Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Cpx-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia

© 2018 by American Society of Clinical Oncology. Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy

Exawatt-Zettawatt Pulse Generation and Applications

A new amplification method, weaving the three basic compression techniques, Chirped Pulse Amplification (CPA), Optical Parametric Chirped Pulse Amplification (OPCPA) and Plasma Compression by Backward Raman Amplification (BRA) in plasma, is proposed. It is called C3 for Cascaded Conversion Compression. It has the capability to compress with good efficiency kilojoule to megajoule, nanosecond laser pulses into femtosecond pulses, to produce exawatt and beyond peak power. In the future, C3 could be used at large-scale facilities such as the National Ignition Facility (NIF) or the Laser Megajoule (LMJ) and open the way to zettawatt level pulses. The beam will be focused to a wavelength spot size with a f#1. The very small beam size, i.e. few centimeters, along with the low laser repetition rate laser system will make possible the use of inexpensive, precision, disposable optics. The resulting intensity will approach the Schwinger value, thus opening up new possibilities in fundamental physics.Comment: 13 pages, 4 figure

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer

Zettawatt-Exawatt Lasers and Their Applications in Ultrastrong-Field Physics: High Energy Front

Since its birth, the laser has been extraordinarily effective in the study and applications of laser-matter interaction at the atomic and molecular level and in the nonlinear optics of the bound electron. In its early life, the laser was associated with the physics of electron volts and of the chemical bond. Over the past fifteen years, however, we have seen a surge in our ability to produce high intensities, five to six orders of magnitude higher than was possible before. At these intensities, particles, electrons and protons, acquire kinetic energy in the mega-electron-volt range through interaction with intense laser fields. This opens a new age for the laser, the age of nonlinear relativistic optics coupling even with nuclear physics. We suggest a path to reach an extremely high-intensity level $10^{26-28}$W/cm$^2$ in the coming decade, much beyond the current and near future intensity regime $10^{23}$W/cm$^2$, taking advantage of the megajoule laser facilities. Such a laser at extreme high intensity could accelerate particles to frontiers of high energy, tera-electron-volt and peta-electron-volt, and would become a tool of fundamental physics encompassing particle physics, gravitational physics, nonlinear field theory, ultrahigh-pressure physics, astrophysics, and cosmology. We focus our attention on high-energy applications in particular and the possibility of merged reinforcement of high-energy physics and ultraintense laser.Comment: 25 pages. 1 figur

The proper name as starting point for basic reading skills

Does alphabetic-phonetic writing start with the proper name and how does the name affect reading and writing skills? Sixty 4- to 5½-year-old children from middle SES families with Dutch as their first language wrote their proper name and named letters. For each child we created unique sets of words with and without the child’s first letter of the name to test spelling skills and phonemic sensitivity. Name writing correlated with children’s knowledge of the first letter of the name and phonemic sensitivity for the sound of the first letter of the name. Hierarchical regression analysis makes plausible that both knowledge of the first letter’s name and phonemic sensitivity for this letter explain why name writing results in phonetic spelling with the name letter. Practical implications of the findings are discussed

Crop Updates 2008 - Lupins, Pulses and Oilseeds

This session covers twenty six papers from different authors: Regional Roundup 1. SOUTH EAST AGRICULTURAL REGION, Mark Seymour Department of Agriculture and Food, and Robert Johnson CBH Group, Esperance 2. CENTRAL AGRICULTURAL REGION, Ian Pritchard, Department of Agriculture and Food 3. GREAT SOUTHERN AND LAKES REGION, Raj Malik, Department of Agriculture and Food 4. NORTHERN AGRICULTURAL REGION, Wayne Parker and Martin Harries, Department of Agriculture and Food LUPINS 5. Cropping lupins in wide rows in Western Australia, Martin Harries and Bob French, Department of Agriculture and Food 6. The effect of sowing time and radish density on lupin yield, Martin Harries and Jo Walker, Department of Agriculture and Food 7. Lupin agronomy affects crop competitiveness with annual ryegrass, Bob French and Laurie Maiolo, Department of Agriculture and Food 8. Identification of lupin mutants with tolerance to isoxaflutole, Leigh Smith, Department of Agriculture and Food PULSES 9. Chickpea 2007 Crop Variety Testing (CVT) and National Variety Testing (NVT), Alan Harris, Rod Hunter, Tanveer Khan and Jenny Garlinge, Department of Agriculture and Food 10. Desi chickpea breeding: Evaluation of advanced lines, Tanveer Khan1, Poran Gaur2, Kadambot Siddique3, Heather Clarke4, Neil Turner4, William MacLeod4, Stuart Morgan1, Alan Harris1, 1Department of Agriculture and Food, 2International Crop Research Institute for the Semi Arid Tropics (ICRISAT); 3The University of Western Australia; 4Centre for Legumes in Mediterranean Agriculture 11. Can wide rows buffer chickpea growth against dry environments? Bob French and Wendy Vance, Department of Agriculture and Food, and School of Environmental Sciences, Murdoch University 12. Field pea 2007 Crop Variety Testing (CVT) and National Variety Testing (NVT), Alan Harris, Rod Hunter, Tanveer Khan and Jenny Garlinge, Department of Agriculture and Food 13. Australian Field Pea improvement Program (AFPIP): Evaluation of advanced breeding lines, Tanveer Khan1, Phillip Chambers1, Chris Veitch1, Stuart Morgan1, Alan Harris1, and Tony Leonforte 2, 1Department of Agriculture and Food, 2Department of Primary Industries, Victoria 14. Ability of semi-leafless field peas to recover after rolling, Mark Seymour and Rodger Beermier, Department of Agriculture and Food 15. Field pea germplasm enhancement for black spot resistance, Tanveer Khan, Stuart Morgan, Alan Harris and Phillip Chambers, Department of Agriculture and Food 16. Application of ‘Blackspot Manager’ model to identifying a low risk sowing date for field pea in South Australia and Western Australia in 2007, Moin Salam1, Jenny Davidson2, Jean Galloway1, Pip Payne2, Tess Humphries2, Bill MacLeod1 and Art Diggle1, 1Department of Agriculture and Food, 2SARDI, South Australia 17. Late post emergent herbicide sprays for field pea, Mark Seymour and Rodger Beermier, Department of Agriculture and Food 18. Adding triasulfuron to croptopping mixes does not affect the yield of field pea, Mark Seymour, Department of Agriculture and Food 18. Herbicide tolerance of field pea varieties, Harmohinder Dhammu and Mark Seymour, Department of Agriculture and Food 19. Breeding highlights of the PBA lentil program, Michael Materne1, Kerry Regan2, Chris Veitch2 and Phil Chambers2, 1Department of Primary Industries, Victoria 2Department of Agriculture and Food CANOLA 20. How late can I sow canola in 2008? Mohammad Amjad, Andy Sutherland and Pat Fels, Department of Agriculture and Food 21. Direct harvesting canola, Glen Riethmuller1, Wallace Cowling2, Milton Sanders2, Eliot Jones2 and Chris Newman1, 1Department of Agriculture and Food, Western Australia, 2Canola Breeders Western Australia Pty Ltd 22. Agronomic performance of new hybrid canola and juncea canola in low, medium and high rainfall environments of Western Australia, Mohammad Amjad, Andy Sutherland and Pat Fels, Department of Agriculture and Food 23. Comparative performance of new canola varieties in commercial-scale field trials of Oilseeds WA – 2007, Mohammad Amjad1, John Duff2 and David Sermon3 1Department of Agriculture and Food, 2Oilseeds Western Australia and John Duff & Associates, Perth; 3ConsultAg, Perth 24. The effect of rotation crops, trash retention and prophylactic sprays on arthropod abundance in a following canola crop, Svetlana Micic, Anthony Dore and Geoff Strickland, Department of Agriculture and Food OATS 25. Fungicide options for controlling disease in oats, Raj Malik and Blakely Paynter, Department of Agriculture and Food 26. Herbicide tolerance of new oat varieties, Harmohinder Dhammu, Vince Lambert and Chris Roberts, Department of Agriculture and Foo

Robo2-Slit1 dependent cell-cell interactions mediate assembly of the trigeminal ganglion

Vertebrate cranial sensory ganglia, responsible for sensation of touch, taste and pain in the face and viscera, are composed of both ectodermal placode and neural crest cells. The cellular and molecular interactions allowing generation of complex ganglia remain unknown. Here, we show that proper formation of the trigeminal ganglion, the largest of the cranial ganglia, relies on reciprocal interactions between placode and neural crest cells in chick, as removal of either population resulted in severe defects. We demonstrate that ingressing placode cells express the Robo2 receptor and early migrating cranial neural crest cells express its cognate ligand Slit1. Perturbation of this receptor-ligand interaction by blocking Robo2 function or depleting either Robo2 or Slit1 using RNA interference disrupted proper ganglion formation. The resultant disorganization mimics the effects of neural crest ablation. Thus, our data reveal a novel and essential role for Robo2-Slit1 signaling in mediating neural crest–placode interactions during trigeminal gangliogenesis

Inhibition of Histone Deacetylase Activity in Human Endometrial Stromal Cells Promotes Extracellular Matrix Remodelling and Limits Embryo Invasion

Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion