Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies.

CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites.

EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal.

The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436).

Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia.

The histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen.

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.

The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif.

Derepression of the Iroquois Homeodomain Transcription Factor Gene IRX3 Confers Differentiation Block in Acute Leukemia.

The Iroquois homeodomain transcription factor gene IRX3 is expressed in the developing nervous system, limb buds, and heart, and transcript levels specify obesity risk in humans. We now report a functional role for IRX3 in human acute leukemia. Although transcript levels are very low in normal human bone marrow cells, high IRX3 expression is found in ∼30% of patients with acute myeloid leukemia (AML), ∼50% with T-acute lymphoblastic leukemia, and ∼20% with B-acute lymphoblastic leukemia, frequently in association with high-level HOXA gene expression.

Secondary syphilis presenting with aortitis and coronary ostial occlusion.

Aortitis is an established manifestation of tertiary syphilis. We report a rare case of aortitis with ostial occlusion and left ventricular failure in secondary syphilis. Her management required a true multidisciplinary approach from multiple specialities due to complications of concomitant psychosis and a history of anaphylaxis to penicillin.

Intensive serial biomarker profiling for the prediction of neutropenic Fever in patients with hematologic malignancies undergoing chemotherapy: a pilot study.

Neutropenic fever (NF) is a life-threatening complication of myelosuppressive chemotherapy in patients with hematologic malignancies and triggers the administration of broad-spectrum antimicrobials. The ability to accurately predict NF would permit initiation of antimicrobials earlier in the course of infection with the goal of decreasing morbid complications and progression to septic shock and death. Changes in the blood level of inflammatory biomarkers may precede the occurrence of NF.

Immobilisation of homogeneous olefin polymerisation catalysts. Factors influencing activity and stability.

The activity and stability of homogeneous olefin polymerisation catalysts, when immobilised on a support, are dependent on both chemical and physical effects. Chemical factors affecting catalyst activity include the ease of formation of the active species, which is strongly dependent on the transition metal. Catalyst productivity is dependent on the balance between activity and stability.

Mono N,C,N-pincer complexes of titanium, vanadium and niobium. Synthesis, structure and catalytic activity in olefin polymerisation.

Transmetallation of 4,4'-bis{(2,6-bis[(dimethylamino)methyl]phenylgold)diphenyl-phosphino}biphenyl (3) with MCl(4) (M = Ti, NbCl, V) in benzene gave the corresponding transition metal pincer complexes (4) and insoluble 4,4'-bis[P-(chloro gold(I))diphenylphosphino]biphenyl (2), which can be quantitatively recovered and recycled. Interestingly, 3 did not react with TiCl(3). However, reaction of 2,6-bis[(dimethylamino)methyl]phenyllithium (1) with TiCl(3) resulted in formation of the novel diaryltitanium(IV) compound 5 (16% yield), comprising one N,C,N-mer bound NCN-pincer ligand and a second NCN-pincer ligand that is rearranged from a 1,2,6-isomer to a 1,2,4 one.

Crystallization and dissolution of flow-induced precursors.

We make use of a specially synthesized linear high density polyethylene with a bimodal molecular weight distribution (MWD) to demonstrate that it is possible to produce a suspension of extended-chain (shish) crystals only. Such a suspension can be generated at high temperatures, above but close to the equilibrium melting temperature of the unconstrained extended-chain crystals (T(m)(0)=141.2 degrees C) and requires stretch of the longest chains of the MWD.

The combined orthodontic and surgical treatment of traumatic Class II division 2 in the adult.

A mild Class II division 2 incisal relationship is often associated with a pleasing facial profile and aesthetically acceptable arrangement of the teeth. Severe cases, however, have the potential to cause trauma and a number of older patients present with extensive soft and hard tissue damage. Management options may range from simple preventive advice to complicated surgical orthodontics.