Assessing socio-economic factors in relation to stigmatization, impairment status, and selection for socio-economic rehabilitation: a 1-year cohort of new leprosy cases in north Bangladesh.

The current leprosy elimination strategy focuses almost exclusively on delivery of leprosy diagnostic services and multi-drug treatment (MDT). However, the specific problems of people newly diagnosed with leprosy or cured with MDT primarily relate to impairment of nerve function and social and economic consequences of the diagnosis of leprosy. This study was carried out to investigate the relation between socio-economic factors and the development of nerve impairments and stigma. In addition the relation between socio-economic factors and selection for socio-economic assistance was studied. The study population was a cohort of 2364 newly diagnosed people with leprosy in rural Bangladesh in 1996, including 42.5% women, with an overall mean age of 31.4 years. Three hundred and sixty people (15.2%) had WHO grade 1 or 2 disability identified at diagnosis, and 50 (2.1%) had stigma identified on interview at home visit conducted within one month of diagnosis. One hundred and eighty-eight people (8%) were selected for specific assistance for rehabilitation, primarily interest-free loans for income generating activities or vocational training. Factors independently associated with WHO grade 1 or 2 disability at diagnosis were multibacillary (MB) classification, adult status, and manual occupations. Smear positivity, female sex, and the presence of dependents were associated with an increase in the experience of stigma. The presence of nerve impairments and stigma, as well as several indices of poverty were clearly associated with selection for inclusion in an integrated program for socio-economic assistance. An increased focus by leprosy services on the socio-economic factors associated with poorer physical and social outcomes is recommended. Where adequate finances and trained staff are available, efforts could be made to identify those at higher risk of poor outcomes, and to provide or to mobilize appropriately targeted socio-economic interventions.

GILZ inhibits the mTORC2/AKT pathway in BCR-ABL(+) cells.

The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34(+) stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL(+) cells and indicate that regulation by GILZ may influence TKI sensitivity.

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism.

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL(+) leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.