James E. Thompson

Putting the Rap on Akt

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction.

Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bone-marrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function.

A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia

Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m2 until evidence of disease progression or unacceptable adverse events occurred. Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m2), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m2. Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to ≤5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m2/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.

Opinions and attitudes of participants in a randomized controlled trial examining the efficacy of SMS reminders to enhance antiretroviral adherence: a cross-sectional survey.

In sub-Saharan Africa antiretroviral therapy (ART) has significantly reduced mortality and morbidity of people living with HIV/AIDS. However incomplete treatment adherence - leading to treatment failure development of drug resistance and HIV disease progression - remains a major concern. Evidence suggests that adherence among individuals in sub-Saharan African declines over time and increasing mobile phone ownership across southern Africa has raised the possibility that text messages using SMS can be used to improve ART adherence. Given varying data about SMS interventions the authors sought to determine the acceptability of SMS interventions among participants in a randomized controlled trial evaluating the efficacy of SMS reminders to improve visit adherence in Gaborone Botswana. The object was to establish whether using SMS reminders was acceptable to patients on ART. The analysis is notable for its implications for the implementation of SMS-based adherence interventions across southern Africa. First it demonstrates that SMS reminders used to remind patients to attend clinic visits and pick up HIV medications are acceptable to patients. Second the data supports the hypothesis that inadvertent HIV status disclosure is an important perceived obstacle to the use of SMS technology in southern Africa. Third the study demonstrates that patients did not want to receive SMS reminders for all areas of their HIV care. [excerpt]

Interferon regulatory factor-8-driven myeloid differentiation is regulated by 12/15-lipoxygenase-mediated redox signaling

OBJECTIVE Several transcription factors determine the cell fate decision between granulocytes and monocytes, but the upstream signal transduction pathways that govern myelopoiesis are largely unknown. Based on our observation of aberrant myeloid cell representation in hematopoietic tissues of 12/15-lipoxygenase (12/15-LOX)-deficient (Alox15) mice, we tested the hypothesis that polyunsaturated fatty acid metabolism regulates myelopoiesis. MATERIALS AND METHODS Multicolor flow cytometric analysis and methylcellulose assays were used to compare myelopoiesis and the differentiative capacity of progenitors from Alox15 and wild-type mice. Furthermore, we elucidated the mechanism by which 12/15-LOX is involved in regulation of myelopoiesis. RESULTS Granulopoiesis in Alox15 mice is increased while monopoiesis is reduced. Moreover, there is an accumulation of granulocyte-macrophage progenitors that exhibit defective differentiation. Mechanistically, we demonstrate that transcriptional activity of interferon regulatory factor-8 (Irf8), which regulates myelopoiesis, is impaired in Alox15 progenitors and bone marrow-derived macrophages due to loss of 12/15-LOX-mediated redox regulation of Irf8 nuclear accumulation. Restoration of redox signaling in Alox15 bone marrow cells and granulocyte-macrophage progenitors reversed the defect in myeloid differentiation. CONCLUSIONS These data establish 12/15-LOX-mediated redox signaling as a novel regulator of myelopoiesis and Irf8.

Evidence of myeloid differentiation in Non-M3 acute myeloid leukemia treated with the retinoid X receptor agonist bexarotene

All-trans-retinoic acid has dramatically changed the treatment paradigm for acute promyelocytic leukemia, however, it has no significant activity in non-M3 acute myeloid leukemia (AML). In vitro, bexarotene, a retinoid X receptor agonist inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts from patients. We hypothesized that there may be similar activity in patients with AML. We report on 2 patients with relapsed or refractory non-M3 AML treated with bexarotene monotherapy. After initiating treatment, both patients showed leukemic differentiation in their peripheral blood and reduction in bone marrow blasts to less than 5%. One patient had a significant improvement in her platelet count with loss of platelet transfusion needs. Differentiation syndrome occurred in one patient and was successfully treated with steroids and discontinuation of bexarotene. These data suggest that bexarotene has clinical activity in non-M3 AML and may be able to induce myeloid differentiation in vivo.

Evaluation of the effect of cellular SMS reminders on consistency of antiretroviral therapy pharmacy pickups in HIV-infected adults in Botswana: a randomized controlled trial

ABSTRACT Objective: Several studies have demonstrated that cellular phone short message service (SMS) improve antiretroviral adherence for people living with HIV in Africa, although less data are available to support using SMS reminders to improve timeliness of antiretroviral therapy (ART) pharmacy pick up. This study tested the efficacy of SMS reminders on timeliness of ART pharmacy pickups at an urban clinic in Gaborone, Botswana. Design: A randomized-controlled trial evaluating the effect of SMS reminders on ART collection for patients with HIV on treatment. Methods: One hundred and eight treatment-experienced adult patients were enrolled and randomly assigned to a control group or an intervention group. Participants in the intervention group received SMS reminders that were sent in advance of monthly ART refills that needed to be collected. The primary outcome was 100% timeliness of pharmacy ART pickups. Secondary outcomes included frequency of physician visits, CD4 cell counts and viral loads. Results: Baseline characteristics in the intervention (n = 54) and control arms (n = 54) were similar. After six months, 85% of those receiving SMS reminders were 100% on time picking up monthly ART refills compared to 70% in the control group (p = 0.064). In secondary analysis, there were no significant changes in the CD4 counts and viral loads over the course of the study. Conclusions: Timeliness of ART pickup was not significantly improved by SMS reminders. Additionally, the intervention had no impact on immunologic or virologic outcomes in treatment-experienced patients.

Intensive Chemotherapy vs. Hypomethylating Agents in Older Adults with Newly Diagnosed High-risk Acute Myeloid Leukemia: A Single Center Experience

Acute myeloid leukemia (AML) in older patients is often associated with biologic and clinical characteristics that predict poor outcomes to cytarabine and anthracycline based induction chemotherapy (IC). The impact of hypomethylating agents (HMA) in the treatment of these high-risk patients is unknown. Here we retrospectively examined the remission rates and survival outcomes of 201 newly diagnosed patients ≥60 years old with therapy-related (t-AML), secondary (s-AML), or AML with myelodysplasia-related changes (AML-MRC). Ninety-eight patients received IC, and 103 received HMA. Patients in the IC cohort were younger than those who received HMA (68 vs. 74 years; p < 0.01) with lower comorbidity burden. Composite complete remission rates (CR) were 39% in IC and 27% in the HMA cohorts (p = 0.10). Overall survival (OS) was not significantly different between the two cohorts (7.59 mos vs. 5.49 mos; HR 0.75 95% CI 0.55-1.02) despite the fact that more patients in the IC cohort (33% versus 5%, p < 0.01) underwent allogeneic stem cell transplant. Patients with t-AML (HR 0.56; 95% CI 0.33-0.97) and complex karyotype without monosomal karyotype (CK + MK-; HR 0.37; 95% CI 0.19-0.75) had better OS following IC. Patients with CK + MK+ (HR 2.00; 95% CI 1.08-3.70) had improved OS following HMA. Our results support the use of HMA as an alternative upfront regimen in older individuals with newly diagnosed high-risk AML based on similar clinical outcomes to IC.

Akt and Bcl-xL Are Independent Regulators of the Mitochondrial Cell Death Pathways

In vivo, hematopoietic cells require continuous signals from their microenvironment to prevent activation of the endogenous programmed cell death machinery. Cell survival is therefore limited by the availability of ligands for the receptors that can influence cell survival. Following loss of receptor engagement, IL-3-dependent hematopoietic cells undergo a rapid decline in cellular metabolism, characterized by reductions in surface expression of the glucose transporter GLUT-1, mitochondrial potential, and cellular ATP. Two distinct classes of oncogenes can prevent cell death in response to declines in glucose uptake and metabolism following growth factor withdrawal: pro-survival Bc1-2 proteins, such as Bcl-xL, or an activated form of Akt. However, Bcl-xL and Akt appear to promote survival by distinct mechanisms. Expression of activated Akt leads to maintenance of glucose transporter expression, glycolytic activity, mitochondrial potential, and cell size, while Bcl-xL-expressing cells deprived of growth factor survive in a more vegetative state characterized by small cells with reduced mitochondrial potential and glycolytic activity. Akt-mediated survival is dependent on promoting glycolysis and maintaining a physiologic mitochondrial potential. In contrast, Bcl-xL maintains mitochondrial integrity in the face of a reduced mitochondrial membrane potential in growth factor-deprived cells. Thus, Akt and Bcl-xL suppress mitochondrial-initiated apoptosis by distinct mechanisms.

Current awareness for better library acquisitions

The acquisitions librarian needs to keep him/herself apprised of a wide variety of extramural developments, especially those occurring within the rapidly changing publishing and bookselling industries. One can keep in touch with acquisitions-related developments by participating in organized activities, by monitoring appropriate publications, and by informally exchanging information with both booksellers and other librarians. The author details those activities and publications he believes most valuable to the student of acquisitions, and he also gives an example of a successful attempt by acquisitions persons to better exchange information among themselves.