very potent photosensitizing and therapeutically effective furocoumarin in the treatment of psoriasis. When administered orally, however, it is significantly less photosensitizing and therapeutically a less effective drug than the commonly used furocoumarin 8-methoxypsoralen.

Photosensitized effects of furocoumarins: the possible role of singlet oxygen.

The capacity of various furocoumarins to generate singlet oxygen in aqueous solution has been determined. The antiproliferative and the skin-photosensitizing activities of the same furocoumarins did not show any correlation with the capacity to generate the singlet oxygen, while these photobiological properties could be correlated with the capacity of furocoumarins to induce photolesions to the DNA.

Sequence specificity in DNA for the interaction with adriamycin or daunomycin.

The interactions of adriamycin and daunomycin with various polydeoxyribonucleotides and some natural DNAs having different base pairs composition were studied by means of fluorimetric titrations. The quenching of the fluorescence occurring in the drugs complexed with polynucleotides and DNA is more efficiently induced by the C-G rich regions than by the A-T rich ones. By contrast, the affinity of the drugs for polynucleotides and DNAs in forming the molecular intercalated complexes is correlated mainly with the sequence of purines and pyrimidines in each strand of the duplex polymers, fairly independently of their nature.

Photoreactive water-soluble derivatives of psoralen.

Photobinding to DNA and cross-linking formation in vitro, as well as the skin photosensitizing activity on guinea pigs of two water-soluble derivatives of psoralen (5 and 8-diethylaminopropyloxypsoralen hydrochloride) have been studied. For purposes of comparison, the results have been correlated with those obtained, in the same experimental conditions, with 5- and 8-methoxypsoralen. The water-soluble 8-derivative showed an increased photoaddition to DNA and cross-linking formation, when compared with 8-methoxy-derivative; on the contrary, the water-soluble 5-derivative was less photoreactive than the corresponding 5-methoxy-derivative.

Drug-protein interaction: plasma protein binding of furocoumarins.

The binding of six furocoumarins (angelicin, psoralen, 8-methoxypsoralen, 5-methoxypsoralen, 8-methylpsoralen, 4,5'8-trimethylpsoralen) to human serum and human serum albumin was studied by equilibrium dialysis using tritium labelled compounds. The results indicated that in serum all furocoumarins are bound mostly by albumin, the extent of binding being related to the structure of the furocoumarins; at any rate, high values of the bound drug, ranging from 84 to 97% were observed. The percentage of binding is strictly related to the water solubility of the compounds.

New studies on the interaction between 8-methoxypsoralen and DNA in vitro.

Some aspects of the interactions between DNA and 8-methoxypsoralen (8-MOP) in its ground state (complex formation) or in its excited state (photobinding) have been investigated. 8-MOP shows a low affinity towards DNA in the complex formation; this fact minimizes the possible biological consequences deriving from this interaction, when it occurs in vivo. In covalent photobinding to DNA, 8-MOP forms mainly monofunctional adducts, and to a lesser extent bifunctional adducts, showing a behavior similar to that of other linearly condensed furocoumarins (psoralens); the ratio between mono- and bifunctional adducts was found to be 9:1.

Drug-protein interaction: 8-methoxy psoralen as photosensitizer of enzymes and amino acids.

For a better insight of the molecular basis of the photobiological effects of furocoumarins, the relevance of proteins oxydation by singlet oxygen produced by these substrates under irradiation with long u. v. light was studied.

Synthesis and photobiological properties of 4,8-dimethyl-5'-carboxypsoralen: a major metabolite of 4,5',8-trimethylpsoralen.

Recently a major metabolite of 4,5',8-trimethylpsoralen (TMeP) (a photochemotherapeutic agent), was isolated from the urine of mice and human volunteers receiving the drug orally; it was identified as 4,8-dimethyl-5'-carboxypsoralen. The synthesis of this compound has been carried out to obtain a distinct confirmation of the structure of the urinary metabolite and to study its photochemical and photobiological properties. The results obtained showed that this interaction and photoreaction with DNA are very poor; this fact can be correlated with the presence of the ionizable carboxylic group that undergoes a repulsion by the phosphate residues of the macromolecule.

The binding of 8-methoxypsoralen by human serum albumin.

The ability of 8-methoxypsoralen (8-MOP) to bind human serum albumin has been investigated in vitro through equilibrium dialysis and fluorescence quenching. By means of the first technique it was observed that, at concentrations presumably close to those obtainable in vivo following its administration in the photochemotherapy of psoriasis, over 80% of 8-MOP was bound to serum albumin. In human serum albumin fluorescence techniques revealed a preferential site of binding for 8-MOP with a high binding constant (Ka = 0.

Studies on the mechanism of action of mitomycin C.

The in vitro formation and properties of the molecular complex between mitomycin C and native DNA were examined by means of various experimental methods; the data obtained indicate that the complex is extremely weak and that the chromophoric moiety of the antibiotic is not involved in its formation. The alkylating activity of mitomycin C was also studied using 3H-mitomycin C; while monofunctional alkylation increases almost in parallel with the concentration of the antibiotic, the difunctional alkylation, causing inter-strand cross-linkages in DNA, rapidly reaches a maximum and then remains constant even when increasing the concentration of the antibiotic and monofunctional alkylation. On the basis of these results, the currently accepted molecular model of the mitomycin--DNA interaction must be revised; a new model of this interaction is presented, which is in better agreement with the properties of mitomycin C and with the latest findings on the subject.