Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy

Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival. From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival. In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.This work was supported by the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Madrid, Spain) and the Fundación Rafael del Pino (Madrid, Spain) and both CIBERONC (CB16/12/00400, CB16/12/00233, CB16/12/00480) and grant PI16/00787 from Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, Madrid, Spain)

Selective Vulnerability in Striosomes and in the Nigrostriatal Dopaminergic Pathway After Methamphetamine Administration: Early Loss of TH in Striosomes After Methamphetamine

Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson’s disease, in early Huntington’s disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

Introduction: We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Methods: Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. Discussion: This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain.The study was partially funded by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT- 2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the The Catalan Government DURSI grant 2009SGR1489

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain. Psychopharmacology (Berl

Abstract Rationale Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. Objectives We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. Materials and methods Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30°C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. Results In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol. Conclusions Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition

Early loss of dopaminergic terminals in striosomes after MDMA administration to mice

The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA or >Ecstasy>) is a popular drug of abuse which causes different neurotoxic effects in the mouse compared with the rat. In mice, MDMA produces damage to striatal dopamine terminals, having little long-term effects on serotonin (5-HT) containing neurons. A relevant feature of the striatum is its striosome/matrix compartmental organization; defined by different connexions, and functions. In this study we examined the long-term effect induced by MDMA on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the striosomes and matrix compartments of mouse striatum. Mice given MDMA showed significant reductions in TH and DAT immunostaining in striatum compared with control animals. Interestingly, this effect was considerably more pronounced in striosomes than in the matrix. These data provide the first evidence that striosomes and matrix compartments of the mouse striatum have differential vulnerability to MDMA and that the long-term neurotoxicity induced by MDMA in mice is primarily associated with a loss of striosomal dopamine fibres. © 2007 Wiley-Liss, Inc.Peer Reviewe

Studies on the effect of MDMA (‘ecstasy') on the body temperature of rats housed at different ambient room temperatures

1. 3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (T(a)) conditions (⩾20°C), but hypothermia when in cool conditions (T(a)⩽17°C). We have now investigated some of the mechanisms involved. 2. MDMA (5 mg kg(−1) i.p.) produced a rapid decrease in rectal temperature in rats at T(a) 15°C. This response was blocked by pretreatment with the dopamine D(2) receptor antagonist remoxipride (10 mg kg(−1) i.p.), but unaltered by pretreatment with the D(1) antagonist SCH23390 (1.1 mg kg(−1) i.p.). 3. MDMA (5 mg kg(−1)) did not alter the tail temperature of rats at T(a) 15°C, but decreased the tail temperature of rats at T(a) 30°C. 4. A neurotoxic dose of MDMA (three doses of 5 mg kg(−1) given 3 h apart) decreased cortical and hippocampal 5-HT content by approximately 30% 7 days later. This lesion did not influence the rise in tail temperature when rats were moved from T(a) 20°C to 30°C compared to nonlesioned controls, but did result in a lower tail temperature than that of controls when they were returned to T(a) 24°C. 5. Acute administration of MDMA (5 mg kg(−1)) to MDMA-lesioned rats produced a sustained decrease in tail temperature in rats housed at T(a) 30°C compared to nonlesioned controls. 6. These data suggest that the thermoregulatory problems previously observed in MDMA-lesioned rats housed at T(a) 30°C result, partially, from their inability to lose heat by vasodilation of the tail, a major heat-loss organ in this species

The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') to rats

1. The pharmacology of the acute hyperthermia that follows 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') administration to rats has been investigated. 2. MDMA (12.5 mg kg(−1) i.p.) produced acute hyperthermia (measured rectally). The tail skin temperature did not increase, suggesting that MDMA may impair heat dissipation. 3. Pretreatment with the 5-HT(1/2) antagonist methysergide (10 mg kg(−1)), the 5-HT(2A) antagonist MDL 100,907 (0.1 mg kg(−1)) or the 5-HT(2C) antagonist SB 242084 (3 mg kg(−1)) failed to alter the hyperthermia. The 5-HT(2) antagonist ritanserin (1 mg kg(−1)) was without effect, but MDL 11,939 (5 mg kg(−1)) blocked the hyperthermia, possibly because of activity at non-serotonergic receptors. 4. The 5-HT uptake inhibitor zimeldine (10 mg kg(−1)) had no effect on MDMA-induced hyperthermia. The uptake inhibitor fluoxetine (10 mg kg(−1)) markedly attenuated the MDMA-induced increase in hippocampal extracellular 5-HT, also without altering hyperthermia. 5. The dopamine D(2) antagonist remoxipride (10 mg kg(−1)) did not alter MDMA-induced hyperthermia, but the D(1) antagonist SCH 23390 (0.3 – 2.0 mg kg(−1)) dose-dependently antagonized it. 6. The dopamine uptake inhibitor GBR 12909 (10 mg kg(−1)) did not alter the hyperthermic response and microdialysis demonstrated that it did not inhibit MDMA-induced striatal dopamine release. 7. These results demonstrate that in vivo MDMA-induced 5-HT release is inhibited by 5-HT uptake inhibitors, but MDMA-induced dopamine release may not be altered by a dopamine uptake inhibitor. 8. It is suggested that MDMA-induced hyperthermia results not from MDMA-induced 5-HT release, but rather from the increased release of dopamine that acts at D(1) receptors. This has implications for the clinical treatment of MDMA-induced hyperthermia