Search

Antibodies (or immunoglobulins) are crucial for defending organisms from pathogens, but they are also key players in many medical, diagnostic and biotechnological applications. The ability to predict their structure and the specific residues involved in antigen recognition has several useful applications in all of these areas. Over the years, we have developed or collaborated in developing a strategy that enables researchers to predict the 3D structure of antibodies with a very satisfactory accuracy. The strategy is completely automated and extremely fast, requiring only a few minutes (∼10 min on average) to build a structural model of an antibody. It is based on the concept of canonical structures of antibody loops and on our understanding of the way light and heavy chains pack together.

An efficient and straightforward twostep procedure for the synthesis of N1 alkylarylsubstituted hydantoins was developed, starting from easily available starting materials. The procedure envisages a highly regiospecific domino condensationazaMichael nucleophilic substitutionO→N acyl migration between activated α,βunsaturated carboxylic acids or αhaloaryl acetic acids, respectively, and Ntertbutyl or Ntritylcarbodiimides, leading to the regioselective formation of hydantoins bearing the tertiary alkylic substituent in the 3position, followed by selective removal the substituent. This process avoids the use of harsh reaction conditions and toxic reagents and is high yielding. A detailed study of the influence of the structure of the reactants on the reaction outcome is presented. A wide variety of final products having a primary, secondary, cyclic and aryl substituent at the N1 position were successfully synthesized by this method. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Milani:Janssen: Other: Speaker honoraria; Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria. Nuvolone:Janssen: Honoraria.Bortezomib in AL amyloidosis

No relevant conflicts of interest to declare.

Several agents inhibiting the JAK2V617F mutation are actively investigated in patients with polycythemia vera (PV) and other chronic myeloproliferative neoplasms (MPN) with promising results. Givinostat, an HDAC inhibitor, specifically inhibits proliferation of cells bearing the JAK2V617F mutation and has shown significant activity with good tolerability in clinical studies in MPN patients. The aim of the present study was to evaluate safety and efficacy of two oral doses of Givinostat (50 or 100 mg daily) in combination with hydroxyurea (HU) in PV patients.In this multicenter, randomized, open-label, phase II study, we treated 44 patients with JAK2V617F positive PV, non-responders (NR) to the maximum tolerated doses of HU monotherapy for at least 3 months. The clinical -hematological response criteria developed by the European LeukemiaNet (ELN) consensus conference (complete and partial response) were used to assess the primary endpoint after 12 weeks of treatment. Recruited patients were randomly assigned to receive Givinostat (50 or 100 mg/die) in combination with the maximum tolerated dose of HU. After week 12, NR patients increased the initial daily dose of Givinostat by 50 mg, while responders continued Givinostat at the initial daily dose. Overall, the treatment lasted up to a maximum of 24 cumulative weeks of drug administration.Baseline demographic and hematological parameters were balanced between the two randomized groups. The mean weekly dose of HU at baseline was 6.75 (range 1.75–14) and 6.25 (1–14) grams and was reduced during the study to 6.25 (range 1.75–14) and 5.75 (0.75-12.25) grams, in the 50 (group A) and 100 mg (group B) Givinostat groups, respectively.The combination of Givinostat and HU was well tolerated. Only five out of 44 evaluable patients dropped-out before week 12, respectively 2 in group A and 3 in group B. Reasons for treatment discontinuation were grade 2 thrombocytopenia and iperkalemia in group A and panic attack, withdrawal of consent and investigator decision due to safety reason (detection of familiar cardiac disorder unknown at recruitment) in group B. Only two grade 3 not drug related adverse events (AEs) were observed (hyperkalemia and platelet count increase), both occurring in group B. The most frequent grade 2 AEs were thrombocytopenia (4 cases, two in each group), leukopenia (2 cases both in group B) and diarrhea (2 cases, one in each group).Complete (CR) plus partial (PR) response according to ELN response criteria was observed in 50% and 45% of patients in group A and B respectively. Moreover, a notable control of itching was observed at week 12 in most of the 21 evaluable patients affected by severe itching (grade ≥ 2) at baseline. Seven out of 11 (64%) and 8 out of 10 (80%) patients had a complete itching relief, in group A and B respectively.The combined use of Givinostat and HU is well tolerated and about 50% of patients resistant to HU monotherapy achieved an overall ELN response (PR or CR). At week 12 no differences were found in the two randomized arms in term of hematological responses and itching relief. Givinostat confirms to be active in PV through the control of myeloproliferation and of some specific clinical needs, such as severe itching. Completed clinical and molecular data (after 24 cumulative weeks of treatment) will be presented at the meeting.Rambaldi: Italfarmaco S.p.A.: Consultancy, Honoraria. Vannucchi:Italfarmaco S.p.A.: Consultancy, Honoraria. Barbui:Italfarmaco S.p.A.: Consultancy, Honoraria.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Venous Thromboembolism (VTE) in cancer patients recognizes a multifactorial pathogenesis, depending on endogeous and esogenous factors. However, the relationship among VTE and laboratoristic thrombophilic alterations in cancer patients is not clearly known. Aim of our trial has been to evaluate changes in the levels of physiological coagulation inhibitors and some thrombophilic acquired factors in a cohort of gastrointestinal tumours patients considering four timepoints of their medical history. All patients over 18 years with a new diagnosis of malignant gastrointestinal neoplasm observed in the Surgery department of the University Hospital “Campus Bio-Medico” from October 2002 to June 2004 have been included in this trial. Patients with antineoplastic previous treatment, anticoagulant current therapies, autoimmune or hematological diseases were not included. The following physiological coagulation inhibitors have been tested: Protein C, Protein S, Antithrombin III. Moreover, we tested also the presence of Lupus Anticoagulant by mean of Silica Clotting Time (SCT), Diluted Russel Viper Venom Test (DRVVT) and Anticardiolipin Antibodies of IgG type (ACA IgG). Furthermore, we investigated also the levels of homocysteine and annexin V as well as the presence of activated Protein C resistance. Tests were performed on samples taken just before and after surgery as well as before and at the end of the chemotherapeutic protocols. In addiction, VTE’s prevalence has been evaluated. A total of 102 patients (60 males and 42 females) have been included; median age was 67 years (range 28–92). A significant modification in the values of DRVVT, ACA IgG, PS, ATIII has been observed in the samples taken just after surgery (P <.001) and just before chemotherapy (P <.004). Moreover, PC levels were significantly reduced only after surgery (P <.000); SCT was significantly prolonged before starting chemotherapy (P <.003) while homocysteine levels were significantly reduced (P <.001) just after the end of the chemotherapeutic protocols. In this cohort of patients, VTE’s prevalence has been 7,8% (8/102) of these, 5/8 (62,5%) were treated with FU-based therapies and 3/8 (37,5%) had a Central Venous Catheter. None of the thrombophilic parameters tested was correlated with the development of VTE, while an advanced disease (P<.024) was strongly correlated to VTE. These preliminar results agree with other published trials as for the reduction in physiological coagulation inhibitors after surgery and VTE’s prevalence in cancer patients. Moreover, as expected, patients with advanced inoperable disease experience more easily VTE. Surprisingly, FU-based therapies reduce the levels of homocysteine in this cohort of patients. Increasing the number of studied patients may better clarify which are, in addiction to advanced disease, the more useful parameters for identifying those patients with gastrointestinal cancers at risk of VTE who may, therefore, benefit of a correct VTE prophylaxis.