Archive for the “Therapeutics” Category
Though risky, transplants are crucial treatment interventions for many patients.They can save lives of cancer patients, others with severely ill organs and recently there are trials to make them a mainstream treatment for autoimmune disease patients ( i’ve just read an article about that topic and i’d really love to write about it soon too).
But the major problem with transplants, other than the agonizing wait for the right donor on endless lists for sometimes many years, is that when things go wrong with transplants, the patient’s life becomes at mortal risk. Almost 40% of transplant patients will show rejection episodes within the first year after the operation. The detection of these immunological reactions are usually so late, and the only solution will be to flush the patient’s system with huge doses of immunosuppressive drugs that are toxic themselves and can have debilitating effects on cancer patients for instance. Also, to be able to detect rejection reactions, the doctors should take biopsies of the new organ, a process that can cause damage to the organ itself, let alone the stress and the already fragile patient condition. Transplant patients have to undergo exploratory biopsies monthly for one year after the operation!!!!!
Will these risky, life-saving procedures be safer in the future?
Early detection of these reactions was an interesting topic and a field of research for the cardiologist Hannah Valantine of Stanford University School of Medicine in Palo Alto, California. In 2009, she devised a new test that detects the immunological changes in a transplant patient in an episode of rejection. The test, called AlloMap, became the first of its kind to be approved by the FDA for use in the detection of heart transplant rejections. Yet, it failed to detect the rejections early in about half the patients.This, of course, didn’t satisfy Valantine.
Along with biophysicist Stephen Quake of Stanford, they came out with a much more sensitive test. The idea was that DNA from the new organ constitutes around 1% of the free DNA in blood of transplant patients. This DNA is foreign from the DNA of the patient and using her test, it can be very sensitively detected, despite the fact that it is circulating in minute amounts. To validate their test, they used it on stored plasma samples from transplant patients that later showed rejection signs. It was found that the amounts of the rejected organ’s DNA in such episodes are elevated soon after the surgery and constitutes around 3% of the free DNA in plasma, and of course, will be much elevated later, in the peak of the episode. They reported the results in The Proceedings of National Academy of Sciences.
The good thing about this test, besides its high sensitivity, is that it is much less invasive than a biopsy, and the biopsy will not be needed except for confirmation, in case the test is positive and the DNA % is higher than normal. Also, early detection will allow doctors to use much smaller doses of immunosuppressives to control the case and therefore, less side effects will be experienced. Valantine is a cardiologist, but believes the test can be used with other types of transplanted organs, other than hearts.
, organ rejection
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For a long time, mental retardation was believed to be incurable, as it is usually caused by gene mutations that disrupt brain development right from the beginning and even before birth. But thanks to a lot of hard-working scientists, there are trials now to improve the quality of life of such patients, along with their caregivers. The work has been focused on a condition known as “Fragile X syndrome”. In this disease, a mutation takes place in a gene called FMR1 , which is responsible for the production of proteins, that regulate neural development, usually leading to mental retardation according to the extent of such mutations.
Fragile X syndrome's common physical symptoms : elongated face, large ears, etc
Another important contributor to the condition is the metabotropic glutamate receptor-5, abbreviated to mGluR5. It is responsible for controlling the process of protein synthesis at the neuronal synapses, becoming hyperactive in case of fragile X. Being an interesting therapeutic target, a major pharmaceutical company developed AFQ056, an mGluR5-receptor blocker, in the hope that it’ll restore normal transcription levels. The results of the initial double blind clinical trials, conducted on 30 patients, were evaluated through the notes taken by the caregivers about the behavioral improvements of the patient. This included less repetitive behavior, less hyperactivity, less tantrums and having better chances of establishing communication with the patients.
What seemed like a puzzle is that some caregivers reported no change at all after the patients took the drug. So after data analysis, the researchers found that the only patients affected by the treatment were the ones (7 patients out of 30) having a certain genetic marker: complete methylation of the FMR1 gene regulator sequence, and therefore, complete lack of FMR1 transcription. Another disappointment was that the drug didn’t improve cognition or memory, but this, they say, might be attributed to the short duration of the trial, lasting for only 4 weeks.
The next step is to repeat the trial, but this time on 160 selected patients, after testing them for the marker and the experiment will last for 3 months, hoping to obtain better results that are more significant to the patients of this illness.
Sources: Wikipedia and Science News
, fragile X syndrome
, mental retardation
, metabotropic Glutamate receptor 5 blockers
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So you drive over to the lab to have your blood work? In the near future, that would totally be ‘old-school’. Even if you so much as consider making that journey, you have GOT to be tempted to please think again! Time has been proven, repeatedly, to be of the essence, both for the sake of the diagnosis & treatment and the patient’s quality of life. For instance, imagine the convenience it will provide for an HIV-infected patient, who is what a lab technician would probably call a regular customer, due to the regular follow-up tests needed to monitor the development and treatment. Through a $10 piece of hardware connected to your cell phone, you will have your medical test results ready on the go. All you’d have to do is insert a slide containing a drop or two of your blood and leave the rest of the work up to the chip, as demonstrated on a prototype. I will even bet that, those who choose not to use it, would be charged extra for lab work!!!
The Ozcan Research Group at UCLA will already begin their field tests in Africa concerning the new cell phone/microscope gadget. I had to see to believe. Aside from all the engineering & technological aspects, which I am sure are quite many, if this were to be actually implicated worldwide, the possibilities of its application are endless, including, but not necessarily limited to, pretty much all of the blood-borne diseases. For instance, malaria, which is fairly common in many African countries, can be instantly diagnosed. The hospital would get the patient’s blood picture, through the cellular networks for analysis by physicians and there you have it.
Tags: advances in medicine
, blood borne
, blood picture
, blood test
, blook work
, cell phone
, lab work
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Yediot Ahronot (Literally: Latest News)
Cure for radiation sickness found?
A team of scientists has succeeded in developing an anti-radiation. “The process that led up to the medical innovation dates back to 2003, when Professor Gudkov –the head of the team- came up with the idea of using protein produced in bacteria found in the intestine to protect cells from radiation.” Mice received that purified protein survived the amount of radiation that killed the control group.
What kind of news is that?! Do that legendary bacteria and that miraculous protein actually have names?! If so, why don’t newspapers include it? Should bloggers do everything?!
Professor Andrei Gudkov – Chief Scientific Officer at Cleveland BioLabs, is interested in protecting cells against apoptosis induced by cancer therapy as well as radiotherapy. He worked on p53 –the famous tumor suppressor- and found that p53 has a role in inducing apoptosis. The research group suggested that p53 inhibitors can protect normal cells against chemo- and radiotherapy, and it’s been found that it sensitizes tumor cells to the therapy (PMID: 15865929). They also showed that PFTmu (pifithrin-mu), a small isolated inhibitor of p53, protected primary mouse thymocytes from p53-induced apoptosis caused by radiation (PMID: 18403709).
The breakthrough discovery mentioned above has been published in Science – 11 April 2008. It is about the injection of “flagellin” purified from Salmonella enterica serovar Dublin into mice and monkeys. It causes suppression of apoptosis by binding to Toll-like receptor 5 (TLR5) and activation of the nuclear factor–kappaB (NF-kappaB) pathway, the same mechanism used by tumor cells to inhibit the function of the p53 pathway (PMID: 18403709). To reduce its immunogenecity and toxicity, they engineered a polypeptide derived from flagellin with the “important” domains only, N and C termini separated by a linker. The engineered protein (named: CBLB502) was found to provide radioprotection in rhesus monkeys and mice against lethal doses of gamma-radiation and accompanied hematopoietic system and gastrointestinal tract acute radiation syndrome, with no alteration of the efficacy of the radiotherapy.
Tags: Andrei Gudkov
, p53 inhibitor
, Salmonella enterica
, Yediot Ahronot
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When you hear/ read the term “Phage Therapy“, you’ll be automatically directed to the concept of using bacteriophages, the virus-like particles that infect bacteria, to kill/ lyse the resistant bacterial strains, instead of the “useless” antibiotics that allowed bacteria to fool them & develop resistance against them. The initial target of phage therapy was to kill the bacteria using phages; because they act like any other virus; get in, multiply and lyse the cell. But, by this way, bacteria develop resistance against phages more rapidly. So, they may become useless by time. In this paper from PNAS: “Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy,” two bioengineers, Timothy K. Lua and James J. Collins, from Boston University successfully engineered the Enterobacteria filamentous phage M13 to weaken bacteria not to kill it. Sounds strange, right? By engineering M13, they gave us a variety of options:
1st, we may make M13 overexpress a bacterial protein named lexA3 which inhibits the ability of the bacteria to repair their damaged DNA by the action of Ofloxacin –as pharmacophils, who had 2 consecutive chemotherapeutics courses, we may recall that quinolones’ MOA is generation of ROS. So, the repressor suppresses the bacterial SOS mechanism. Very promising results were observed; the adjuvant therapy increased the survival rate of mice infected with resistant E. coli. It was also observed that the adjuvant therapy reduced the rate of developing mutations/ resistance within the E. coli population.
2nd, bacteriophage can be responsible for expression of certain proteins that can attack gene networks in bacteria which are not target for existing antibiotic classes. I will mention just one example here, expression of CsrA which is a “global regulator of glycogen synthesis and catabolism, gluconeogenesis, and glycolysis, and it also represses biofilm formation,” biofilms is thought to be related to antibiotic-resistance and OmpF porin which is used by quinolones to enter the bacterial cell, it may enhance its entrance.
Now, thanks to the engineered phages, we can use the old beloved antibiotic classes to treat bacterial infection using the engineered phages as an adjuvent therapy to potentiate the cidal action of the antibiotic on the former-resistant strains. A precaution was made to ensure that no lysogeny would take place in the human cells is that the phages were engineered to be “nonreplicative”. But we still have two problems regarding Phage Therapy in general: identifying the strain responsible for the infection & making sure that the human immune system won’t elicit an immune response against phages, they’re “foreigners” after all!
1- “Schematic of combination therapy with engineered phage and antibiotics. Bactericidal antibiotics induce DNA damage via hydroxyl radicals, leading to induction of the SOS response. SOS induction results in DNA repair and can lead to survival. Engineered phage carrying the lexA3 gene (lexA3) under the control of the synthetic promoter PLtetO and an RBS acts as an antibiotic adjuvant by suppressing the SOS response and increasing cell death”: http://www.pnas.org/content/106/12/4629.figures-only
2- “CsrA suppresses the biofilm state in which bacterial cells tend to be more resistant to antibiotics. OmpF is a porin used by quinolones to enter bacterial cells. Engineered phage producing both CsrA and OmpF simultaneously (csrA-ompF) enhances antibiotic penetration via OmpF and represses biofilm formation and antibiotic tolerance via CsrA to produce an improved dual-targeting adjuvant for ofloxacin”: http://www.pnas.org/content/106/12/4629.figures-only
, engineered bacteriophage
, phage therapy
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Despite great advances in cancer therapy, conventional therapies are still implementing drawbacks and dilemmas that drives cancer research to consider other strategies to overcome the drawbacks implicated by conventional cancer therapy. The cancer treatment using anticancer agents possesses many adverse events related to bone marrow suppression and death of other rapidly proliferating cells is resulting from the either of the two following reasons:
- The narrow therapeutic index of anticancer agents that is in many cases hard to adjust with the inter-individual Pharmacokinetic &/or pharmacogenetic variation among cancer patients.
- The lack of specificity in most of anticancer agents systemically administered where anticancer agents kill both tumor cells and healthy cells.
Both of the above facts driven cancer therapy research in to many different aspects in the hope of optimizing the therapy & providing new techniques to get over the drawbacks of conventional therapy; The pharmacokinetics & /or pharmacogenetics, gene therapy in addition to the targeting therapy including the nanotherapy.
Professor Mostafa El Sayed was awarded the 2007 US National Medal of Science for his huge contribution in the field of nanotherapy in cancer as a molecular targeting approach that overcomes side effects of conventional cancer therapy. The idea lies in two main aspects: The first is molecular targeting & the second is photothermal destruction of malignant cells. The technique encompasses injecting gold nanoparticles conjugated with anti- Epidermal Growth Factor Receptor “anti -EGFR” monoclonal antibody , where the anti-EGFR is responsible for the the specific targeting which is molecularly based on the fact that epithelial carcinoma cells, particularly over-expresses “EGFR”. Regarding the tumor cidal effect it is mainly dependent on the photothermal destruction which is the role of the laser beam & gold nanoparticles, where particular nano size of gold makes it able to absorb light in Near Infra Red Region , which is the region where optical penetration is optimal & scatter laser beam and convert the light energy to thermal energy that is able to damage cell membrane and release the digestive enzymes and hence the death of cancer cells.
Image credit: www.gatech.edu
The choice of the laser light is a matter of the cancer location , where in case of cancer under the skin, Near Infra Red “NIR” laser light is recommended for its larger penetration depth. Gold particles are especially used because they are easily bioconjugated & they served as photoabsorbers due to overlap of absorption band of their specific nanosize with with argon laser beam. The gold nanoparticles are having a silica core and a gold shell & their absorption in the NIR is tuned by adjusting gold layer thickness as well as the size of silica core.
The pioneering success of the technique has been proved effective upon accumulation of Anti-EGFR antibody conjugated gold nanoparticles selectively in carcinoma cells and survival of benign cells as demonstrated by microscopic pictures of both benign & cancer cells as follows:
Gold nanoparticles are concentrated in cancer cells. “Pic 1”
Image credit: www.gatech.edu
Gold nanoparticles are not retained in benign cells. “Pic 2”
Image credit: www.gatech.edu
- Ivan H. El Sayed, Xiaohua Huang, Mostafa A. El Sayed, ” Selective laser Photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles”, Cancer Letters 239 (2006) 129-135.
- Erin B. Dickerson, Erick C. Dreaden, Xiaohua Huang, Ivan H. El Sayed,Hunghao Chu, Sujatha Pushpanketh, John F. Mcdonald, Mostafa A. El Sayed, ” Gold nano assiated near-infrared Plasmonic Phototheramal Therapy (PPTT) of squamos cell carcinoma in mice”, Cancer Letters 269 ( 2008) 57- 66.
Tags: adverse events
, argon laser
, bone marrow suppression
, Epithelial Carcinoma
, Gene Therapy
, Molecular targetting
, monoclonal antibody
, narrow therapeutic index
, Photo-Thermal Destruction
, Professor Mostafa El Sayed
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Who could possibly believe that our anaerobic spore-forming Clostridia will be used as an anti-tumor therapy?! It’s called Clostridium-based tumor targeted therapy. “Give me a break,” that’s exactly what I said when I read the review of the new book Clostridia: Molecular Biology in the Post-genomic Era.
So, how does it work? There are various non-pathogenic Clostridia strains which could replicate within solid tumors upon systemic administration. The interesting part is coming right up: Why solid tumors?! It’s because of its very unique physiology; it characterized by hypoxia & necrosis which totally fits the anaerobic Clostridia. The advantage will be the selectivity & targeting of the cancer cells leading to destroying them.
It was news to me to know that Cl. perfringens causes food poisoning like any food-borne illness & causes antibiotic-associated diarrhea (When I hear the name Cl. perfringens, I orient myself toward gas gangrene right away). Its enterotoxin gene (cpe) is present on the chromosome itself (in food poisoning isolates) and on the plasmid (in the antibiotic-associated diarrhea isolates). The enterotoxin binds to claudin receptors, then there’s oligomerization or “prepore” formation & finally prepore insertion takes place to form the functional pore which kills the cells by apoptosis. So CPE/CPE derivatives could be used for cancer therapy.
, Clostridium-based tumor targeted therapy
, solid tumors
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Aethlon Medical has developed a new device called Hemopurifier® which acts a lot like the usual hemodialysis machine used in patients with end-stage renal disease but targets a different kind of particle within the blood, it captures viruses! The machine uses thin filters to capture & remove viruses from the blood. This requires an artery to act as an entry point of the blood to the machine, where it is filtered, and then sent back to the body, only cleaner.
The whole blood circulation passes through the machine almost once every 8 minutes. The entire process itself requires a few hours. Needless to say, this might prove to be revolutionary in the treatment of all sorts of viral infections: measles, mumps, hepatitis, west-nile virus, smallpox, HIV, avian flu, even the seemingly harmless human flu..just to name a few.
The device has already received a lot of attention & was in fact awarded. In a pre-clinical study, an astonishing 99.4% of H5N1 flu virus, as verified by real-time PCR, was eliminated from the patient’s blood within an operating time of 6 hours.
This state-of-the-art device functions through using antibodies to capture viruses & toxins before their actual attack on the human organs. Patients can even be started on the machine before the physicians find out the cause of the disease.
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