Efficacy and safety of bosutinib in patients treated with prior imatinib and/or dasatinib and/or nilotinib: Subgroup analyses from the phase 4 BYOND study.

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382.

A Survey of Patient Experience in CML: American and Canadian Perspectives.

Purpose: With treatment, chronic myeloid leukemia (CML) has a favorable prognosis, however, individuals with CML experience impairment to their quality of life (QoL). The aim of this study was to examine the perspectives and experiences of individuals with CML and to understand their challenges communicating with their CML physician. Patients and Methods: An online survey in adults with CML (n=100) in the US and Canada assessed QoL, patient-provider relationships, treatment satisfaction, and understanding of CML and treatment goals via the MD Anderson Symptom Inventory, the Cancer Therapy Satisfaction Questionnaire and de novo survey questions. Participants were recruited via an external patient recruiter and CML Patient Groups. Results: Many participants reported hardships due to CML and its treatment. The main impacts were on the ability to work (21%), engage in personal activities (e.g., hobbies, 28%), and to enjoy sexual relations (median=2.00, IQR=8.50). A substantial proportion (21-39%) wished to discuss additional topics with their providers (e.g., management of CML and/or its impacts). While participants reported satisfaction with therapy overall (median=85.71, IQR=17.86), they indicated low to moderate treatment satisfaction with specific components, including concerns regarding side effects (median=43.75, IQR=43.75). Participants generally had a good understanding of CML (97%) and its treatment goals (92%). Conclusion: These findings advance our understanding of issues that need improvement to support QoL for individuals living with CML. Future work is needed to improve patient-provider relationships, address treatment-related side effects, and provide clinical information that is easier for patients to understand.

Integration of apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/protein kinase B-IκB kinase cascade.

Cellular processes are tightly controlled through well-coordinated signaling networks that respond to conflicting cues, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress signals, and survival factors to ensure proper cell function. We report here a direct interaction between inhibitor of κB kinase (IKK) and apoptosis signal-regulating kinase 1 (ASK1), unveiling a critical node at the junction of survival, inflammation, and stress signaling networks. IKK can be activated by growth factor stimulation or tumor necrosis factor alpha engagement. IKK forms a complex with and phosphorylates ASK1 at a sensor site, Ser967, leading to the recruitment of 14-3-3, counteracts stress signal-triggered ASK1 activation, and suppresses ASK1-mediated functions. An inhibitory role of IKK in JNK signaling has been previously reported to depend on NF-κB-mediated gene expression. Our data suggest that IKK has a dual role: a transcription-dependent and a transcription-independent action in controlling the ASK1-JNK axis, coupling IKK to ROS and ER stress response. Direct phosphorylation of ASK1 by IKK also defines a novel IKK phosphorylation motif. Because of the intimate involvement of ASK1 in diverse diseases, the IKK/ASK1 interface offers a promising target for therapeutic development.

Laboratory worker knowledge, attitudes and practices towards smallpox vaccine.

BACKGROUND: Recent cases of laboratory-acquired vaccinia virus (VV) infection highlight the need for laboratory safety. AIMS: To determine laboratory worker adherence to the Advisory Committee for Immunization Practices smallpox vaccination recommendations, assess potential barriers to vaccination and determine the influence of training on laboratory worker attitudes. METHODS: Ninety-two laboratory workers in Pennsylvania were contacted and asked to complete an online survey about VV usage; 45 responded. RESULTS: Eighty-seven per cent had received a smallpox vaccination in their lifetime; 73% received vaccination in the past 10 years. More workers had been given training regarding the potential risks, versus the potential benefits of vaccination, and most perceived that adverse outcomes were more likely to occur following vaccination versus accidental infection. CONCLUSIONS: The results of this study suggest that the main barrier to vaccination may be fear associated with possible vaccine adverse effects and a willingness to risk accidental infection rather than be vaccinated. More information and training about the potential benefits of vaccination, as well as the potential adverse outcomes associated with accidental infection, is therefore warranted.

Progressive ORF virus infection in a patient with lymphoma: successful treatment using imiquimod.

Orf virus is a parapoxvirus that infects small ruminants worldwide. We present the case report of a 73-year-old woman with non-Hodgkins lymphoma who developed progressive orf virus lesions that were unresponsive to surgical debridement and to cidofovir therapy. The patient's orf virus infection was successfully treated with topical imiquimod despite progression of her malignancy.

Ocular vaccinia infection in laboratory worker, Philadelphia, 2004.

We report a case of ocular vaccinia infection in an unvaccinated laboratory worker. The patient was infected by a unique strain used in an experiment performed partly outside a biosafety cabinet. Vaccination should continue to be recommended, but laboratories with unvaccinated workers should also implement more stringent biosafety practices.

Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034.

Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase that mediates cell stress signaling initiated by diverse stimuli, such as H(2)O(2) and TNF alpha. Owing to its critical role in promoting apoptosis, ASK1 activity is highly controlled in cells. Phosphorylation of ASK1 at Thr-845 has been correlated with its activation, while phosphorylation at Ser-967 negatively controls its death promoting activity. Here, we report the identification of a novel phosphorylation site at Ser-1034 in the C-terminal regulatory domain of ASK1. Mutating Ser-1034 to an unphosphorylatable Ala led to increased catalytic activity of ASK1 and enhanced proapoptotic function of ASK1. Thus, the proapoptotic function of ASK1 is suppressed in part by phosphorylation at its C-terminal regulatory domain, which may couple upstream survival kinases to the death regulatory machinery.

Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation.

Oxidative stress has been indicated in a variety of pathological processes such as atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative insults such as hydrogen peroxide (H(2)O(2)) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H(2)O(2)-initiated signals. How ASK1 is activated by H(2)O(2), though, remains a subject of intense investigation. Here we report a mechanism by which H(2)O(2) induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H(2)O(2) triggers dephosphorylation of Ser-967 through an okadaic acid-sensitive phosphatase, resulting in dissociation of the ASK1.14-3-3 complex with concomitant increase of ASK1 catalytic activity and ASK1-mediated activation of JNK and p38 pathways.