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Background: The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials., Materials and Methods: The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines., Results: Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines., Conclusion: Our data provide the rationale to evaluate birabresib in patients affected by MCL., Competing Interests: Competing interests: Francesco Bertoni and Anastasios Stathis have received institutional research funds from Oncology Therapeutic Development. Maria E. Riveiro was an employee of Oncology Therapeutic Development. EC is a Founder, Chief Scientific Officer, shareholder of Oncoethix SA, holder of birabresib license. EZ has received research funds from Celgene, Novartis, Mundipharma, Roche, Pharmacyclics Inc., Johnson & Johnson’s Janssen Pharmaceutical, Gilead. The remaining Authors have no conflict of interest.

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC)., Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day., Results: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months., Conclusions: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Functional neuroimaging studies in schizophrenia have often been confounded by various factors including medication status. To explore the effects of antipsychotic medications on relative regional cerebral perfusion, we scanned a group of 33 persons with schizophrenia twice, while receiving a stable dose of antipsychotic and after being off antipsychotics for 3 weeks, using technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography (Tc-99m HMPAO-SPECT. We found that antipsychotic significantly increased the mean relative cerebral perfusion in the left basal ganglia. Additionally, patients receiving thiothixene (n = 9) had a significantly greater increase in relative cerebral perfusion in the basal ganglia than patients receiving haloperidol (n = 12). These findings indicate that antipsychotics lead to regional increases in cerebral perfusion and that antipsychotic status must be controlled for in functional neuroimaging studies. Functional neuroimaging techniques such as SPECT may be useful in furthering our understanding of the mechanism of antipsychotics.

Xenopus oocytes, arrested in late prophase of the meiotic cell cycle, undergo nuclear membrane breakdown (Germinal Vesicle Breakdown, GVBD) in response to progesterone stimulation. During this prophase/M-phase transition the oocytes undergo an increase in their intracellular pH (pHi) from 7.3 to 7.7 in response to the steroid. This increase in pHi appears to be due to the activation of Na+/H+ antiporters in the oocyte plasma membrane. Several studies have shown that the pathway leading to GVBD is blocked by forskolin or methylxanthines which elevate cAMP levels within the oocyte. We have found that these same compounds also blocked the up-regulation of the Na+/H+ exchangers during oocyte meiotic maturation.