More good bacteria

Not all bacteria are bad, as we know. There are "good bacteria" that live in our gut and help us to digest our food. Now, bacteria have been harnessed to help doctors and clinicians as a vector to treat or prevent disease. This bacterial gene therapy is known as "bactofection".

Peter Celec and his team in the Slovak Republic researched the usage of bacteria to treat inflammatory bowel disease.¹ The Salmonella bacteria carried genes for an antioxidant (superoxide dismutase) and a protein that stimulates the immune response (monocyte chemoattractant protein-1). Bactofection was applied to mice suffering from inflammatory bowel disease (colitis), and alleviated colitis symptoms in these mice when compared to untreated mice.

Listeria has been tested as a vector to deliver therapeutic genes and proteins to cancer cells and immune cells.² Listeria is a particularly good candidate as it is very efficient at entering host cells, and can move from cell to cell without having to exit it anywhere. Moreover it is safe and effective in clinical trials. Anti-cancer genes can be targeted to tumours by packaging them inside this pathogen.


Salmonella has also been used as a vehicle to treat cancer. ³ Both Listeria and Salmonella infect and can survive in antigen presenting cells (cells that form part of the immune system). They can be engineered to express tumour-like proteins which stimulates the body's immune system to break tolerance against tumour cells that look a lot like "self" to the body.



Image: Salmonella enterica serovar typhimurium



¹Palffy R, Gardlik R, Behuliak M, Jani P, Balakova D, Kadasi L, Turna J, Celec P. Salmonella-mediated gene therapy in experimental colitis in mice. Exp Biol Med (Maywood). (2011) 236:177-83.

²Tangney M, Gahan CGM. Listeria monocytogenes as a Vector for Anti-Cancer Therapies. Current Gene Therapy (2010) 10: 46-55.

³Paterson Y, Guirnalda PD, Wood LM. Listeria and Salmonella bacterial vectors of tumor-associated antigens for cancer immunotherapy. Seminars in Immunology (2010) 22: 183-189.

Christmas special: the weird and the wonderful

In the process of looking for hot new research topics (or just in the course of my daily working day) I find a fair amount of curious papers. So, as a final entry for the year I thought I'd post a special edition, listing a few of my favourites.

From the department of Advanced Medical Science (literally)¹:

"Obesity significantly increases the difficulty of patient management in the emergency department."

With the objective to "... determine which aspects of ED management are adversely affected by patient obesity, to determine the level of obesity above which management is made more difficult and to make recommendations on how these effects might be mitigated...", this study showed that patient obesity makes it difficult to manage an emergency department. And offered no solutions.


Ever wondered if watching TV or working on your computer late at night affects your sleep? So did a couple of researchers in Brazil who investigated the "Quality of sleep among university students: effects of nighttime computer and television use."²

The internet lost out in this study as it seems to affect sleep a lot more than television. Interestingly, if you manage to use the internet untill 3am, you sleep a bit better. This blogger wonders how much of the "affected sleep" is due to online arguing...



The title of this paper says it all, really: PMS: premenstrual storm? An unusual cause of electrical storm in a young woman with vasospastic angina. ³
Never underestimate how hard it is to be a girl...



Apparently "Hearing loss in stranded odontocete dolphins and whales" ⁴ is a big problem. Researchers speculate that this may have somethig to do with the actual stranding. How do you measure hearing in a dolphin? Well, with great difficulty, but apparently "in all cases, a jawphone consisting of an ITC-1042 piezoceramic transducer embedded in a RTV silicone suction cup was placed on the lower jaw fat pad to deliver sound stimuli." If a response could be detected from the dolphin or whale, then that was marked as the level at which the animal could "hear". There was a strong correlation between stranding and hearing loss in some of the species. (Picture below: a hydrophone)




The brushtail possum is a major pest species of New Zealand. Some researchers are investigating a nanoparticle system containing a chemical sterilitant which could be used orally to control their numbers.⁵ Poor little possums.




Our last two entries are shamelessly of a scatological nature:

A woman with a history of depression presents with abdominal bloating. Her doctor sends her for a colonoscopy. It turns out she's fine, but they do find something odd. A cockroach. ⁶


And finally... Apparently "robotic assisted laparoscopic radical prostatectomy" is a fairly uncomfortable procedure used in prostate cancer. So a few researchers in Seattle wondered whether a suppository containing belladonna (that's deadly nightshade to me and you) and opium would help.⁷ And indeed it did! With no adverse events noted either!





¹ Kam J, Taylor DM. Emerg Med Australas. 2010 Aug;22(4):316-23. Source

² Mesquita G, Reimão R. Arq Neuropsiquiatr. 2010 Oct;68(5):720-5. Source

³ Li J, Zitron E, Katus HA, Becker R. Clin Res Cardiol. 2010 Nov 30. [Epub ahead of print] Source

⁴ Mann D, Hill-Cook M, Manire C, Greenhow D, Montie E, Powell J, Wells R, Bauer G, Cunningham-Smith P, Lingenfelser R, DiGiovanni R Jr, Stone A, Brodsky M, Stevens R, Kieffer G, Hoetjes P. PLoS One. 2010 Nov 3;5(11):e13824. Source

⁵ Kafka AP, McLeod BJ, Rades T, McDowell A. J Control Release. 2010 Oct 31. [Epub ahead of print] Source

⁶ Kumar AR, Perez JA, Miick R, Govil YK Endoscopy. 2010;42 Suppl 2:E209-10. Epub 2010 Sep 15. Source - INCLUDES FULL ARTICLE PLUS PHOTO!

⁷ Lukasewycz S, Holman M, Kozlowski P, Porter CR, Odom E, Bernards C, Neil N, Corman JM. Can J Urol. 2010 Oct;17(5):5377-82. Source

New skins for old wine

Curcumin is the metabolite that's responsible for the yellow colour of the spice, tumeric. It can be used for food colouring (it's E number is E100), to quantify boron ¹, and to treat a number of ailments.

The first research on curcumin looked at its antibacterial properties ², and since then researchers have looked at its antioxidant properties ³, its use as an antirheumatic ⁴, a potential cholesterol-lowering role for it ⁵ and many other medicinal applications.

Recently a group in Canada investigated the effect of tumeric on cancer treatment.⁶ Previous research showed that curcumin also has an anti-cancer effect, but these researchers wanted to know if curcumin given in addition to standard chemotherapy could improve the efficacy of the treatment while keeping side-effects to a minimum. The researchers found that the combined treatment worked at lower doses than monotherapy; that non-cancerous cells remained unaffected; and that cancer cells still responded to the treatment even after the drugs were removed.

Many people scoff at the idea of "natural therapies", but it is important to remember that aspirin was originally made from willow bark. Tumeric might be the next aspirin!


¹Roth HJ, Miller B. On the color reaction between boric acid and curcumin. I. Boric acid-curcumin complexes. Arch Pharm (Weinheim)297:617-23 (1964)

²SCHRAUFSTATTER E, BERNT H. Antibacterial action of curcumin and related compounds. Nature. 164(4167):456 (1949)

³ Sharma OP. Antioxidant activity of curcumin and related compounds. Biochem Pharmacol. 25:1811-2 (1976)

⁴Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 71:632-4 (1980)

⁵Soudamini KK, Unnikrishnan MC, Soni KB, Kuttan R. Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin. Indian J Physiol Pharmacol. 36:239-43 (1992)

⁶
Chatterjee SJ, Pandey S. Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy. Cancer Biol Ther. 2011 Jan 29;11(2). [Epub ahead of print]

Nanotherapy for targeted cancer treatment

Many researchers are currently investigating more effective, targeted ways of delivering cancer drugs and therapies to patients.

Two such innovative studies have looked at the use of wheat germ agglutinin and folic acid, respectively, as a conjugate to target tumors.

A team in Singapore have modified the nano-encapsulated drug, paclitaxel, with wheat germ agglutinin (WGA) to target colon cancer cells.¹ These cells express a greater amount of WGA-binding glycoproteins. Nanoparticles modified with WGA showed greater uptake into cancer cells when compared to unmodified particles. The WGA-modified particles also showed an enhanced anti-proliferative activit.

In India, a research team have modified nanoparticles loaded with grape seed extract(active as a neutraceutical), in order to target them to folate receptor over-expressing cancers.² The nanoparticles were conjugated with folic acid in order to target them to these cells. Folate receptor positive cancer cells readily took up the nanoparticles, showing enhanced bioavailability to tumor cells, sparing the normal ones.

Both these reports underline the application of modifications to target cancer therapies - strategies that may greatly improve the side-effects of chemotherapy.

¹ Wang C, Ho PC, Lim LY. Wheat germ agglutinin-conjugated PLGA nanoparticles for enhanced intracellular delivery of paclitaxel to colon cancer cells. Int J Pharm 400:201-10 (2010).

² Narayanan S, Binulal NS, Mony U, Manzoor K, Nair S, Menon D. Folate targeted polymeric 'green' nanotherapy for cancer. Nanotechnology 21:285107 (2010).

Antibody therapy

Ron Levy, professor of Medicine at Stanford University, is the man who took the first steps in the development of antibodies as a therapy.¹ In 1976 Dr. Levy discovered that antibodies can be made in the lab that will identify and bind to cancerous cells, triggering an immune response that destroys the cancerous cells. His initial work focused on creating tailor-made antibodies for use in individual patients, but as this would be unfeasible at an industrial level, the treatment was developed into a large-scale drug. This drug didn't target only cancer cells, but targeted all B-cells of the immune system. The results were surprising, as people did very well despite having their bodies depleted of B-cells - cells that form a significant part of the immune system. This drug is marketed under the name "Rituximab" or "Rituxan".

Rituximab works by identifying a specific protein on the outside of B-cells, called CD20.² When Rituximab binds to CD20, the body's immune system is triggered, leading to the destruction of that B-cell. Since Rituximab doesn't distinguish between cancerous and non-cancerous B-cells, all B-cells in the body are targeted. This therapy has a number of serious potential side-effects, but is attractive to use since it doesn't cause the nausea and malaise caused by other treatments like chemotherapy. It can also be used repeatedly if relapse occurs, with improved response at each consecutive treatment.

Rituximab has been used successfully in the treatment of lupus³, rheumatoid arthritis⁴, and in transplants to prevent rejection of transplanted tissue.⁵

Since the development of Rituximab, a large amount of research has been done on the usage of antibodies to treat various cancers and diseases. As can be seen from the illustration below, antibody therapies have been developed to treat blood-related cancers (hematologic malignancies) and solid tumors, targeting a number of surface proteins on B-cells. There is an excellent review on the topic of antibody therapies, their development and application, as well as their potential use in the targeting of influenza virus here.<sup>6



1</sup> http://stanmed.stanford.edu/2004fall/levy.html
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²Pescovitz M.D. Rituximab, an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action. American Journal of Transplantation 6:859-866 (2006).
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³ Eisenberg R. SLE - Rituximab in lupus. Arthritis Res Ther. 5: 157–159 (2003).
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⁴ http://www.rituxan.com/ra/patient/index.xhtml
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⁵ Salama A. and Pusey C.D. Drug Insight: rituximab in renal disease and transplantation. Nature Clinical Practice Nephrology 2: 221-230 (2006).
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⁶ Guzmán F. Overview on monoclonal antibody therapy: PPT, images and videos. Pharmacology Corner http://pharmacologycorner.com/overview-on-monoclonal-antibody-therapy-ppt-images-and-videos/
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