Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.

Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53 -442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC 50 48000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL.

Suicide remains a significant public health problem for the United States military. Trauma-related diagnoses such as acute stress disorder (ASD) or posttraumatic stress disorder (PTSD) may exacerbate suicide risk, particularly among service members psychiatrically hospitalized following suicide-related events. To date, treatments to address suicide risk and trauma symptomatology among service members within inpatient milieus have been nonexistent. To address this gap, a randomized controlled pilot trial of Post-Admission Cognitive Therapy (PACT) was conducted to evaluate a targeted cognitive-behavioral program among traumatized military personnel (N = 36) hospitalized following a recent suicide attempt. All participants met criteria for ASD or PTSD and were randomly assigned to receive either PACT and enhanced usual care (PACT + EUC) or EUC alone. PACT consisted of six 60- to 90-min individual psychotherapy sessions, adapted from Brown et al.'s (2005) cognitive therapy protocol for suicide prevention. Blinded follow-up assessments were conducted at 1-, 2-, and 3-months postpsychiatric discharge. The primary outcome was days until repeat suicide attempt. Secondary outcomes included depression, hopelessness, suicide ideation, and PTSD symptoms. Participants did not significantly differ in reattempt status. However, based on reliable change index analyses, a greater proportion of PACT + EUC versus EUC participants met criteria for clinically significant change on measures of depression (100% vs. 78%), hopelessness (83% vs. 57%), and PTSD symptom severity (100% vs. 38%), but not for suicide ideation (60% vs. 67%). PACT is an innovative inpatient protocol, currently under evaluation in a well-powered multisite RCT for its efficacy in reducing subsequent suicidal behaviors. (PsycINFO Database Record