Gene expression profiling on CML patients with Philadelphia translocation.

OBJECTIVE: The use of tyrosine kinase inhibitors (TKIs) and other targeted therapeutics plays a pivotal role in treatment management for individuals diagnosed with chronic myeloid leukemia (CML). However, some patients may experience fewer favorable outcomes and treatment resistance. Our work aims to use whole transcriptome sequencing to evaluate the variations in gene expression patterns among individuals with CML based on their response to TKI therapy. PATIENTS AND METHODS: Ten blood samples were obtained from two groups of patients diagnosed with CML: those at the initial diagnosis stage and those at the recurrence stage. RNA extraction was performed on all samples and used for next-generation sequencing. The data analysis was performed using the DESeq2 R program. RESULTS: In total, 499 genes were identified as having statistically significant differences in expression levels between the two groups. Of these, 122 genes exhibited upregulation, and 377 genes exhibited downregulation. We observed a notable dysregulation in the expression levels of NTRK2 (with a fold change more significant than +5). A significant proportion of the genes that were expressed demonstrated involvement in several biological processes, including the cell cycle, PI3K-AKT signaling system, cellular senescence, oxidative phosphorylation, microRNA in cancer, FOXO signaling pathway, P53 signaling pathway, and other related pathways. CONCLUSIONS: The results demonstrate a correlation between signaling pathways and the development of treatment resistance in patients with CML. These pathways exhibited enhanced efficacy in transmitting signals downstream of the TKI target, BCR-ABL. Several target genes require additional validation in a more extensive cohort study to verify their correlation with TKI resistance. The present research highlights that many BCR-ABL-independent pathways may be correlated with resistance, thus enhancing the prospective therapy options for patients with CML.

Methylation of the suppressor of Cytokine Signaling 1 Gene (SOCS1) in Philadelphia-negative myeloproliferative neoplasms.

OBJECTIVE: Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation is initiated by mutations in the JAK2 gene. This activation is in turn, a vital pathogenetic mechanism in myeloproliferative neoplasms (MPNs). However, several factors affect the pathogenesis of MPNs other than the JAK2 gene mutations, such as the downregulation of cytokine signaling (SOCS) proteins, which are potent inhibitors of the JAK/STAT pathway. Therefore, we hypothesized that the regulation of SOCS protein system might be a possible pathogenetic mechanism of MPNs through activating the JAK/STAT pathway. PATIENTS AND METHODS: Our study aimed to investigate the status of the Suppressors of cytokine signaling 1 (SOCS1) in 125 MPNs specimens at the level of mutated points. The acquired mutations, aberrant expression, and/or CpG island hypermethylation of SOCS1 were analyzed among Philadelphia-negative myeloproliferative neoplasm patients. RESULTS: SOCS1 was identified in 20.0% of all patients with Philadelphia-negative myeloproliferative neoplasm. At the diagnosis, the prevalence of methylation was 41.0% for Polycythaemia Vera (PV), 27.7% for Essential Thrombocythaemia (ET), and 6.6% for Primary Myelofibrosis (PMF). The methylation was not detected in 20 healthy adult people. A significant association was found between disease groups (p=.077). The presence of methylated SOCS1 was found to be significantly correlated with age (p=.005), total RBCs count (p=.019), hemoglobin (Hb) concentration (p=.002), and Hematopoietic cell transplant (HCT) (p=.007) in PV patients. However, the presence of methylated SOCS1 was found to be significantly associated with age (p=.012), total RBCs count (p=.022), Hb concentration (p=.024), HCT (p=.033), and platelets count (p=.037) in ET patients. Moreover, the presence of methylated SOCS1 was significantly associated with Hb concentration (p=.046) and HCT (p=.040) in PMF patients. CONCLUSIONS: We concluded that the activation of the JAK/STAT signaling pathway in alternative or with JAK2 mutations leads to SOCS1 hypermethylation, which could represent a potential therapeutic target.

Resident reflections on end-of-life education: a mixed-methods study of the 3 Wishes Project.

OBJECTIVE: The objectives of this study were to describe residents' experiences with end-of-life (EOL) education during a rotation in the intensive care unit (ICU), and to understand the possible influence of the 3 Wishes Project. DESIGN: We enrolled dying patients, their families and 1-3 of their clinicians in the 3 Wishes Project, eliciting and honouring a set of 3 wishes to bring peace to the final days of a critically ill patient's life, and ease the grieving process for families. We conducted semistructured interviews with 33 residents who had cared for 50 dying patients to understand their experiences with the project. Interviews were recorded, transcribed verbatim, then analysed using a qualitative descriptive approach. SETTING: 21-bed medical surgical ICU in a tertiary care, university-affiliated hospital. RESULTS: 33 residents participated from internal medicine (24, 72.7%), anaesthesia (8, 24.2%) and laboratory medicine (1, 3.0%) programmes in postgraduate years 1-3. 3 categories and associated themes emerged. (1) EOL care is a challenging component of training in that (a) death in the ICU can invoke helplessness, (b) EOL education is inadequate, (c) personal connections with dying patients is difficult in the ICU and (d) EOL skills are valued by residents. (2) The project reframes the dying process for residents by (a) humanising this aspect of practice, (b) identifying that family engagement is central to the dying process, (c) increasing emotional responsiveness and (d) showing that care shifts, not stops. (3) The project offers experiential education by (a) intentional role modelling, (b) facilitating EOL dialogue, (c) empowering residents to care in a tangible way and (d) encouraging reflection. CONCLUSIONS: For residents, the 3 Wishes Project integrated many forms of active learning for residents. Practice-based rather than classroom-based programmes may engage trainees to develop EOL skills transferable to other settings.