Tuesday, July 31, 2012

New study finds low levels of MLV GAG sequences in samples from CFS patients

Just spotted this today -- the authors appear to have carefully controlled for mouse contamination (using the mitochondrial DNA assay), and found that 2 of 12 CFS patient samples were positive for MLV-GAG region sequences...they were unable to find other genes related to MLVs...sound familiar?  Again, if all these patients that come up negative for mouse DNA come up positive for MLV GAG -- but not for env or other genes...maybe people are looking for the wrong genes...the title of the paper is somewhat misleading but perhaps necessary to get it published "Xenotropic and polytropic murine leukemia virus-related sequences are not detected in the majority of patients with chronic fatigue syndrome", it is by an Italian group --Paolucci et al. and you can find it here

Sunday, July 22, 2012

Congratulations Katy and Matt! The newest addition to the lab has (finally!) arrived!

It is my absolute pleasure to welcome Samuel Steven Sobek into the world...born last night, July 21 - 21.25 inches and 8lbs 3oz (hey, I think that means I win the weight/length bet...!) -- Mom and Dad are ecstatic - Samuel was born the day after Katy uploaded all but one file to submit her first paper from her PhD studies -- so effectively she has given birth twice in the space of 24 hours!

we look forward to meeting Samuel in person, and putting him to work at the bench :)

Friday, July 20, 2012

PSMA as a therapeutic target for most cancers: one step closer to the clinic

As I mentioned previously, there's several papers that I want to blog about right now but I have been too busy writing grants and papers.  But as another paper goes off today, I am going to write about this really awesome work that was published a couple of weeks ago by Sam Denmeade and John Isaacs, and their collaborators.  Sam and John are at Hopkins, and have been working on targeting PSMA for a very long time - Let me digress for a minute and give some of the background - PSMA is an abbreviation for Prostate-Specific Membrane Antigen, but the term is somewhat a misnomer as it is expressed in a variety of tissues. The protein and the gene encoding it were identified in the lab of Skip Heston in 1993 --  who was at that time leading a lab at Memorial Sloan-Kettering Cancer Center.  Skip was actually looking to use a bacterial glutamate carboxypeptidase to activate methotrexate triglutamate, a prodrug (meaning once the additional glutamates are removed, the drug will be active).  I like to think of this story as a classic example as to how including the correct controls in an experiment, and being open to the unexpected, might lead to a serendipitous finding - in this case (as the story was told to me), the control cells (no bacterial glutamate carboxypeptidase added), unexpectedly died after addition of the prodrug.  The cells were LNCaP, a prostate cancer cell line that, like most prostate cancer, expresses large amounts of PSMA. Together with John Pinto and apparently over a couple of beers, Skip figured out that PSMA was a glutamate carboxypeptidase itself, and in fact it is the previously sought-after folate hydrolase that removes glutamates from dietary folates so that they can be absorbed by the small intestine.  Dean Bacich - at the time a postdoc in Skip's lab at Sloan made several types of PSMA transgenic mice - mice don't normally express PSMA in the prostate so Dean engineered the mice so that they expressed moderate levels (equivalent to humans) in the prostate epithelial cells.  These mice got what is considered the precursor to prostate cancer, PIN, suggesting that PSMA expression can cause or promote cancer, and later he showed that if the mice lived as long as humans, it would have been cancer.  David Silver and Sam Chang, both fellows at Sloan were the lead authors on papers showing the expression of PSMA on tumor-associated vasculature.  This was really exciting because almost all tumors that we looked at expressed PSMA in the endothelial cells of the vasculature, and the one non malignant tumor we looked at, which from memory was a hemangioma, did not express it -- and so the idea of targeting PSMA in tumor-associated vasculature was born.  Although he officially retired on July 1, Skip is now at the Cleveland Clinic and still working on targeting PSMA (the word retirement is not exactly in his vocabulary...but anyone who knows him won't be surprised about that).  As Bob Silverman pointed out at Skip's "transition" party, there are currently 26 clinical trials registered that target PSMA either as a therapeutic or for imaging for prostate and kidney cancer.  So back to the current work -- the major leaders of this study, Sam and John, are two of the guys whom I most respect as scientists.  It seems to me that a lot of people are in this field for all the wrong reasons -- but these guys are genuinely driven to help people -- and are truly excited by science [I'm sorry but its almost impossible to stop John from talking about his and anybody else's research - not that that's a bad thing :) - we could use a lot more people like him around here!] -- their paper, published in Science Translational Medicine, is entitled "Engineering a Prostate-Specific Membrane Antigen Activated Tumor Endothelial Cell Prodrug for Cancer Therapy".  To summarize, they took a peptide that specifically binds to PSMA, and coupled it to the toxin thapsigargin (and called it G202). There are two major differences between this and other chemotherapeutic drugs; first, it targets the tumor vasculature, meaning the cells that supply the tumor with the nutrients it needs to grow.  Secondly, the cells don't need to be dividing to be effected - most chemotherapies target some aspect of dividing cells, which is also why any other rapidly dividing cells, for example gut cells, are also targeted, leading to side-effects for the patient.  They tested the drug in mice against a number of human cancers, and it caused regression while causing very little toxicity to the animals.  The drug is now entering a phase I clinical trial.  I highly recommend reading this paper - it may seem like a logical series of successful experiments, but it is really the culmination of nearly 20 years of work done by many dedicated scientists, whom I feel honored to be acquainted with.

Tuesday, July 17, 2012

Another great link for scientists...

Nature now has a new website to help you find antibodies against your target of interest... complete with an easy-to-use system that let's you compare demonstrated usefulness of the we all know, just because the company says it works, doesn't actually mean that it does that can get to the new site, called Antibodypedia, by clicking here

Another great site, and my personal favorite, is this one, protein atlas -- it comes with actual pictures of antibodies used in immunohistochemistry of particular tissues, including normal samples and cancer. You can get there by clicking here

Tuesday, July 10, 2012

Next gen sequencing reveals that Pre-XMRV-2 is part of an evolutionarily young clade and more issues with PCR amplification of MLV-related sequences

There are a load of papers I'd love to blog about right now, but have been too busy writing grants to get them up -- this one however caught my eye today -- I think we have a lot of very interesting data yet to be revealed by next-gen sequencing - this paper, in Virus Research, compares pre-XMRV-2 sequences found in both wild-mice and inbred mouse populations.  It also seems that despite the fact that the virus appears to be a polytropic non-ecotropic virus [thus can infect other wild mice], not all wild mice in the same geo area carry the virus (in this case, Germany), and phylogenetic analysis implies that the clade is evolutionarily young and wide-spread amongst M.m. domesticus.  Also interesting is that the authors, Mayer et al., demonstrate the issues involved with PCR amplifying the gag region from these mice - and the utility of high throughput deep sequencing.  If you have access to Virus Research, you can read all about it - click here for the abstract -