Quantum mechanics: why complex Hilbert space?

We outline a programme for an axiomatic reconstruction of quantum mechanics based on the statistical duality of states and effects that combines the use of a theorem of Solér with the idea of symmetry. We also discuss arguments favouring the choice of the complex field.This article is part of the themed issue 'Second quantum revolution: foundational questions'.

Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect.

BACKGROUND: The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof. PATIENTS AND METHODS: From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case. RESULTS: All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand-dependent activation was confirmed. CONCLUSIONS: We confirm the clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture.

Proteomics study of medullary thyroid carcinomas expressing RET germ-line mutations: identification of new signaling elements.

Proteomics may help to elucidate differential signaling networks underlying the effects of compounds and to identify new therapeutic targets. Using a proteomic-multiplexed analysis of the phosphotyrosine signaling together with antibody-based validation techniques, we identified several candidate molecules for RET (rearranged during transfection) tyrosine kinase receptor carrying mutations responsible for the multiple endocrine neoplasia type 2A and 2B (MEN2A and MEN2B) syndromes in two human medullary thyroid carcinoma (MTC) cell lines, TT and MZ-CRC-1, which express the RET-MEN2A and RET-MEN2B oncoproteins, respectively. Signaling elements downstream of these oncoproteins were identified after treating cells with the indolinone tyrosine kinase inhibitor RPI-1 to knock down RET phosphorylation activity. We detected 23 and 18 affinity-purified phosphotyrosine proteins in untreated TT and MZ-CRC-1 cells, respectively, most of which were shared and sensitive to RPI-1 treatment. However, our data clearly point to specific signaling features of the RET-MEN2A and RET-MEN2B oncogenic pathways. Moreover, the detection of high-level expression of minimally phosphorylated epidermal growth factor receptor (EGFR) in both TT and MZ-CRC-1 cells, together with our data on the effects of EGF stimulation on the proteomic profiles and the response to Gefitinib treatment, suggest the relevance of EGFR signaling in these cell lines, especially since analysis of 14 archival MTC specimens revealed EGFR mRNA expression in all samples. Together, our data suggest that RET/EGFR multi-target inhibitors might be beneficial for therapy of MTC.

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid.

To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent and -independent pathways, regulated by MAP kinases, which likely play a protective role.

Properties of the Escherichia coli rhodanese-like protein SseA: contribution of the active-site residue Ser240 to sulfur donor recognition.

The product of Escherichia coli sseA gene (SseA) was the subject of the present investigation aimed to provide a tool for functional classification of the bacterial proteins of the rhodanese family. E. coli SseA contains the motif CGSGVTA around the catalytic cysteine (Cys238). In eukaryotic sulfurtransferases this motif discriminates for 3-mercaptopyruvate:cyanide sulfurtransferase over thiosulfate:cyanide sulfurtransferases (rhodanese). The biochemical characterization of E. coli SseA allowed the identification of the first prokaryotic protein with a preference for 3-mercaptopyruvate as donor substrate. Replacement of Ser240 with Ala showed that the presence of a hydrophobic residue did not affect the binding of 3-mercaptopyruvate, but strongly prevented thiosulfate binding. On the contrary, substitution of Ser240 with an ionizable residue (Lys) increased the affinity for thiosulfate.

Biosynthetic anthracyclines.

This review summarizes the structure, the occurrence and the available data concerning the bioactivity of biosynthetic anthracyclines. The anthracyclines represent an important family of natural products produced by microorganisms of Streptomyces and related genera and include clinically useful agents for the medical treatment of human cancer. Chemically, the anthracyclines are glycosides characterized by a quinone tetracyclic aglycone and one or more deoxysugar units, mostly belonging to the L-hexopyranoside series, comprising generally an aminosugar. The different compounds belonging to this family are structurally related as they share a common biosynthetic pathway. Although some statements concerning structure activity relationships and molecular requirements for activity can be made, published data are not adequate for the comparative evaluation of potential antitumor efficacy of biosynthetic anthracyclines. This family of natural products is therefore still open for pharmacological investigation.

Cephem sulfones as inactivators of human leukocyte elastase. 5. 7 alpha-Methoxy- and 7 alpha-chloro-1,1-dioxocephem 4-ketones.

Studies on cephem sulfones as inhibitors of human leukocyte elastase (HLE) have been extended to the new class of cephem 4-ketones. tert-Butyl and phenyl ketones were prepared from 4-carboxycephem derivatives, at either the sulfide or sulfone oxidation level, by chemoselective Grignard reaction. Obtained products were functionalized with heterocyclothio and acyloxy substituents at C-3', C-2, or both positions. tert-Butyl ketones of the 7 alpha-chlorocephem series were in general at least as potent as the corresponding esters at inhibiting the enzyme, but improvements in hydrolytic stability were only marginal. On the other hand, tert-butyl ketones of the 7 alpha-methoxycephem series combined potent biochemical activity with acceptable hydrolytic stability, thus overstepping the esters, thiolesters, and amides reported previously. In particular, the tert-butyl ketones possessing a heterocyclothio group at C-3' or C-2 were at least as active as the corresponding tert-butyl esters but 1 order of magnitude more stable in physiologic buffers (pH 7.4, 37 degrees C). Introduction of acyloxy groups at C-2 delivered the most potent HLE inhibitors of the cephem class ever reported, with inhibition parameters often outside the determination limits of our standard protocol (second-order rate constant kon > 2,000,000 M-1 s-1; Ki at steady state < 2 nM). Keto-enol tautomerism was found to depress activity and boost hydrolytic stability. Thus, double substitution with heterocyclic thiols produced compounds with diverging properties, according to the extent of enolate formation at the investigated pH (7.4): the weakly acidic tert-butyl ketones (pKa > or = 5.8) proved to be potent inhibitors (kon over 10(4) M-1 s-1) with reasonable hydrolytic stability (t1/2 = 30-75 h), while the phenyl ketones (pKa < 4) were fair inhibitors (kon over 10(3) M-1 s-1; Ki at steady state approximately 50 nM) with hydrolytic half-lives exceeding 1000 h. Selected compounds efficiently inhibited the degradation of insoluble bovine neck elastin by HLE in a concentration-dependent manner. Intracellular HLE of polymorphonuclear leukocytes was in general unaffected; however, a lipophilic cephem sulfone apparently able to inactivate the enzyme in living cells was identified.

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.8, 5.5, 81.3, and 128 microM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu(6)Ala(3)Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation.

Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance.

In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.

Synthesis, biological and biochemical properties of new anthracyclines modified in the aminosugar moiety.

New 4'-C-methyl analogues of daunorubicin, synthesized by the coupling reaction of daunomycinone with 1-chloroderivatives of protected 4-C-methyldaunosamine analogues, were chemically transformed to the corresponding doxorubicin analogues. Their cytotoxic effect against HeLa cells, ability to bind to DNA, and in vivo toxicity and antitumor activity were compared with those of daunorubicin, doxorubicin, and their 4'-O-methyl analogues. The cytotoxic effect of the new anthracyclines could be correlated with their ability to bind to DNA and with their toxicity in experimental animals; however, the antitumor effectiveness did not seem to be related to these parameters. In general all the compounds retained a remarkable antitumor activity at their optimal doses. The most active compound against P388 leukemia was 4'-O-methyldoxorubicin, which was also more active than doxorubicin against L1210 leukemia.

Structure elucidation of clavilactone D: an inhibitor of protein tyrosine kinases.

Clavilactones D and E were isolated from an agar culture of the Basidiomycetous fungus Clitocybe clavipes, and their structure was elucidated by 1H- and 13C-NMR studies. Clavilactone D is an inhibitor of tyrosine kinases.

New anthracycline glycosides obtained by the nitrous acid deamination of daunorubicin, doxorubicin and their configurational analogues.

The new anthracyclines 7-O-(2,3,5-trideoxy-3-C-formyl-alpha-L-threo-pentofuranosyl)daunomyci none (8) and -adriamycinone (10) have been obtained upon nitrous acid deamination of daunorubicin and doxorubicin respectively. Deamination of the L-ribo analogue of daunorubicin (6) gave a mixture of 2,3,6-trideoxy-L-glycero-hexopyranosid-4-ulose (alpha-L-cinerulosyl) (11) and 2,6-dideoxy-alpha-L-arabino-hexopyranosyl (12) glycosides. The corresponding adriamycinone glycosides 13 and 14, obtained by deamination of the doxorubicin L-ribo analogue 7, were found to display an outstanding antileukemic activity in mice.

New anthracycline glycosides from Micromonospora. II. isolation, characterization and biological properties.

Four glycosides, designated A, B, C and D, are the main components of the anthracycline complex produced by cultures of Micromonospora sp. nov. They were extracted by solvent partition, separated by column chromatography and characterized by chemical and physical methods as 11-deoxy analogues of daunorubicin. Among these new anthracyclines, displaying antibacterial and cytotoxic activity in vitro, 11-deoxydaunorubicin and 11-deoxydoxorubicin are also active against P388 leukemia in mice.

New anthracycline glycosides: 4-O-demethyl-11-deoxydoxorubicin and analogues from Streptomyces peucetius var. aureus.

The new anthracyclines 4-O-demethyl-11-deoxydoxorubicin, 4-O-demethyl-11-deoxydaunorubicin along with its 13-dihydro and 13-deoxo analogues are the main components of the anthracycline complex produced by cultures of Streptomyces peucetius var. aureus. They were isolated by solvent partition, separated by column chromatography and characterized by chemical and physical methods. Among these new anthracyclines, displaying antibacterial and cytotoxic activity "in vitro", 4-O-demethyl-11-deoxydoxorubicin and the corresponding daunorubicin analogue were also active against experimental tumors.

New biosynthetic anthracyclines related to barminomycins incorporating barbiturates in their moiety.

Three new anthracyclines, FCE 21424 (2), FCE 24366 (3) and FCE 24367 (4), were isolated from culture broths of Streptomyces peucetius and its mutant strains after addition of sodium barbiturates during the fermentation. Structural assignment, achieved through spectroscopic and degradative studies, that the new anthracyclines had a common barminomycin-like structure incorporating different barbiturate moieties. The new anthracyclines were found to display outstanding cytotoxicity and remarkable potency "in vivo" against P388 ascitic leukemia.

Preparation and biological evaluation of 4-O-demethyldaunorubicin (carminomycin I) and of its 13-dihydro derivative.

A mutant strain of Streptomyces peucetius produced an anthracycline antibiotic whose structure has been established to be 4-O-demethyl-13-dihydrodaunorubicin (4), by application of spectroscopic methods and chemical degradation. A new synthesis of 4-O-demethyl-daunorubicin (carminomycin I, 2) starting from daunomycinone, together with the comparison of the antitumor activity of the anthracycline glycosides 2 and 4 are also reported.

[Diffuse entero-mesenteric lipomatosis]. / La lipomatosi entero-mesenterica diffusa

Successful surgical management of an unusual case of diffuse lipomatosis is reported. The clinical and radiological pictures are described and the essential points to be taken into consideration in differential diagnosis are illustrated.

[Right hypogastric artery steal syndrome caused by a traumatic aneurysm of the gluteal artery with consequent ischemic necrosis of the foot]. / Sindrome da furto dell'arteria ipogastrica di destra da aneurisma traumatico dell'arteria glutea con conseguente necrosi ischemica del piede.

A case of aneurysm of the right gluteal artery with ischaemia of the lower limb due to a recent hypogastric steal syndrome is reported. Attention is drawn to the unusual nature of this finding and its aetiopathogenesis is discussed. Reference is made to the clinical and therapeutic aspects of the case, and the soundness of surgical procedure, which brought about a cure.

[Digestive hemorrhage secondary to fistula between hepatic artery and jejunal stump following duodenocephalopancreasectomy. A clinical case]. / Emorragia digestiva secondaria a fistola tra arteria epatica e moncone digiunale in esiti di duodenocefalopancreasectomia. Caso clinico.

The authors describe a case of one patient who underwent duodenocephalopancreasectomy for CBD cancer 6 years ago and developed gastrointestinal bleeding caused by a fistula between the hepatic artery and the jejunal stump. They discuss the differential diagnosis problem in the gastrointestinal bleeding syndrome caused by this rare pathology.

[Epidemiological behavior of perforated peptic ulcer before and after the introduction of the antisecretory drug therapy. Our experience]. / Il comportamento epidemiologico dell'ulcera peptica perforata prima e dopo l'introduzione della terapia medica antisecretiva.

The diagnostic iter and treatment of peptic ulcer have evolved considerably over the past 20 years. The capillary spread of endoscopy has permitted secure and precise diagnoses to be made, in terms of both the site and size of the anatomic lesion, on the one hand, and on the other, the introduction of antisecretory drugs has led to the resolution of the majority of ulcers, so much so that the ulcer is no longer managed using strictly surgical methods but is now treated medically and only emergency cases, such as perforations, undergo surgery. Complications, such as digestive hemorrhage, penetration and stenosis, may lead to the need for surgery. In particular, perforation seems to be the only complication which has not been significantly influenced by the introduction of antisecretory therapy, the point that its status as a "complication" has been questioned leading to the suspicion of its nosological autonomy. The authors review the series of ulcer patients admitted to hospital during the period 1968 to 1991, paying special attention to the correlation with the use of antisecretory drugs which were introduced during the period 1978-1981, the trend of ulcer complications over the entire period, the duration of symptoms and the epidemiology of peptic and perforated ulcers.