ABSTRACT
AIM: Identifying the best care for a patient can be extremely challenging. To support the creation of multifactorial Decision Support Systems (DSSs), we propose an Umbrella Protocol, focusing on prostate cancer. MATERIALS & METHODS: The PRODIGE project consisted of a workflow for standardizing data, and procedures, to create a consistent dataset useful to elaborate DSSs. Techniques from classical statistics and machine learning will be adopted. The general protocol accepted by our Ethical Committee can be downloaded from cancerdata.org . RESULTS: A standardized knowledge sharing process has been implemented by using a semi-formal ontology for the representation of relevant clinical variables. CONCLUSION: The development of DSSs, based on standardized knowledge, could be a tool to achieve a personalized decision-making.
Subject(s)
Decision Support Systems, Clinical , Medical Informatics/methods , Precision Medicine , Prostatic Neoplasms/diagnosis , Software , Humans , Machine Learning , Male , Precision Medicine/methods , Prognosis , WorkflowABSTRACT
PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin and paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The treatment regimen was given as defined in a phase I investigation in patients with previously treated ovarian cancer. It consisted of paclitaxel 175 mg/m(2) (1-h infusion) and oxaliplatin 130 mg/m(2) (2-h infusion) given every 21 days. Eligible patients had stage IIIB (pleural effusion)/IV NSCLC, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic function. RESULTS: A total of 38 patients were enrolled with the following characteristics: 29% male (n = 11); 71% female (n = 27); median age 64.5 years (range 37-78); performance status of 0-1 84% (n = 32); stage IIIB 8% (n = 3); stage IV 92% (n = 35). One hundred and eighty-one cycles were administered, with a median of four per patient (range one to 12). The overall objective response rate for all 38 patients was 34.2% [95% confidence interval (CI) 19.6% to 51.4%]. This response rate includes 13 patients who met criteria for a partial response. No complete responses were observed. Median overall survival time was 9.2 months (95% CI 6-12.4) and median progression-free survival time was 4.3 months (95% CI 2.1-6.5). The 1- and 2-year overall survival rates were 37% and 21%, respectively. Hematological toxicity included six patients with grade 4 neutropenia. Non-hematological toxicity consisted mainly of grades 1 and 2 neurosensory toxicity. Laryngodysesthesia was observed in two patients following oxaliplatin infusion. No grade 4 non-hematological toxicities were encountered. CONCLUSION: This regimen is well tolerated, and demonstrates activity in patients with advanced NSCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Organoplatinum Compounds/administration & dosage , Paclitaxel/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Disease Progression , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/adverse effects , Oxaliplatin , Paclitaxel/adverse effects , Survival Analysis , Treatment OutcomeABSTRACT
A phytochemical investigation of the extracts obtained from bulbs of leek. Allium porrum L. has led to the isolation of five flavonoid glycosides based on the kaempferol aglycone. Two of them are new compounds and have been identified as kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-beta-D-galactopyranosyl]-(1-->4)-O-beta-D-glucopyranoside, and kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-beta-D-glucopyranosyl]-(1-->6)-O-beta-D-glucopyranoside, on the basis of spectroscopic methods, including 2D NMR. The isolated compounds have been evaluated for their human platelet anti-aggregation activity.
Subject(s)
Flavonoids/isolation & purification , Flavonoids/pharmacology , Kaempferols , Onions/chemistry , Platelet Aggregation/drug effects , Quercetin/isolation & purification , Flavonoids/chemistry , Humans , Magnetic Resonance Spectroscopy , Quercetin/analogs & derivatives , Quercetin/chemistry , Quercetin/pharmacologyABSTRACT
A kaempferide triglycoside has been found as a constitutive component in an uninfected carnation (Dianthus caryophyllus) of the cultivar Novada. The chemical structure has been determined mainly by the use of spectroscopic methods, including 2D NMR experiments. It showed a strong activity in restricting fungal parasite development, which could contribute to the known ability of carnation cv. Novada to resist to Fusarium oxysporum f. sp. dianthi infection.
Subject(s)
Flavonoids , Fusarium/pathogenicity , Kaempferols , Magnoliopsida/microbiology , Magnoliopsida/physiology , Quercetin/chemistry , Trisaccharides/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Immunity, Innate , Magnoliopsida/chemistry , Molecular Conformation , Molecular Sequence Data , Molecular Structure , Plant Diseases/microbiology , Quercetin/analogs & derivatives , Quercetin/isolation & purification , Trisaccharides/isolation & purificationABSTRACT
Investigation of polar extracts from ripe fruits of Capsicum annuum L. var. acuminatum yielded three new glycosides, capsosides A (1) and B (2) and capsianoside VII (3), along with seven known compounds (4-10). The chemical structures were elucidated mainly by extensive nuclear magnetic resonance methods and mass spectrometry, and the biological activities of icariside E(5) (4) were tested by different assays. Icariside E(5), in contrast to capsaicin, neither induces an increase in the intracellular levels of reactive oxygen species nor affects the mitochondria permeability transition, and it does not signal through the vanilloid receptor type 1. Interestingly, this compound protects Jurkat cells from apoptosis induced by the oxidative stress mediated by serum withdrawal. These results suggest that icariside E(5) may have antioxidant properties that strengthen the importance of peppers in the Mediterranean diet.
Subject(s)
Capsicum/chemistry , Glycosides/isolation & purification , Plants, Medicinal , Glycosides/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Plant Extracts/chemistry , Reactive Oxygen SpeciesABSTRACT
An extensive phytochemical analysis of the saponin content has been undertaken on leek, Allium porrum L., sown and collected at different seasons. As a result of this investigation, eight saponins (1-8) have been isolated, four of them (5-8) being novel compounds. Compounds 5 and 6, possessing the same tetrasaccharide moiety of compounds 1 and 3, display very unusual spirostane aglycones, 12-ketoporrigenin and 2,12-diketoporrigenin (named porrigenin C), respectively, recently isolated for the first time as free sapogenin in the same plant. Compounds 7 and 8 are rare cholestane bidesmosides possessing a di- and trisaccharide residues linked to a polyhydroxycholesterol aglycone, respectively. The structures of the isolated compounds have been determined by nondegradative spectroscopic analysis, mainly based on NMR. All the eight saponins isolated from leek were tested for their cytotoxic activity against two different cell lines in vitro, and compounds 1, 2, and 6 resulted particularly active.
Subject(s)
Allium/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Saponins/isolation & purification , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Carbohydrate Sequence , Drug Screening Assays, Antitumor , Mice , Molecular Sequence Data , Saponins/chemistry , Saponins/pharmacology , Tumor Cells, CulturedABSTRACT
We investigated the effect of cyclolinteinone, a sesterterpene from Caribbean sponge Cacospongia linteiformis, on inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2) protein expression in lipopolysaccharide (LPS)-stimulated J774 macrophages. Incubation of J774 cells with LPS (1 microgram/ml) caused an increase of both iNOS and COX-2 protein expression, which was prevented in a concentration-dependent fashion by cyclolinteinone (12.5, 25 and 50 microM). Electrophoretic mobility-shift assay indicated that cyclolinteinone blocked the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor necessary for either iNOS or COX-2 induction. Cyclolinteinone also blocked disappearance of I(kappa)B-alpha from cytosolic fraction and nuclear translocation of NF-kappaB subunits p50 and p65. These results show that cyclolinteinone down-regulates iNOS and COX-2 protein expression by inhibiting NF-kappaB activation and suggest that it may represent a novel anti-inflammatory compound capable of controlling the excessive production of prostaglandins and nitric oxide occurring in several inflammatory diseases.
Subject(s)
4-Butyrolactone/analogs & derivatives , Cyclohexanones/pharmacology , Enzyme Inhibitors/pharmacology , Isoenzymes/drug effects , Macrophages/drug effects , NF-kappa B/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Prostaglandin-Endoperoxide Synthases/drug effects , 4-Butyrolactone/pharmacology , Animals , Biological Transport , Cell Line , Cell Nucleus/metabolism , Cyclooxygenase 2 , Hydrolysis , Isoenzymes/metabolism , Macrophages/enzymology , Macrophages/metabolism , Mice , NF-kappa B/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Prostaglandin-Endoperoxide Synthases/metabolismABSTRACT
An investigation of the extracts from bulbs of Allium porrum L. has led to the isolation of four spirostanol saponins. Two of them are new compounds and have been identified as: (25R)-5 alpha-spirostan-3 beta, 6 beta-diol 3-O-{O-beta-D-glucopyranosyl-(1-->2)-O-[beta-D-xylopyranosyl-(1-->3)]-O- beta -D-glucopyranosyl-(1-->4)-beta-D-galactopyranoside} (3) and (25R)-5 alpha-spirostan-3 beta,6 beta-diol 3-O-{O-beta-D-glucopyranosyl-(1-->3)-O-beta-D-glucopyranosyl-(1-->2)-O- [beta-D-xylopyranosyl-(1-->3)]-O-beta-D-glucopyranosyl-(1-->4)-beta-D- galactopyranoside} (4). The isolated compounds were evaluated for their antifungal activity.
Subject(s)
Allium/chemistry , Saponins/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Saponins/isolation & purification , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
Two new sesterterpenes, lintenolides F (6 a, b) and G (7 a, b), were isolated from the Caribbean sponge Cacospongia cf. linteiformis. Their stereostructures were determined using spectroscopic and chemical methods. The new compounds (6 a, b and 7 a, b) and the related compounds lintenolides A-E (1 a, b-5 a, b), previously isolated from the sponge, exhibited antiproliferative activity on four cell lines.
Subject(s)
Cell Division/drug effects , Porifera/chemistry , Terpenes/pharmacology , Animals , Cattle , Cell Line , Chromatography, High Pressure Liquid , Endothelium, Vascular , Fibrosarcoma , Macrophages , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Monocytes , Sesterterpenes , Terpenes/chemistry , Terpenes/isolation & purification , Tumor Cells, CulturedABSTRACT
The DNA Holliday junction is a central intermediate in genetic recombination. We have designed and synthesized a DNA oligomer, J1a, as a model compound for the Holliday junction suitable to be studied by NMR spectroscopy and future molecular modelling. The design was based on a 46-base oligomer, J4, previously studied by Pikkemaat, J. A., van den Elst, H., van Boom, J. H. & Altona, C. [Biochemistry 33, 14896-14907 (1994)], including the propensity to undergo a self-folding process to give a four-way junction in which three of the four arms are capped with a hairpin loop. J1a, however, is considerably shortened by eight bases and thus contains only 38 residues which significantly facilitates the proton resonance assignments. The base sequence at the branch point is identical to that in J4. 1H-NMR data clearly point to the presence of three hairpin loops in J1a and show that the double-helical arms adopt the B-DNA form. Quasicontinuous pairwise stacking between helical arms to give a single preferred stacked X-conformation is evident. The extent of folding into this stacked conformation is strongly dependent upon the magnesium concentration. Full Watson-Crick base pairing at the branch point is completely preserved. The A/D-stacking preference of the small junction is the same as that exhibited by J4.
Subject(s)
DNA/chemistry , Nucleic Acid Conformation , Oligodeoxyribonucleotides/chemistry , Base Sequence , Indicators and Reagents , Nuclear Magnetic Resonance, Biomolecular/methods , Oligodeoxyribonucleotides/chemical synthesisABSTRACT
Four new sapogenins, porrigenins A (2a) and B (3a), identified as (25R)-5 alpha-spirostan-2 beta,3 beta,6 beta-triol and (25R)-2-oxo-5 alpha-spirostan-3 beta,6 beta-diol, respectively, and neoporrigenins A (2b) and B (3b) were also isolated from Allium porrum. In addition, the known agigenin (1a) and its 25S epimer, neoagigenin (1b), were also identified. Their structure elucidation was provided by comprehensive spectroscopic analyses. Compounds 1a, 2a, and 3a exhibited cytotoxicity and high antiproliferative activity on four different tumor cell lines in vitro.
Subject(s)
Allium/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Sapogenins/isolation & purification , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Carbohydrate Sequence , Cell Division , Drug Screening Assays, Antitumor , Humans , Leukemia P388/drug therapy , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Molecular Sequence Data , Sapogenins/pharmacology , Tumor Cells, CulturedABSTRACT
An investigation of the extracts from Allium neapolitanum has led to the isolation of 13 flavonoid glycosides, based on kaempferol, quercetin and isorhamnetin. Four of them are new compounds and have been identified as: kaempferol 3-O-[[2-O-alpha-L-rhamnopyranosyl-4-O-beta-D-glucopyranosyl]-beta-D- glucopyranoside]], isorhamnetin 3-O-[[2-O-alpha-L-rhamnopyranosyl-6-O-beta- D-glucopyranosyl]-beta-D-glucopyranoside], isorhamnetin 3-O-[[2-O-alpha-L-rhamnopyranosyl-6-O-beta-D-glycopyranosyl] beta-D-glucopyranoside]-7-O-beta-D-glucopyranoside and isorhamnetin 3-O-[[2-O-alpha-L-rhamnopyranosyl-6-O-beta-D-gentiobiosyl]- beta-D-glucopyranoside]]. The isolated compounds were evaluated for their anti-aggregation human platelet activity.
Subject(s)
Allium/chemistry , Flavonoids/chemistry , Flavonoids/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Flavonoids/isolation & purification , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/pharmacology , Humans , Italy , Magnetic Resonance Spectroscopy , Plant Extracts/isolation & purification , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/isolation & purificationABSTRACT
From wild garlic Allium ursinum three new flavonoid glycosides were identified as kaempferol 3-O-beta-neohesperidoside-7-O-[2-O-(trans-p-coumaroyl)]-beta -D- glucopyranoside, kaempferol 3-O-beta-neohesperidoside-7-O-[2-O-(trans-feruloyl)]-beta-D- glucopyranoside, kaempferol 3-O-beta-neohesperidoside-7-O-[2-O-(trans-p-coumaroyl)-3-O-b eta-D- glucopyranosyl]-beta-D-glucopyranoside and characterized as the peracetates. Additionally, two known flavonoid glycosides kaempferol 3-O-beta-glucopyranoside and kaempferol 3-O-beta-neohesperidoside were isolated. The isolated compounds showed an inhibition of human platelet aggregation.
Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Garlic/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plants, Medicinal , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Blood Platelets/drug effects , Carbohydrate Sequence , Flavonoids/isolation & purification , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Plant Extracts/isolation & purification , Platelet Aggregation Inhibitors/isolation & purification , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, UltravioletABSTRACT
In recent years various examples of highly stable two-residue hairpin loops (miniloops) in DNA have been encountered. As the detailed structure and stability of miniloops appear to be determined not only by the nature and sequence of the two bases in the loop, but also by the closing base pair, it is desirable to carry out in-depth studies of especially designed small model DNA compounds. Therefore, a circular DNA dumbbell-like molecule is tailored to consist of a stem of three Watson-Crick base pairs, flanked on each side by a minihairpin loop. The resulting circular DNA decamer 5'-d
Subject(s)
DNA, Circular/chemistry , Nucleic Acid Conformation , Base Sequence , Kinetics , Molecular Sequence Data , ThermodynamicsABSTRACT
The conformational behavior of DNA minihairpin loops is sensitive to the directionality of the base pair that closes the loop. Especially tailored circular dumbbells, consisting of a stem of three Watson-Crick base pairs capped on each side with a minihairpin loop, serve as excellent model compounds by means of which deeper insight is gained into the relative stability and melting properties of hairpin loops that differ only in directionality of the closing pair: C-G vs G-C. For this reason the thermodynamic properties of the circular DNA decamers 5'-d
Subject(s)
DNA, Circular/chemistry , Nucleic Acid Conformation , Base Sequence , Chemical Phenomena , Chemistry, Physical , Molecular Sequence Data , ThermodynamicsABSTRACT
The circular DNA decamer 5'-d
Subject(s)
DNA, Circular/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Nucleic Acid Conformation , ProtonsABSTRACT
The circular DNA decamer 5'-d [formula: see text] 3' is studied in solution by means of NMR spectroscopy. At low temperature the molecule adopts a dumbbell structure with three Watson-Crick C-G base pairs and two two-residue loops in opposite parts of the molecule. On raising the temperature another conformer appears, in which the closing C-G base pair in the 5'-GTTC-3' loop is disrupted, whereas the opposite 5'-CTTG-3' loop remains stable. The two conformers are in slow equilibrium over a limited temperature range.
Subject(s)
DNA, Circular/chemistry , Nucleic Acid Conformation , Oligodeoxyribonucleotides/chemistry , Base Composition , Base Sequence , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Protons , ThermodynamicsABSTRACT
Two novel glycolipids with a very rare alpha(1-->4) diglucosyl structure have been isolated from the thermophilic bacterium Thermotoga maritima. The structures of these compounds, on the basis of chemical procedures and spectroscopic studies (FAB-MS and NMR), were shown to be: 1(3),2-dipalmitoyl-3(1)-[glucopyranosyl-(6-decanoyl)-alpha-D-(1-->4)- glucopyranosyl-alpha-D]-glycerol (Glycolipid 1) and 1(3),2-dipalmitoyl-3(1)-[glucopyranosyl-alpha-D-(1-->4)-glucopyranosyl- alpha-D]-glycerol (Glycolipid 2).
Subject(s)
Glycolipids/isolation & purification , Glycosides/isolation & purification , Gram-Negative Anaerobic Bacteria/metabolism , Chromatography, Gas , Glycolipids/chemistry , Glycolipids/metabolism , Glycosides/metabolism , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
From the fruit body of the fungus Marasmius oreades (family Tricholomataceae), 4,4-dimethyl-5 alpha-ergosta-8,24(28)-dien-3 beta-ol (1), probably a biogenetic precursor of ergosterol, has been isolated along with ergosterol. Its stereostructure has been established unequivocally by spectroscopic methods, including 13C nuclear magnetic resonance.
Subject(s)
Agaricales/chemistry , Ergosterol/analogs & derivatives , Ergosterol/chemistry , Ergosterol/isolation & purification , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular StructureABSTRACT
Diaziquone (AZQ), a synthetic quinone with demonstrated activity against acute nonlymphocytic leukemia (ANLL), primary CNS tumors, and non-Hodgkin's lymphoma (NHL), is virtually devoid of nonhematopoietic toxicity at conventional doses. As a prelude to its inclusion into bone marrow transplant (BMT) preparative regimens, a phase I study of high-dose AZQ with autologous BMT (ABMT) was performed. Patients with refractory solid tumors and lymphomas were treated with a single 24-hour infusion of AZQ at 50 to 355 mg/m2 in dose escalations of 20%. Fifty-six patients received 69 courses. Those receiving greater than 60 mg/m2 had nadir granulocyte and platelet counts less than 500/microL and 20,000/microL, respectively. Nausea, vomiting, stomatitis, and diarrhea were mild, transient, and not dose-related. Transient minimal elevations of liver function tests were seen in five patients and were also not dose-related. The maximally tolerated dose (MTD) of high-dose AZQ was found to be 245 mg/m2, with nephrotoxicity being dose-limiting. Significant azotemia was seen in four of 12 patients treated at 295 and 355 mg/m2, including fatal anuric renal failure in three of these patients. Reversible proteinuria also occurred in 24 of 26 courses above 150 mg/m2, including nephrotic range proteinuria in eight courses, all at doses of 205 to 355 mg/m2. The proteinuria was also associated with multiple proximal tubular defects including generalized aminoaciduria and proximal renal tubular acidosis. There were six early deaths including two of early renal failure (295 and 355 mg/m2), two of sepsis (205 and 245 mg/m2), one of a pulmonary embolus (85 mg/m2), and one of progressive disease (60 mg/m2). Of 50 patients who were assessable for response, there were seven responses including two of 10 with primary CNS tumors, one of 12 with malignant melanoma, one of five with non-small-cell lung carcinoma, two of two with breast carcinoma, and one of one with ovarian carcinoma. Because of its activity in ANLL and NHL and its unique toxicity spectrum, high-dose AZQ may improve the efficacy of current BMT preparative regimens without significantly increasing their nonhematopoietic toxicity.