We identified five common stages experienced by patients with CML and suggest several recommendations for HCPs on the management of patients through their disease journey. By providing support, education, and reassurance, HCPs can help patients as they move through the early stages of crisis and hope. When patients are in the adaptation and new-normal stages, HCPs can help patients achieve and maintain a new normality by setting expectations for the risks/benefits of long-term chronic drug therapy and disease monitoring and by continuing to support patient adherence.

Inflammation and the associated release of inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) may be a component of neurodegenerative diseases associated with aging or chronic HIV-1 infection. Most of the neurons that are affected under these conditions require a constant supply of trophic factors such as nerve growth factor (NGF) for survival. NGF acts via binding to a specific tyrosine kinase receptor (TrkA). NGF also binds to the common neurotrophin receptor (p75(NTR)), a member of the TNFalpha receptor (TNFR-I) superfamily, whose function may be to modulate apoptosis via the release of ceramide and the activation of the transcription factor nuclear factor kappa B (NFkappaB). The similarity between p75(NTR) and TNFR-I signal transduction pathways suggests that one of the mechanisms by which TNFalpha affects neuronal survival is by impacting upon these pathways that normally promote NGF support of neurons. Here we show that arachidonic acid (AA), a signaling lipid potentially associated with TNFR-I signal cascade, induces apoptosis in PC12 cells through inhibition of both protein kinase C zeta (PKCzeta) and NFkappaB activity. We also show that apoptosis induced by AA cannot be prevented by NGF. These data support the idea that PKCzeta and NFkappaB are both essential signaling elements for mediating NGF-promoted rescue from apoptosis. Our results also suggest that AA, an inflammatory signal lipid induced by TNFalpha via binding to TNFR-I, may reduce neuronal survival by inhibiting elements of the signal cascade induced by NGF.

PurposeThe tyrosine kinase inhibitor (TKI) imatinib has improved outcomes for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), and for patients receiving adjuvant therapy following GIST resection. This qualitative study explored the experiences and emotions of patients through GIST diagnosis, treatment initiation, disease control, and in some patients, loss of response and therapy switch.Patients and methodsEthnographic investigations were conducted, including semi- structured qualitative interviews of patients with resected or metastatic/unresectable GIST and their caregivers, from Canada (n = 15); the United States (n = 10); and Brazil, France, Germany, Russia, and Spain (n = 5 each). Some interviewees also kept 7-day photo journals. Responses were qualitatively analyzed to identify gaps and unmet needs where communication about disease, treatments, and adherence could be effective.ResultsPatients shared common experiences during each stage of disease management (crisis, hope, adaptation, new normal, and uncertainty). Patients felt a sense of crisis during diagnosis, followed by hope upon TKI therapy initiation. Over time, they came to adapt to their new lives (new normal) with cancer. With each follow-up, patients confronted the uncertainty of becoming TKI resistant and the possible need to switch therapy. During uncertainty many patients sought new information regarding GIST. Cases of disease progression and drug switching caused patients to revert to crisis and restart their emotional journey. Patients with primary or unresectable/metastatic GIST shared similar journeys, especially regarding uncertainty, although differences in the scope and timing of phases were observed. Strategies patients used to remain adherent included obtaining family support, setting reminder mechanisms, taking medicine at routine times, and storing medicine in prominent places.ConclusionsPhysicians and support staff can manage patient expectations and encourage adherence to therapy, which may facilitate optimal patient outcomes. Patient education about current GIST developments and adherence across all phases of the patient journey are of benefit.

Age-associated neurodegenerative diseases such as Alzheimer's disease are characterised by neuronal impairment that leads to cognitive deficits. As certain affected neurons depend on trophic factors such as neurotrophins (NTs), impairment in NT function has been suggested to be a component of neuronal damage associated with such disorders. Age-related neurodegenerative diseases are also characterised by high levels of proinflammatory cytokines such as tumour necrosis factor alpha (TNFα) in the CNS. Because TNFα receptors and certain NT receptors share a high degree of homology and are capable of activating similar signalling pathways, one possibility is that altered cytokine levels may affect NT function in the aged or diseased CNS. Here we wish briefly to review the evidence suggesting a role for cytokine and NT in the onset of age-associated neurodegenerative diseases. We propose that cytokine\NT interactions may alter neuronal homeostasis, thus possibly contributing to some of the neuronal degeneration occurring during such age-associated CNS diseases.

SummaryPerturbations of neuronal physiological homeostasis are likely to underscore neuronal demise/impairments that are reportedly associated with aging of the central nervous system and age-related neurodegenerative diseases such as Alzheimer's disease (AD). A number of ageand/or disease-associated neurotoxic events has been described. These include abnormally modified proteins such as beta amyloid and hyper-phosphorylated Tau, cytokines such as tumour necrosis factor-alpha (TNFα α α α ), high levels of free radicals conducive to oxidative stress, and impaired/decreased neuronal trophic support by neurotrophic factors. Overall, it could be argued that toxic events in the aged brain are either active, such as those due to a direct action of cytokines, or passive, such as those due to lack of growth factor support. It is therefore conceivable that cellular responses to such diverse toxic stimuli are different, suggesting that interventions should be targeted accordingly. In order to begin answering this question, we determined in PC12 cells the time course of activity, in response to TNFα α α α (active) or growth factor withdrawal (passive), of protein kinase c-zeta (PKCζ ζ ζ ζ ), nuclear factor kappa B (NFκ κ κ κ B), caspases 3 and 8, and poly (ADP-ribose) polymerase (PARP), key signal transduction elements associated with modulation of cell death/survival in PC12 cells. We found that the overall activity of PKCζ ζ ζ ζ , NFκ κ κ κ B and caspase 8 was significantly different depending on the apoptotic initiator. The pattern of caspase 3 and PARP activity, however, was not statistically different between serum-free-and TNFα α α α -induced cell death conditions. This suggests that two distinct cell responses are elicited that converge at caspase 3, which then induces downstream events involved in the execution of a common apoptotic programme. These results contribute to the aim of differentially targeting neuronal death in the aged brain (characterized by neurotrophic factor impairments) or in the diseased brain (e.g. AD, characterized by elevated levels of pro-inflammatory cytokines).