Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.     

Modulation of the in vivo effects of gabapentin by vigabatrin and SKF89976A

Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.     

Sexual fantasies and impotence. Apropos of 2 cases

Sexual fantasies, drawn of the erotic memory that constitutes himself the long of the sexual history of each, are indispensable, for the good sexual working. Some authors tend to consider the imagination like a "veritable intra psychic erogenous zone". However, people who, for a reason or an another, persisted to avoid all sexual activity before the marriage and to separate all erotic velleity, don't they risk to have an erotic imaginary atrophied, who could sound negatively once on their sexual behaviour, after the marriage, when all is suddenly authorized for them? Through two clinical observations of secondary sexual impotence, we are going to try to show the ominous consequences of such a relentlessness (imposed by the education, the social morals or the religion), against sexual stimulation, on the sexuality. These consequences are more easily observable in men, of the fact of their active role, in the sexual activity. Our purpose is to insist on the necessity to explore the sexual history owing all sexual dysfunction, and to place it in the biographic setting of the impatient; but also and especially to attract the attention on the importance of a precocious sex education, adapted to age, to the personal maturation and the cultural and educational context.     

Biphenotypic acute leukaemia: a case series

Biphenotypic acute leukaemia (BAL) is a rare type of leukaemia. Whether patients with BAL should be treated with regimens designed for acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) or both remain unclear. We have reviewed the clinical data for 31 BAL patients. Most patients co-expressed B-lymphoid and myeloid markers. No specific chromosomal abnormality was identified. The majority of the patients were treated with regimens devised for treating ALL. Seven patients were treated with regimens designed for AML. Complete remission (CR) rates of 78% and 57% were noted respectively. The overall survival probability at 2 years was 60%.     

Novel agents in acute myeloid leukemia

In the past 40 years, advances in supportive care and development of chemotherapeutic agents have led to improved outcomes in patients with acute myeloid leukemia. High relapse rates following remission have led to extensive efforts to develop techniques and regimens for detecting and eliminating minimal residual disease. However, the best postremission therapy has not been identified. Better understanding of the biology and the molecular pathogenesis of AML has led to the development of new, more specific agents and strategies for AML treatment. Targeted therapy has improved outcomes in some patients. Most of the new agents are less toxic then their predecessors, and they can be used in combination with the more intensive traditional regimens.     

The adaptation of Rice yellow mottle virus to the eIF(iso)4G-mediated rice resistance

The rymv1-3 allele of the eIF(iso)4G-mediated resistance to Rice yellow mottle virus (RYMV) is found in a few Oryza glaberrima cultivars. The same resistance-breaking (RB) mutations emerged in the central domain of the VPg after inoculation of isolates of different strains. The RB mutations were fixed, often sequentially, at codons 41 and 52 which paralleled an increase in virus accumulation. RB mutations also emerged after inoculation of an avirulent infectious clone, indicating that they were generated de novo in resistant plants. Only virus isolates with a threonine at codon 49 of the VPg broke rymv1-3 resistance, those with a glutamic acid did not. A small subset of these isolates overcame rymv1-2 resistance, but following a specific pathway. Comparison with the RB process of rymv1-2, a resistance allele found in a few Oryza sativa cultivars, showed similarities in the mode of adaptation but revealed converse virulence specificity of the isolates.     

Effect of Argania spinosa oil extract on proliferation and Notch1 and ERK1/2 signaling of T-cell acute lymphoblastic leukemia cell lines

The Argan tree, called Argania spinosa (L.) Skeels, is a tropical plant, which belongs to the Sapotaceae family, it is exploited essentially for its fruits. The endosperm seed of the fruit constitutes a good potential source of edible oil for human consumption and is endowed with important medicinal properties such as antioxidant, antimalarial and anti-proliferative. The aim of the present work is to evaluate the anti-proliferative effect of the oil extracted from seeds of A. spinosa in T-cell acute lymphoblastic leukemia human (T-ALL) context. The activity was assessed through an in vitro test on three T-ALL cell lines: JURKAT, MOLT3 and DND41. The cytotoxicity effects of A. spinosa oil extract were checked by MTT assay and the change in the activity levels of two T-ALL proliferation-related proteins (Notch1 and ERK) was investigated by Western blot, the results demonstrate that treatment with A. spinosa oil extract at the dose of 100?μg/mL inhibited the growth of JURKAT, MOLT3 and DND41 cells, and reduced the expression levels and the activity of proliferation-related proteins such as ERK1/2 and Notch1 intracellular domain. A. spinosa oil extract could be a potential preventive and therapeutic approach recommended as anti-proliferative against leukemia.