mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.

Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.

PKCß Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling.

B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCßII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCßII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCßII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCßII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCß expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model.

Problems in Malaysian children with large angle infantile esotropia: Children and parents' perspectives.

INTRODUCTION: There is limited information regarding the problems faced by children with large angle infantile esotropia (LAIE). The aim of this study was to explore the problems that children with LAIE encounter from both their perspectives and those of their parents. METHODS: This study included children who had LAIE (with angle of 40 prism dioptres or greater), aged 5 and 17 years who had attended the Ophthalmology Clinic, Hospital Universiti Sains Malaysia from March to September 2016. The children and their parents or guardians were interviewed face-to-face using a validated semi-structured interview guide. Interviews were tape-recorded and transcribed verbatim. Content analysis was performed using the NVivo 12 software. RESULTS: A total of 30 children and 30 parents were interviewed. The most common problems identified by the children were social interactions (73.3%, 22 children), visual functions (60.0%, 18 children), emotions (60.0%, 18 children), physical issues (40.0%, 12 children) and difficulties regarding treatment options (26.7%, eight children). The parents reported that their children were more affected in terms of visual functions (100.0%, 30 parents), social interactions (56.7%, 17 parents), emotions (43.3%, 13 parents), physical issues (20.0%, six parents), and difficulties regarding treatment options (16.7%, five parents). CONCLUSION: The major problems that the children with LAIE identified were social interactions, while the parents observed that problems with visual functions was the most common issue encountered by their children. This suggests that the children affected have different perspectives from their parents and require support.

Inter-rater and intra-rater reliability of the Bahasa Melayu version of Rose Angina Questionnaire.

The objective of the study is to translate the Rose Questionnaire (RQ) into a Bahasa Melayu version and adapt it cross-culturally, and to measure its inter-rater and intrarater reliability. This cross sectional study was conducted in the respondents' homes or workplaces in Kelantan, Malaysia. One hundred respondents aged 30 and above with different socio-demographic status were interviewed for face validity. For each inter-rater and intra-rater reliability, a sample of 150 respondents was interviewed. Inter-rater and intra-rater reliabilities were assessed by Cohen's kappa. The overall inter-rater agreements by the five pair of interviewers at point one and two were 0.86, and intrarater reliability by the five interviewers on the seven-item questionnaire at poinone and two was 0.88, as measured by kappa coefficient. The translated Malay version of RQ demonstrated an almost perfect inter-rater and intra-rater reliability and further validation such as sensitivity and specificity analysis of this translated questionnaire is highly recommended.

Identification of psychosocial factors of noncompliance in hypertensive patients.

This cross-sectional study was aimed to identify the predictors of medication noncompliance in hypertensive patients. The study was conducted at the Family Medicine Clinic, Hospital Universiti Sains Malaysia, Kelantan, Malaysia, which is a university-based teaching hospital. All hypertensive patients aged 40 or over-registered from January to June 2004, who had been on treatment for at least 3 months, were screened. Previously validated self-administered questionnaires were used to assess the compliance and psychosocial factors. A total of 240 hypertensive patients were recruited in the study. Of these, 55.8% were noncompliant to medication. Logistic regression showed that age (adjusted odds ratio (OR): 0.96; 95% confidence interval (CI): 0.92-0.997; P: 0.035), patient satisfaction (adjusted OR: 0.97; 95% CI: 0.93-0.998; P: 0.036) and medication barrier (adjusted OR: 0.95; 95% CI: 0.91-0.987; P: 0.009) were significant predictors of medication noncompliance. Therefore, younger age, poor patient satisfaction and medication barrier were identified as independent psychosocial predictors of medication noncompliant in hypertensive patients.