Metformin and cancer

Cell signaling pathways: Cell survival, proliferation and differentiation pathways:

The following section are notes from: Ampuero et al., World J Hepatol. 2015 May 18; 7(8): 1105-1111.

Metformin decreases hyperglycemia partly through 5′-adenosine monophosphate-activated protein kinase (AMPK) pathway activation (reduces gluconeogenesis).

Proposed anti-tumoral mechanisms of metformin include:

  • activated AMPK has growth inhibition effects on human cancer cell lines, via inhibition of mTOR[32];
  • metformin limits cell growth through cell cycle G0/G1 arrest in hepatoma cell lines, by inhibiting cyclin D1 expression[33];
  • metformin also inhibits carcinogenesis by downregulating c-Myc and upregulating miR-33a, which require activation of AMPK[34];
  • metformin is able to modulate the expression of cytokines, such as TNFα, and oxidative stress[35];
  • metformin, through AMPK, decreases β-catenin protein levels leading to suppression of Wnt/β-catenin signaling[36];
  • metformin is taken up in hepatocytes by the organic cation transporter-1 (OCT-1), which is an essential step for the glucose-lowering effect[37,38]. Interestingly, OCT-1 and OCT-3 expression has been found downregulated in HCC patients and associated with impaired prognosis[39].

metf1

Fig is from: Ampuero et al., World J Hepatol. 2015 May 18; 7(8): 1105-1111.

also see Regulation of growth by the mTOR pathwayYouTube

Cancer and biosynthetic pathways

Not my own words! Copy and pasted from cited sources:

1. Tumor suppressor protein 53 (p53) is mutated early in the disease .[31] p53 is the “guardian of the genome,” which, during DNA and cell duplication, makes sure the DNA is copied correctly and destroys the cell (apoptosis) if the DNA is mutated and cannot be fixed. When p53 itself is mutated, other mutations can survive.

Phosphatase and tensin homolog (PTEN), another protein that also helps destroy cells with dangerous mutations, is itself lost or mutated.

Epidermal growth factor receptor, a growth factor that normally stimulates cells to divide, is amplified and stimulates cells to divide too much.

Together, these mutations lead to cells dividing uncontrollably, a hallmark of cancer. Recently, mutations inIDH1 and IDH2 were found to be part of the mechanism and associated with a more favorable prognosis.[32] The IDH1 and IDH2 genes are significant because they are involved in the citric acid cycle in mitochondria. Mitochondria are involved in apoptosis. Furthermore, the altered glycolysis metabolism in some cancer cells leads to low oxygen (hypoxia). The normal response to hypoxia is to stimulate the growth of new blood vessels (angiogenesis). So, these two genes may contribute to both the lack of apoptosis and vascularization of gliomas.

– from: https://en.wikipedia.org/wiki/Glioma

Spirals of Inquiry

The spirals of inquiry model (Fig. 1) was developed by Halbert and Kaser is a method by which teaching, learning and professional development training can be continually reevaluated and perfected through a process of reflection and implementation [1]. I have used a similar model for many years in my teaching to continually improve student learning and my own teaching strategies – however, the learning step would be replaced by an ‘implementation’ step, with subsequent steps reflecting on the outcome of that implementation, i.e., evaluation of the assessment. This too would be a spiral (although the term cycle would arguably be just as valid). The spiral of inquiry framework, presented by Halbert and Kaser, is therefore quite different since the whole model is the evaluation. I must admit, I do find the spiral method a little confusing.

Fig. 1. The spiral of inquiry model [1].

Whilst I am continually reflecting on my practice, perhaps the time of largest reflection and change is after the University academic year has completed. To do so before would add confusion and put students at a disadvantage. At the end of the academic year, I can properly survey/reflect upon (the scanning phase) my teaching and the students learning on a particular unit and think about what can be changed. Items that are usually ‘scanned’ include:

• End of unit exam results

• Comments by external examiners and unit coordinators

• Feedback from students in the form of documented questions, emails, feedback questionnaires issued near the end of my teaching, formal end-of-unit and mid-unit student feedback

• Responses to 10-point quiz formative assessments on the virtual learning environment (VLE)

• Results from or action debased enquiries (4th student projects looking at 2nd and 3rd year teaching – with the project student providing a level of triangulation)

• New teaching and learning innovations/technologies and learnt theories

• Implementation of evidence-based practice research

• New content

• Personal reflections/gut feelings on ‘how things went’

• Ideas from colleagues

• New policy changes

• Timetable constraints

The ‘developing a hunch’ phase is essentially forming a hypothesis, although without the statistical rigour normally associated with hypothesis generation. Hunches I have formed during my teaching have included:

• Could a flipped lecture style allow more flexible and individualised learning for my students and free up the lecture time for more active learning?

• Some exam question answers are looking very similar to chunks of student notes. Are these students actually learning? What can be done?

• I think students would benefit with a 10-point informal quiz on moodle at the end of each lecture week for the students to rate their understanding.

• Are the students finding this material relevant/interesting/difficult?

• How does this particular learning theory/model apply in this context? Am I already unknowingly using it?

In the next part of this essay, I’ve attempted to use the formal spiral curriculum to reflect upon the current status of my 3rd year University teaching (Fig. 2). The ‘frozen single twist’ of the spiral homes in on a need to switch from a memory intensive mode of learning to a self-regulated and cooperative learning ‘deeper’ approach. This unit ran for the first time this year and so quite a few areas for improvement were found.

I would recommend this approach to my colleagues, although my natural instinct would be to have learners implementing the change suggested by the hypothesis as part of the spiral. The authors do show such a version in their other published work [2].

Fig. 2. The spiral of inquiry model as applied to my current 3rd year university teaching.

References

1. Halbert, J., Kaser, L., MacBeath, J. Foundations of Teaching for Learning 5: Planning for Teaching and Learning, Commonwealth Education Trust, Coursera, 2015.

2. Halbert, J., Kaser, L., Koehn, D. Spirals of Inquiry: Building Professional Inquiry to Foster Student Learning, ICSEI 2011, Limassol, Cyprus, What is Inquiry and How Does it Work? Examining Linkages in Assessment, Leadership, Teacher and Student Inquiry Ref # 0053 January 6 2011 15:45

Assessment Assessment

Coursera 6 week 2

Reflect on some of the key ideas from Weeks One and Two and how they might impact your assessment practices. Describe what you understand to be the relationship between assessment, curriculum, and teaching. Compare and contrast your preferred ideal setup or arrangement and what you believe is actual for your context. Consider the purposes and consequences attached to the various assessments, the degree to which the assessments reflect your curriculum goals, and the degree to which the assessments serve or control your classroom teaching.

Due 9th July 2015

Fellow teacher relationships

Coursera 8 essay 2:
Reflect on some of the key ideas from weeks three and four and how they might impact on planning for improving relationships in your classroom, your school or your community.

Weeks three and four considered the role of relationships with fellow teachers and administrators on the one hand and with parents on the other. Choose one of these and discuss what key factors need to be considered to enable the relationships that you establish with this group to be as positive as they could be. Describe an activity (or set of activities) that might enable you to promote positive relationships with your chosen group.

Your response should come in the form of an essay of between 500 and 700 words. We expect you to refer to the materials that have been presented in the course, or other sources, to support the arguments that you are making.