Efficacy and tolerability of gemtuzumab ozogamicin (anti-CD33 monoclonal antibody, CMA-676, Mylotarg(®)) in children with relapsed/refractory myeloid leukemia

BACKGROUND: Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2(nd )relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases. METHODS: GO was administered alone, at a unit dose of 3–9 mg/m(2), once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8–585 d). RESULTS: There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred. CONCLUSION: These results warrant a prospective trial of GO in a larger population of children with AML

Induction of apoptosis in myeloid leukaemic cells by ribozymes targeted against AML1/MTG8

The translocation (8;21)(q22;q22) is a karyotypic abnormality detected in acute myeloid leukaemia (AML) M2 and results in the formation of the chimeric fusion gene AML1/MTG8. We previously reported that two hammerhead ribozymes against AML1/MTG8 cleave this fusion transcript and also inhibit the proliferation of myeloid leukaemia cell line Kasumi-1 which possesses t(8;21)(q22;q22). In this study, we investigated the mechanisms of inhibition of proliferation in myeloid leukaemic cells with t(8;21)(q22;q22) by ribozymes. These ribozymes specifically inhibited the growth of Kasumi-1 cells, but did not affect the leukaemic cells without t(8;21)(q22;q22). We observed the morphological changes including chromatin condensation, fragmentation and the formation of apoptotic bodies in Kasumi-1 cells incubated with ribozymes for 7 days. In addition, DNA ladder formation was also detected after incubation with ribozymes which suggested the induction of apoptosis in Kasumi-1 cells by the AML1/MTG8 ribozymes. However, the ribozymes did not induce the expression of CD11b and CD14 antigens in Kasumi-1 cells. The above data suggest that these ribozymes therefore inhibit the growth of myeloid leukaemic cells with t(8;21)(q22;q22) by the induction of apoptosis, but not differentiation. We conclude therefore that the ribozymes targeted against AML1/MTG8 may have therapeutic potential for patients with AML carrying t(8;21)(q22;q22) while, in addition, the product of the chimeric gene is responsible for the pathogenesis of myeloid leukaemia. © 1999 Cancer Research Campaig

Treatment options for patients with triple-negative breast cancer

Breast cancer is a heterogeneous disease composed of different subtypes, characterized by their different clinicopathological characteristics, prognoses and responses to treatment. In the past decade, significant advances have been made in the treatment of breast cancer sensitive to hormonal treatments, as well as in patients whose malignant cells overexpress or amplify HER2. In contrast, mainly due to the lack of molecular targets, little progress has been made in the treatment of patients with triple-negative breast cancer. Recent improved understanding of the natural history, pathophysiology, and molecular features of triple-negative breast cancers have provided new insights into management and therapeutic strategies for women affected with this entity. Ongoing and planned translational clinical trials are likely to optimize and improve treatment of women with this disease

Long-Term Cold Acclimation Extends Survival Time at 0°C and Modifies the Metabolomic Profiles of the Larvae of the Fruit Fly Drosophila melanogaster

Drosophila melanogaster is a chill-susceptible insect. Previous studies on this fly focused on acute direct chilling injury during cold shock and showed that lower lethal temperature (LLT, approximately -5°C) exhibits relatively low plasticity and that acclimations, both rapid cold hardening (RCH) and long-term cold acclimation, shift the LLT by only a few degrees at the maximum.We found that long-term cold acclimation considerably improved cold tolerance in fully grown third-instar larvae of D. melanogaster. A comparison of the larvae acclimated at constant 25°C with those acclimated at constant 15°C followed by constant 6°C for 2 d (15°C→6°C) showed that long-term cold acclimation extended the lethal time for 50% of the population (Lt(50)) during exposure to constant 0°C as much as 630-fold (from 0.137 h to 86.658 h). Such marked physiological plasticity in Lt(50) (in contrast to LLT) suggested that chronic indirect chilling injury at 0°C differs from that caused by cold shock. Long-term cold acclimation modified the metabolomic profiles of the larvae. Accumulations of proline (up to 17.7 mM) and trehalose (up to 36.5 mM) were the two most prominent responses. In addition, restructuring of the glycerophospholipid composition of biological membranes was observed. The relative proportion of glycerophosphoethanolamines (especially those with linoleic acid at the sn-2 position) increased at the expense of glycerophosphocholines.Third-instar larvae of D. melanogaster improved their cold tolerance in response to long-term cold acclimation and showed metabolic potential for the accumulation of proline and trehalose and for membrane restructuring

The Human Sweet Tooth

Humans love the taste of sugar and the word "sweet" is used to describe not only this basic taste quality but also something that is desirable or pleasurable, e.g., la dolce vita. Although sugar or sweetened foods are generally among the most preferred choices, not everyone likes sugar, especially at high concentrations. The focus of my group's research is to understand why some people have a sweet tooth and others do not. We have used genetic and molecular techniques in humans, rats, mice, cats and primates to understand the origins of sweet taste perception. Our studies demonstrate that there are two sweet receptor genes (TAS1R2 and TAS1R3), and alleles of one of the two genes predict the avidity with which some mammals drink sweet solutions. We also find a relationship between sweet and bitter perception. Children who are genetically more sensitive to bitter compounds report that very sweet solutions are more pleasant and they prefer sweet carbonated beverages more than milk, relative to less bitter-sensitive peers. Overall, people differ in their ability to perceive the basic tastes, and particular constellations of genes and experience may drive some people, but not others, toward a caries-inducing sweet diet. Future studies will be designed to understand how a genetic preference for sweet food and drink might contribute to the development of dental caries

Measurement of VH, H → b b ¯ production as a function of the vector-boson transverse momentum in 13 TeV pp collisions with the ATLAS detector

Cross-sections of associated production of a Higgs boson decaying into bottom-quark pairs and an electroweak gauge boson, W or Z, decaying into leptons are measured as a function of the gauge boson transverse momentum. The measurements are performed in kinematic fiducial volumes defined in the `simplified template cross-section' framework. The results are obtained using 79.8 fb-1 of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 13 TeV. All measurements are found to be in agreement with the Standard Model predictions, and limits are set on the parameters of an effective Lagrangian sensitive to modifications of the Higgs boson couplings to the electroweak gauge bosons

Search for heavy neutral Higgs bosons produced in association with b-quarks and decaying into b-quarks at root s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons produced in association with one or two b -quarks and decaying to b -quark pairs is presented using 27.8  fb − 1 of √ s = 13  TeV proton-proton collision data recorded by the ATLAS detector at the Large Hadron Collider during 2015 and 2016. No evidence of a signal is found. Upper limits on the heavy neutral Higgs boson production cross section times its branching ratio to b ¯ b are set, ranging from 4.0 to 0.6 pb at 95% confidence level over a Higgs boson mass range of 450 to 1400 GeV. Results are interpreted within the two-Higgs-doublet model and the minimal supersymmetric Standard Model

Identification of boosted Higgs bosons decaying into b-quark pairs with the ATLAS detector at 13 TeV

This paper describes a study of techniques for identifying Higgs bosons at high transverse momenta decaying into bottom-quark pairs, H→bb¯ , for proton–proton collision data collected by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy s√=13 TeV . These decays are reconstructed from calorimeter jets found with the anti- kt R=1.0 jet algorithm. To tag Higgs bosons, a combination of requirements is used: b-tagging of R=0.2 track-jets matched to the large-R calorimeter jet, and requirements on the jet mass and other jet substructure variables. The Higgs boson tagging efficiency and corresponding multijet and hadronic top-quark background rejections are evaluated using Monte Carlo simulation. Several benchmark tagging selections are defined for different signal efficiency targets. The modelling of the relevant input distributions used to tag Higgs bosons is studied in 36 fb −1 of data collected in 2015 and 2016 using g→bb¯ and Z(→bb¯)γ event selections in data. Both processes are found to be well modelled within the statistical and systematic uncertainties