Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC-ι-mediated signaling cascade in glioblastoma.

The objective of this research was to study the potential function of protein kinase C (PKC)-ι in cell cycle progression and proliferation in glioblastoma. PKC-ι is highly overexpressed in human glioma and benign and malignant meningioma; however, little is understood about its role in regulating cell proliferation of glioblastoma. Several upstream molecular aberrations and/or loss of PTEN have been implicated to constitutively activate the phosphatidylinositol (PI) (3)-kinase pathway. PKC-ι is a targeted mediator in the PI (3)-kinase signal transduction repertoire. Results showed that PKC-ι was highly activated and overexpressed in glioma cells. PKC-ι directly associated and phosphorylated Cdk7 at T170 in a cell cycle-dependent manner, phosphorylating its downstream target, cdk2 at T160. Cdk2 has a major role in inducing G(1)-S phase progression of cells. Purified PKC-ι phosphorylated both endogenous and exogenous Cdk7. PKC-ι downregulation reduced Cdk7 and cdk2 phosphorylation following PI (3)-kinase inhibition, phosphotidylinositol-dependent kinase 1 knockdown as well as PKC-ι silencing (by siRNA treatment). It also diminished cdk2 activity. PKC-ι knockdown inhibited overall proliferation rates and induced apoptosis in glioma cells. These findings suggest that glioma cells may be proliferating through a novel PI (3)-kinase-/PKC-ι/Cdk7/cdk2-mediated pathway.

Review: Improving the therapeutic index of 8-aminoquinolines by the use of drug combinations: review of the literature and proposal for future investigations.

Because 8-aminoquinolines affect critical survival stages of Plasmodium parasites, treatment and control of malaria could be markedly improved by more widespread use of these drugs; however, hemolytic toxicity, which is widely prevalent in G6PD-deficient patients, severely constrains this use. Primaquine was approved more than 50 years ago after extensive clinical testing. Review of the mid-20th century literature in the light of present understanding of pharmacokinetics and metabolism suggests that manipulation of these factors might dissociate 8-aminoquinoline efficacy from toxicity and lead to an improved therapeutic index.

The educational environment and self-perceived clinical competence of senior medical students in a Malaysian medical school.

INTRODUCTION: The educational environment is widely considered to be a major factor affecting students' motivation and learning outcomes. Although students' perceptions of their educational environment are often reported, we are unaware of any published reports that relate this information to students' clinical competence, either self-perceived or objectively measured. OBJECTIVES: We aimed to correlate students' perceptions of their learning environment and their self-perceived competence in clinical, practical and personal skills, using validated scales. METHODS: Subjects included a cohort of 71 final-year medical students who were posted to a peripheral campus affiliated with a district hospital. Two questionnaires were administered concurrently: a modified DREEM (50 items) to assess the learning environment and an abbreviated IMU Student Competency Survey (29 items) to examine self-perceived competence across a wide range of skills and work-readiness. We correlated the major domains in both surveys using Spearman's Correlation. FINDINGS: Fifty-nine students (83%) completed the questionnaires. Comparing correlations of the five major domains of the modified DREEM questionnaire ("Perception of learning", "Perception of teachers", "Academic self-perception", "Perception of atmosphere" and "Social self-perception") with all subscales in the abbreviated IMU Student Competency Survey (clinical, practical, personal skills and overall work-readiness), we found that academic self-perception domain had the strongest correlations (r:0.405 to 0.579, p:0.002 to < 0.001) and perception of teachers bears the weakest correlations (r:0.171 to 0.284, p:0.254 to 0.031). Self-perceived competence in practical skills in the IMU Student Competency Survey correlated the weakest with all domains of the modified DREEM (r:0.206 to 0.405, p:0.124 to 0.002). DISCUSSION AND CONCLUSION: The overall weak-to-moderate correlations between perceptions of learning environment and self-perceived clinical competence suggest that other factors might interact with the learning environment to determine students' confidence and achievements.

Are Indians and females less tolerant to pain? An observational study using a laboratory pain model.

In Malaysia, it is a common belief among health care workers that females and Indians have lower pain threshold. This experience, although based on anecdotal experience in the healthcare setting, does not allow differentiation between pain tolerance, and pain expression. To determine whether there is a difference in the tolerance to pain between the three main ethnic groups, namely the Malays, Chinese and Indians as well as between males and females. This was a prospective study, using a laboratory pain model (ischaemic pain tolerance) to determine the pain tolerance of 152 IMU medical students. The mean age of the students was 21.8 years (range 18-29 years). All of them were unmarried. The median of ischaemic pain tolerance for Malays, Chinese and Indians were 639s, 695s and 613s respectively (p = 0.779). However, statistically significant difference in ischaemic pain tolerance for males and females Indian students were observed. Possible ethnic difference in pain tolerance in casual observation is not verified by this laboratory pain model. Difference in pain tolerance between genders is shown only for Indians.

Atypical protein kinase C phosphorylates IKKalphabeta in transformed non-malignant and malignant prostate cell survival.

Mechanistic pathways involving atypical protein kinase C-iota (aPKC-iota) have been targeted in various cancer cells such as lung cancer, brain and prostate due to PKCiota's antiapoptotic function, and role in cell proliferation and cell survival. In the current study, we examined the involvement of PKC-iota in the NF-kappaB pathway following treatment of prostate cells with the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Results demonstrated that androgen-independent DU-145 prostate carcinoma is insensitive to TNFalpha while transformed non-tumorigenic prostate RWPE-1 cells showed a slight sensitivity to TNFalpha. However, androgen-dependent LNCaP prostate cells are more sensitive to TNFalpha treatment and undergo apoptosis. Results demonstrated that in DU-145 cells, TNFalpha-induced PKC-iota in phosphorylation of IKKalphabeta. In RWPE-1 cells, PKC-zeta phosphorylates IKKalphabeta. Degradation of IkappaBalpha was observed in all three cell lines, allowing NF-kappaB/p65 translocation to the nucleus. Although, IKKalpha is weakly activated in LNCaP cells, the upstream kinase phosphorylation of IKKalphabeta via aPKCs was not observed. Hence, aPKCs may play a role in activation of NFkappaB pathway in prostate cancer cells.

The global distribution of clinical episodes of Plasmodium falciparum malaria.

Interest in mapping the global distribution of malaria is motivated by a need to define populations at risk for appropriate resource allocation and to provide a robust framework for evaluating its global economic impact. Comparison of older and more recent malaria maps shows how the disease has been geographically restricted, but it remains entrenched in poor areas of the world with climates suitable for transmission. Here we provide an empirical approach to estimating the number of clinical events caused by Plasmodium falciparum worldwide, by using a combination of epidemiological, geographical and demographic data. We estimate that there were 515 (range 300-660) million episodes of clinical P. falciparum malaria in 2002. These global estimates are up to 50% higher than those reported by the World Health Organization (WHO) and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries. Without an informed understanding of the cartography of malaria risk, the global extent of clinical disease caused by P. falciparum will continue to be underestimated.