Health Science Reviews

by Carl Belger

Doxorubicin or DOX is an anti-cancer drug currently used to treat a variety of cancers. However, one of its common side effects is cardiotoxicity or damage to the heart. This is caused by heart cells dying during treatment and is commonly known as DOX-induced cardiotoxicity. Patients treated with DOX can experience heart disfunction anytime from a few hours after treatment to years later. DOX-induced cardiotoxicity has prompted the search for supplementary cardioprotective agents which could prevent heart damage and minimize side effects.

Please welcome to the stage: Sphingosine-1-phosphate AKA S1P. In a paper by Miguel Frias et al., it was successfully shown that S1P administered before DOX treatment caused fewer cells to die. But how exactly was this done, and, more importantly, can we trust the results? As usual with science, the answer is yes but also no.

Firstly, the researchers in this paper used cell culture experiments; essentially, they treated cells in a plastic dish with different reagents and measured how many cells lived and died. For this paper they used a type of heart cells called cardiomyocytes. The cardiomyocytes were treated with S1P, DOX, both, or neither and cell death was measured through something known as caspase3 activity. Caspase3 is an enzyme that is upregulated in cells undergoing cell death. 

As you can see from the figure above, adding increased concentrations of S1P, progressively decreased the amount of cell death caused by DOX. This figure along with many others in the paper gave strong evidence for the cardioprotective qualities of S1P.

However, there are some important limitations to this paper. Firstly, and most obviously, cells in a dish do not accurately represent the human body and its complex functions; S1P may have a completely different affect in vivo. In addition to this, these experiments ignored one important factor related to DOX-induced cardiotoxicity: cancer. Patients who receive S1P and DOX will do so because they have cancer. Thus, it is important to recognize that their bodies will be affected by this. Perhaps further experiments could be performed on cardiomyocytes in a cancer environment to see if this affects the protective characteristics of S1P.

Overall this paper shed light on a potential drug that could help millions of cancer patients around the world. However, it is vital that we confirm its protective potential before we implement it as a common treatment.

References:

Frias, Miguel A, Ursula Lang, Christine Gerber-Wicht, and Richard W James. 2010. “Native and Reconstituted HDL Protect Cardiomyocytes from Doxorubicin-Induced Apoptosis.” Cardiovascular Research 85 (1): 118–26. https://doi.org/10.1093/cvr/cvp289.

by Motshidisi Matela

Can you take quick guess which neurological disease is most prevalent in the world? If you guessed epilepsy, you are correct. Epilepsy is a condition in which one experiences recurrent and unprovoked seizures, it affects 50 million people worldwide both males and females of all races, ethnic backgrounds, and ages. Epileptic patients must take medication to help with their seizures, however 30 % of these patients develop drug resistant epilepsy (DRE) and only 60% of DRE patients respond to surgery. Many people can unfortunately suffer from cognition impairments because of epilepsy.

While surgery seemed to be the light at the end of the tunnel for patients with DRE, it seems the light might not last for long as many patients develop speech impairments because of resections performed during surgery to remove the epileptic regions of the brain.  To operate effectively, areas of the brain that are necessary for language formation and comprehension must be identified so that they are spared during surgery. This can be accomplished by with Functional Magnetic Resonance Imaging (FMRI). This technique uses blood oxygen dependent levels (BOLD) contrast to measure oxygen changes within the brain in response to different tasks.

UCT researchers had then set out to investigate how fMRI could be used as an effective method for preoperative language mapping. This can help maximize resections of epileptic regions while minimizing impairments.

To see which brain regions are responsible for language, Ives-Deliperi et al performed blocked tasks in which patients were subjected to a stimulus at active to activate the brain regions, while at rest no stimulus was given.

Fig. 1. Functional mapping blocked paradigm.

The authors used different methods to map areas that responsible for comprehension of language and those responsible for expressive of language.

The results were good areas that are involved in both receptive and expressive language were not only localized meaning which part of the brain region is responsible for the activity, but also lateralized meaning can be seen in which brain hemisphere are these regions located. The bold signal increased with activation of these regions.

Fig. 3. BOLD signal increase produced in the group analysis of the verb generation task showing activation in left posterior inferior frontal gyrus (Broca’s area) and left superior temporal gyrus (Wernicke’s area).

Fig. 4. BOLD signal increases produced in the group analysis of the passive listening task in the superior temporal lobes bilaterally (Wernicke’s area).

The preservation of neurological function in epileptic patients during surgery is key to successful treatment. The success of this technique may have positive treatment implications for other neurological diseases as well, including traumatic brain injury and brain infection diseases. In simple words performing fMRI before surgery might keep the light at the end of the tunnel for patients with DRE.

References

1.            Ives-Deliperi, V. L.;  Butler, J. T.; Meintjes, E. M., Functional MRI language mapping in pre-surgical epilepsy patients: findings from a series of patients in the Epilepsy Unit at Mediclinic Constantiaberg. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 2013, 103 (8), 563-7.

by Talia Gabay

Cervical cancer is the fourth most common cancer globally. This is largely attributed to the oncoproteins E6 and E7, which are produced by the body following infection and integration into the human DNA by a high-risk strain of the Human Papillomavirus (HPV). These oncoproteins, can lead to tumour formation and progression,and are therefore considered viral bullies that wreak havoc in our bodies and ultimately cause issues where there would otherwise not be any. A tremendous amount of research has been conducted on the role of these oncoproteins and data points to their course of action in cervical cancer development. Like looking at a connect the dots picture, each dot symbolizes a protein interaction, pathway modulation or function  that E6 and E7 are involved in to drive cervical cancer progression. To make sense of how these proteins initiate and maintain the cancerous phenotype, the dots must be connected. This review by Vats et al. aims to do just that.

The authors firstly highlight the known biochemical interactions between cellular proteins in an attempt to make connections between the various processes. However, this also identified the critical information about E6 and E7 that remains elusive. Cell cycle dysregulation, epigenetics, cancer maintenance, telomerase activation and involvement in all hallmarks of cancer were amongst the key processes discussed by this review to illustrate what is known about the regulatory role of E6 and E7. Indeed, these proteins disrupt cellular normality, leading to the development and maintenance of malignant cervical lesions. However, as a biochemical process is uncovered, its significance or contribution to tumour formation must then be determined. It is not only about which process is occurring but also where, how and why it is happening that is significant. It is interesting how the gaps link back to the viral life cycle and how E6 and E7 activate processes that are not needed by this cycle directly but drive tumorigenesis. Could this result from off-target mistakes? It seems that the closer we look the less we see. However, the more we know about the functionality of E6 and E7, the better equipped we will be to provide the information needed to treat and even prevent cervical cancer by disrupting the protein sidekicks that allow E6 and E7 to carry out their mission of malignant transformation.

Figure 1: An illustration of what is known and still remains elusive about the rosed E6 and E7 play in cervical cancer. This image combined figures from both Mittal and Banks as well as Vats et al to produce the overall map of the processes each oncoprotein is involved in, what they both are involved in, as well as what remains unknown. All that is unknown is illustrated in a red box. If the viral life cycle is involved, this is further highlighted red.  Yellow usually means that it is related to E6 alone. Purple usually means it relates to E7 alone. However, both E6 and E7 are involved in interferon signaling. Red question marks mean the links have yet to be made or that there are gaps in our knowledge.

References

Mittal, S. & Banks, L. 2017. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutation Research/Reviews in Mutation Research. 772:23-35. DOI: 10.1016/j.mrrev.2016.08.001.

Vats, A., Trejo-Cerro, O., Thomas, M. & Banks, L. (2021). Human papillomavirus E6 and E7: What remains? Tumour Virus Research. 11:200213. DOI: 10.1016/j.tvr.2021.200213.