How to get your NIHRO1 grant renewed!

Yikes! It's that time again...our once 5 year grant has 2 and a half years to go, time to think about renewal!  What you say? But you're only half-way through - but think about it - the time from submission to actually getting the $ is 9 months!  And that's assuming you get it funded the first time -- and usually, that's not a safe assumption to make, for anyone [OK good on you people who get everything you put in funded, I'm happy for you!] - as we probably are not the only people in this situation, I thought I would post this link to a very helpful website -- the NIH NIAID has a newsletter covering exactly these topics, and let's face it, if anyone is going to provide good advice, it's likely to be the NIH...read all about it here.

Congratulations Jenn!

A big congrats to Jennifer Gregg in the lab, for placing second in the poster competition at the SBUR meeting in Baltimore over the weekend!  Jenn's poster was regarding the mechanism by which PSMA increases uptake of monoglutamated folates - i.e. folic acid and methotrexate -- Congrats once again Jenn!

Jennifer Gregg, and her winning poster August 2012

Activation of innate anti-viral immune response genes in symptomatic benign prostatic hyperplasia

A big CONGRATS to Allison Atwood-Madigan in the lab, the above paper has just been accepted for publication in Genes & Immunity (a Nature journal)!  Bring on the celebratory laser-tag!

Magical Beets?

We all know you should eat your veggies, and here's another reason -- according to this paper by Hobbs et al., beets (called beetroot down under), pretty much instantly lower blood pressure after they are ingested! My hubby was so excited that he bought a dehydrator to start making beet-chips, which aren't too bad - but these veggies look great in salads or with a sunday roast -- and, unlike some food studies, you don't have to eat 50 beets to get the effect - just one 100g beet should do it!  Try to beet that!

Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects.

Hobbs DA, Kaffa N, George TW, Methven L, Lovegrove JA.

Source

Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, The University of Reading, Whiteknights, PO Box 226, Reading, Berks RG6 6AP, UK.

Abstract

A number of vegetables have a high nitrate content which after ingestion can be reduced to nitrite by oral bacteria, and further to vasoprotective NO endogenously. In the present study, two separate randomly controlled, single-blind, cross-over, postprandial studies were performed in normotensive volunteers. Ambulatory blood pressure (BP) was measured over a 24 h period following consumption of either four doses of beetroot juice (BJ), 0, 100, 250 and 500 g (n 18), or three bread products, control bread (0 g beetroot), red beetroot- and white beetroot-enriched breads (n 14). Total urinary nitrate/nitrite (NOx) was measured at baseline, and at 2, 4 and 24 h post-ingestion. BJ consumption significantly, and in a near dose-dependent manner, lowered systolic BP (SBP, P < 0·01) and diastolic BP (DBP, P < 0·001) over a period of 24 h, compared with water control. Furthermore, bread products enriched with 100 g red or white beetroot lowered SBP and DBP over a period of 24 h (red beetroot-enriched bread, P < 0·05), with no statistical differences between the varieties. Total urinary NOx significantly increased following the consumption of 100 g (P < 0·01), 250 g (P < 0·001) and 500 g BJ (P < 0·001) and after red beetroot-enriched bread ingestion (P < 0·05), but did not reach significance for white beetroot-enriched bread compared with the no-beetroot condition. These studies demonstrated significant hypotensive effects of a low dose (100 g) of beetroot which was unaffected by processing or the presence of betacyanins. These data strengthen the evidence for cardioprotective BP-lowering effects of dietary nitrate-rich vegetables.

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

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 :)

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.