Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.

PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki. Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay. pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively. Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders

Issues and innovations in nursing practice: Palliative care for patients with cancer: district nurses' experiences

Aim. This paper reports a study exploring district nurses' experiences of providing palliative care for patients with cancer and their families. Background. There is an increasing demand for palliative care in the community, as many patients wish to die at home. District nurses are central to providing palliative care in the community, but there is a dearth of literature on district nurses' experiences in palliative care. Method. A Husserlian phenomenological approach was adopted with a purposive sample of 25 female district nurses. Data were collected using unstructured, tape-recorded interviews and analysed using Colaizzi's seven stages of data analysis. Findings. Four themes were identified: the communication web; the family as an element of care; challenges for the district nurse in symptom management and the personal cost of caring. Conclusions. District nurses' experiences of providing palliative care to family units was challenging but rewarding. The emotive nature of the experience cannot be under-estimated, as many district nurses were touched by the varying situations. Whilst acknowledging the need to maintain an integrated approach to care, district nurses should be identified as the key workers in the complex situation of palliative care

Molecular events in uterine cervical cancer

OBJECTIVE: To review the literature regarding the molecular events which occur in the development of uterine cervical cancer, with particular reference to human papillomavirus (HPV) infection. METHODOLOGY: Bibliographic searches of Medline and the ISI citation databases using appropriate keywords, including the following: papillomavirus, cervix, pathology, cyclin, chromosome, heterozygosity, telomerase, smoking, hormones, HLA, immune response, HIV, HSV, EBV. CONCLUSIONS: It has become clear that most cervical neoplasia, whether intraepithelial or invasive, is attributable in part to HPV infection. However, HPV infection alone is not sufficient, and, in a small proportion of cases, may not be necessary for malignant transformation. There is increasing evidence that HPV gene products interfere with cell cycle control leading to secondary accumulation of small and large scale genetic abnormalities. This may explain the association of viral persistence with lesion progression but, in many patients, secondary factors, such as smoking and immune response, are clearly important. However, the mechanisms involved in the interaction between HPV and host factors are poorly understood.