This study carried out a survey in an Italian shelter to analyze adoptions resulting in the rejection of the newly adopted dog. The results of this study show that the number of dogs adopted and ...returned was stable during the study, that more females than males were adopted, and that males were more likely to be returned. Almost all the dogs were returned because of behavioral problems, and most were more than 6 months of age. Some dogs were returned more than once, with 20% of the people who adopted the same dog at different times reporting the same behavioral problem. Having a house with a yard, a garden, or a terrace appeared to be important for better management of the dog and influenced the length of adoption. Half of the adopters had previous experience as caregiver for a dog; compared to adopters who had no previous experience, however, they returned their companion animal after a shorter period and because of behavioral reasons. Understanding why adopters return their dogs to shelters is an important step toward attempting to minimize relinquishments and, thus, optimize adoptions.
The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic ...malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 10
cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.
Abstract Polyvalent mechanical bacterial lysates (PMBLs) have been shown to reduce the number of infectious episodes in patients with recurrent infections of the respiratory tract. Some previous ...investigations have also shown the effectiveness of PMBLs in reducing exacerbations of chronic obstructive pulmonary disease (COPD). The AIACE study, which was developed according to criteria of evidence-based medicine, evaluated whether the administration of PMBLs to COPD patients, in addition to the recommended treatment, was able to reduce the number of exacerbations by 25%. Two hundred eighty-eight patients with moderate to very severe COPD were recruited and randomly assigned to either placebo or PMBLs. The placebo or PMBLs were administered according to the standard scheme. The primary outcome of the study was not achieved. However, the number of days with fever (21 days per year versus 40.15; p < 0.001), the days of hospitalisation (65 days vs 162 days; p < 0.001), the interval between the first and second exacerbations (123.89 days vs 70.36; p = 0.03) and the number of days in poor health (109 days/year vs 171 days/year; p < 0.001) were significantly better in the PMBL group than in the placebo group. In conclusion, the results of this trials showed that Ismigen, in addition to guideline-suggested treatment, could not significantly reduce the number of exacerbations in the considered population; nevertheless, the secondary outcome results demonstrated potential benefits of this compound for relevant clinical outcomes.
Abstract 2877
The Anaplastic Lymphoma Kinase (ALK) gene is fused to several partner genes (mainly NPM) in the majority of Anaplastic Large Cell lymphoma (ALCL) patients (pts). Deregulated ALK ...tyrosine kinase activity represents the driver alteration in this disease, through the phosphorylation of proteins belonging to signal transduction pathways involved in cellular proliferation, apoptosis and differentiation. Although ALK+ ALCL pts are responsive to cytotoxic drugs, relapses occur frequently and bear a dismal prognosis.
Crizotinib is a competitive small-molecule inhibitor of the ALK and c-Met/HGFR receptor tyrosine kinases with cellular IC50 values in NPM-ALK expressing cells comprised between 24 and 60 nM. A dose of 250 mg BID orally was previously established as the recommended dose in a phase I study.
We report here on the safety and activity profile of crizotinib in two ALK+ ALCL pts resistant to cytotoxic therapy who received crizotinib 250 mg BID as part of a compassionate use named patient protocol. No steroids or drugs with antineoplastic activity were allowed; potent CYP3A4 inhibitors/inducers were also excluded.
Pt # 1 is a 26 year old female who received 7 cycles of CHOP-15 with a partial response that lasted only 1 month. Subsequently she was treated with the DHAP and ICE regimens in an attempt to collect stem cells for an autologous BMT. However, even with these two salvage regimens, the pts relapsed within 2–3 weeks after each one. Pretreatment evaluation included fever (>38 C), cervical and inguinal adenopathies, positive PET and CT scans of para-aortic and iliac adenopathies; a bone marrow (BM) aspirate showed 3% of cells with positivity using an ALK break-apart probe by FISH. Fever disappeared within 48 hours after starting crizotinib; by day 7 all superficial adenopathies were no longer present. PET, CT and BM aspirate performed at day 28 days showed regression of previous lesions persisting so far for 2 months. Side effects included transient ocular flashes and grade I LFT elevation.
Pt # 2 is a 21 year old male diagnosed with ALK+ ALCL in August 2009. The pt was treated with 6 cycles of CHOP obtaining a CR that was lost in February 2010. The pt underwent re-induction/mobilization chemotherapy with MAD and received an Autologous Bone Marrow Transplantation in May 2010 after conditioning with the BEAM regimen; he obtained a PR which was lost again after 1 month. Pretreatment evaluation included fever (>39 C, requiring 60 mg prednisone and 3 g paracetamol daily), axillary and inguinal adenopathies, positive PET and CT scans of all internal nodal stations; BM showed 8% of positive cells using an ALK break-apart probe. Within 8 days of treatment constitutional symptoms subsided, all superficial adenopathies disappeared and PET scan shows complete regression of all lesions. Adverse events reported so far include grade I dizziness.
Longer follow-up data along with results from a third ALCL patient will be presented at the meeting.
No relevant conflicts of interest to declare.
Monoclonal immunoglobulin light chains are normally synthesized in excess compared to the heavy chain partners and can be detected in serum and urine ("free" LC). Occasionally free LC are per se ...cause of organ toxicity, as in free LC-related disorders. In AL amyloidosis, the most common of these conditions, free LC with peculiar biophysical properties related to their primary structure damage target organs and organize in amyloid fibrils. Unlimited availability of well-characterized free LC is instrumental to investigate the toxic effect of these proteins and to study their interactions with targets. We present a straightforward strategy to obtain recombinant monoclonal free LC by using a bacterial system. These proteins, expressed as inclusion bodies, were subjected to solubilization and refolding procedures to recover them in native form. To minimize differences from the circulating natural LC, full-length recombinant LC were expressed, i.e. complete of variable and constant regions, with the original amino acid sequence along the entire protein, and with no purification tags. The strategy was exploited to generate free LC from three AL amyloidosis patients. After purification, recombinant proteins were biochemically characterized and compared to the natural Bence Jones protein isolated from one of the patients. Results showed that the recombinant free LC were properly folded and formed homodimers in solution, similar to the natural Bence Jones protein used for comparison. Furthermore, as proof of pathogenicity, recombinant proteins formed amyloid fibrils in vitro. We believe that the present strategy represents a valuable tool to speed research in free LC-related disorders.
Acetyl esterase (acetic-ester acetylhydrolase, EC 3.1.1.6) from citrus peel, whose natural role is not well known, catalyses, in vitro, the hydrolysis of acetyl groups from a wide range of ...substrates. This enzyme was extracted from Mediterranean orange peel, largely available in Italy, and purified 190-fold by a single chromatographic step on Sepabeads FP-HG. SDS polyacrylamide gel electrophoresis of the purified enzyme showed a major protein band, corresponding to a molecular mass of 45 kDa. Both free and immobilised enzyme were used in biotransformations. The enzyme removed the acetyl group in the 3 position of β-lactamic antibiotics, such as cephalosporin C and the intermediate 7-aminocephalosporanic acid with ≥98% conversion and 91-93% product yield.
STI571 (CGP57148B) is an inhibitor of BCR/ABL, the cause of chronic myeloid leukaemia (CML). A difference exists between CML patients in chronic phase, in which responses to STI571are durable, and ...patients in blast crisis, who generally experience only transient responses. Leukaemic cells from six CML patients from whom samples could be obtained during chronic phase and at the time of blast crisis (BC) were compared for sensitivity to STI571, using an in vitro assay. BC samples showed a sensitivity similar to that obtained during chronic phase, suggesting that no substantial intrinsic resistance to STI571 was present in BC.
ABSTRACT
Imatinib mesylate (imatinib) inhibits Bcr/Abl, an oncogenic fusion protein. The
in vitro effects of imatinib on BCR/ABL+ leukemic cells include inhibition of Bcr/Abl tyrosine ...phosphorylation, block of proliferation, and induction of apoptosis. The
in vivo effects of imatinib were evaluated in 12 CML (chronic myeloid leukemia) patients in blast crisis or accelerated phase who were treated with imatinib. Treatment caused a decrease in spontaneous proliferation of leukemic cells in 10 of 12 evaluable patients and the development of apoptosis in 9 of 11 cases. Imatinib also caused an inhibition of Bcr/Abl autophosphorylation; however, the degree of inhibition obtained
in vivo was substantially lower than that achieved
in vitro with similar concentrations of imatinib. In seven patients cells could be evaluated at relapse: spontaneous proliferation was no longer inhibited and Bcr/Abl phosphorylation was comparable or superior to that present at the beginning of treatment, before imatinib administration. Plasma imatinib concentrations were not reduced. Leukemic cells obtained at relapse maintained
in vitro sensitivity (Bcr/Abl autophosphorylation and proliferation inhibition) to imatinib concentration measured
in vivo (3 μM or higher), although a partial resistance to the antiproliferative effects of imatinib was present at low (0.01–0.3 μM) concentrations. In four patients, addition of erythromycin to blood samples obtained at relapse restored imatinib sensitivity in terms of phosphorylation inhibition, indicating that the majority of plasma imatinib was not available to cells and probably bound to α1 acid glycoprotein. These data suggest that measurements of Bcr/Abl kinase activity in peripheral blood samples may represent a more reliable indicator of active concentrations than the measurement of imatinib plasma levels.
This resolution represents the final step in the implementation of the European Take over Directive (20041251EC) in that CONSOB finally completed its duty to issue the rules necessary for certain ...principles set out in the primary legislation to become effective. Tn putting its hand to the matter, CONSOB took the chance to introduce a number of muchneeded modifications to the existing regime. In particular, some of the amendments wifi have a substantial impact on how takeover bids wifi need to be carried out in Italy from now on. This article attempts to summarise the most relevant changes. This new rule applies where, upon announcing the results of the offer, the offeror either declares that the miiiimum acceptance condition, if applicable, has been met or waived, or confirms it has reached a stake representing at least 50% of the company's capital - or two-thirds in the case that 50% was already in its possession. The newly-introduced provisions also list a series of cases in which it is not necessary to reopen the offer period, whether because an equivalent protection for minority shareholders exists (eg, sell-out) or the offer has been approved by the majority of the target's shareholders other than the offeror and its associated parties. The Italian legislator had given a blank mandate to CONSOB for settling the question. The regulator eventually opted for the insertion of a specific, very broad, rule which applies to derivative instruments which confer a long position with respect to the target's voting shares. These instruments shall be taken into account for the purpose of calculating a person's holding under the mandatory tender offer rifies, only subject to limited exceptions. For example, instruments provided for under shareholder agreements as a way to settle deadlock situations wifi not thil within the scope of application of the ruks at hand. A similar `clearing' mechanism applies in respect of mergers and de-mergers: the acquisition of a stake over the mandatory tender offer threshold wifi not result in the obligation to launch an offer provided that the transaction (whether a merger or de-merger) was approved without the opposition of the majority of the target company's shareholders (other than the largest shareholders.)
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