A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours

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Studio di fase i del satraplatino, composto orale del platino, in combinazione sequenziale con capecitabina nel trattamento di pazienti affetti da tumore solido avanzato.

Obiettivo Definire la dose massima tollerata (MTD) della combinazione di satraplatino, composto orale del platino (S) e capecitabina (C) in pazienti affetti da tumore solido avanzato. Obiettivo secondario è la valutazione della risposta tumorale. Metodi Sono stati esplorati quattro livelli di dose: S 60 mg/m2/giorno and C 1650 mg/m2/giorno, S80 and C 1650, S60 and C 2000, S70 and C 2000. Un ciclo corrisponde a 28 giorni di somministrazione sequenziale di S (giorni 1-5) seguito da C (giorni 8-21) e da una settimana di pausa di una settimana. Risultati Trentasette pazienti sono stati trattati, 24 nella fase di aumento di dose e 13 nella fase di espansione; alla MTD definita a S 70 mg/m2/giorno and C 2000 mg/m2/giorno due pazienti hanno presentato le tossicità limitanti la dose (DLTs): mancato recupero dalla neutropenia entro il 42°giorno e nausea con mancata assunzione della dose di C. Altre tossicità frequenti sono state: nausea (57%), diarrea (51%), neutropenia (46%), anoressia, fatica, vomito (38% ciascuno). In 2 pazienti affetti da tumore ovarico platino sensibile e un paziente affetto da tumore prostatico sono state osservate riposte parziali confermate. Conclusione Alla dose di S 70 mg/m2/giorno and C 2000 mg/m2/giorno la combinazione sequenziale di S e C è ben tollerata con tossicità accettabile; è auspicabile l’uso della combinazione in caso di pazienti affetti da tumore noto per la sensibilità al derivati del platino e fluoro uracile soprattutto per la mancanza di nefrotossicità e neurotossicità e la facilità di somministrazione senza necessità di ricovero

Studio di fase i del satraplatino, composto orale del platino, in combinazione sequenziale con capecitabina nel trattamento di pazienti affetti da tumore solido avanzato.

Obiettivo Definire la dose massima tollerata (MTD) della combinazione di satraplatino, composto orale del platino (S) e capecitabina (C) in pazienti affetti da tumore solido avanzato. Obiettivo secondario è la valutazione della risposta tumorale. Metodi Sono stati esplorati quattro livelli di dose: S 60 mg/m2/giorno and C 1650 mg/m2/giorno, S80 and C 1650, S60 and C 2000, S70 and C 2000. Un ciclo corrisponde a 28 giorni di somministrazione sequenziale di S (giorni 1-5) seguito da C (giorni 8-21) e da una settimana di pausa di una settimana. Risultati Trentasette pazienti sono stati trattati, 24 nella fase di aumento di dose e 13 nella fase di espansione; alla MTD definita a S 70 mg/m2/giorno and C 2000 mg/m2/giorno due pazienti hanno presentato le tossicità limitanti la dose (DLTs): mancato recupero dalla neutropenia entro il 42°giorno e nausea con mancata assunzione della dose di C. Altre tossicità frequenti sono state: nausea (57%), diarrea (51%), neutropenia (46%), anoressia, fatica, vomito (38% ciascuno). In 2 pazienti affetti da tumore ovarico platino sensibile e un paziente affetto da tumore prostatico sono state osservate riposte parziali confermate. Conclusione Alla dose di S 70 mg/m2/giorno and C 2000 mg/m2/giorno la combinazione sequenziale di S e C è ben tollerata con tossicità accettabile; è auspicabile l’uso della combinazione in caso di pazienti affetti da tumore noto per la sensibilità al derivati del platino e fluoro uracile soprattutto per la mancanza di nefrotossicità e neurotossicità e la facilità di somministrazione senza necessità di ricovero

Agranulocytosis: an adverse effect of allopurinol treatment

Introduction: Allopurinol is a xanthine oxidase inhibitor that is primarily used to treat hyperuricemia and its complications. The drug is rarely associated with adverse effects, but those that occur can be significant. Hematologic side effects, including bone marrow suppression, severe anemia, thrombocytopenia, and leukopenia, have been reported in 0.2-0.6% of treated patients. Materials and methods: We report a case of agranulocytosis associated with allopurinol therapy in a patient admitted for fever

Development and characterization of K562 cell clones expressing BCL11A-XL: Decreased hemoglobin production with fetal hemoglobin inducers and its rescue with mithramycin

Induction of fetal hemoglobin (HbF) is considered a promising strategy in the treatment of b-thalassemia, in which production of adult hemoglobin (HbA) is impaired by mutations affecting the b-globin gene. Recent results indicate that B-cell lymphoma/leukemia 11A (BCL11A) is a major repressor of g-globin gene expression. Therefore, disrupting the binding of the BCL11A transcriptional repressor complex to the g-globin gene promoter provides a novel approach for inducing expression of the g-globin genes. To develop a cellular screening system for the identification of BCL11A inhibitors, we produced K562 cell clones with integrated copies of a BCL11A-XL expressing vector. We characterized 12 K562 clones expressing different levels of BCL11A-XL and found that a clear inverse relationship does exist between the levels of BCL11A-XL and the extent of hemoglobinization induced by a panel of HbF inducers. Using mithramycin as an inducer, we found that this molecule was the only HbF inducer efficient in rescuing the ability to differentiate along the erythroid program, even in K562 cell clones expressing high levels of BCL11A-XL, suggesting that BCL11A-XL activity is counteracted by mithramycin

Design, Synthesis and Evaluation of New Multifunctional Benzothiazoles as Photoprotective, Antioxidant and Antiproliferative Agents

: A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC50 was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile

Venting and seepage systems associated with mud volcanoes and mud diapirs in the southern Tyrrhenian Sea

High resolution swath bathymetry and backscatter data, seismic CHIRP profiles, multibeam water column acoustic measurements and sediment samples were collected on a cold seep province in the southeastern Tyrrhenian Sea, at a water depth of 500-1000. m. The mud volcanoes, characterized by a high backscatter signature, are the site of gas venting at the seafloor that formed a 630-m-high plume in the water column. The mud volcanoes feature a precipitation of iron-oxy-hydroxide crusts and pyritized and Sulfur burrows in the sub-surface and authigenic siderites, also cementing burrows, further down, showing a sharp transition from the oxic zone toward the sulfate-methanogenic zone.The mud flows are characterized by an intermediate backscatter seafloor and by the presence of gas in the sediment only 2. m below the seafloor. The mud flows consist of 1-m-thick drapes of water-rich mud extending downslope from the mud volcanoes. They act as sealing layers that prevent large fluxes of gas venting at the seafloor (low venting) and favor oxic conditions close to the sediment-water interface and the abundant precipitation of post-oxic siderites a few meters below the seafloor.The mud diapirs are characterized by a low backscatter seafloor and large fields of pockmarks. In coincidence with the normal faults, organogenic carbonate crusts form at or very close to the seafloor and are associated with chemosymbiontic bivalves (lucinids). The youngest shells are AMS radiocarbon dated 640-440. BP, suggesting that the seepage activity may have been clogged by the carbonates, only very recently.Similarities between the normal faults in the study area and the tectonic setting of the inland Calabrian Arc show that normal faults can control the location of fluid pathways and, probably, also the rising of the mud diapir