**BIOTECH AND PHARMA NEWS**

[Preciouslife1]

FDA revises labels for ED drugs Viagra, Levitra and Cialis to reflect side effect

Marketletter - Oct. 29, 2007

The US Food and Drug Administration has approved labeling changes for erectile dysfunction drugs in the class of compounds known as phosphodiesterase type-5 inhibitor that includes Pfizer's blockbuster Viagra (sildenafil), Johnson & Johnson's Cialis (tadalafil) and Bayer's Levitra (vardenafil), which is co-marketed with Schering-Plough and GlaxoSmithKline, to display more prominently the potential risk of sudden hearing loss, and to guide consumers on what to do if they should experience sudden problems with their hearing.

Also changes for Revatio

In addition, the FDA plans to require the same changes in labeling for the drug Revatio (sildenafil), also a member of this drug PDE-5 inhibitors class, but which is indicated for the treatment of pulmonary arterial hypertension. PAH is a serious medical condition in which continuous high blood pressure in arteries of the lungs weakens the heart muscle and often leads to right heart failure and death, the agency notes.

The FDA asked the manufacturers of these drugs to revise product labeling after a very small number of patients taking the PDE-5 inhibitors reported sudden hearing loss, sometimes accompanied by ringing in the ears and dizziness.

"Because some level of hearing loss is usually associated with the aging process, patients on these drugs may not think to talk to their doctor about it," commented Janet Woodcock, Deputy Commissioner for Scientific and Medical Programs, Chief Medical Officer and acting Director of its Center for Drug Evaluation and Research.

The agency says that patients taking Cialis, Levitra, or Viagra who experience sudden hearing loss should immediately stop taking the drug and seek prompt medical attention. Those using Revatio should continue taking their medication, but should contact their health care provider for further evaluation. Because Revatio is used for a life-threatening condition, the FDA does not recommend patients abruptly stop taking it, but should consult their physician if they experience sudden problems with their hearing.

A case report in the April issue of the Journal of Laryngology & Otology involving sudden hearing loss in a man taking Viagra prompted the FDA to search its own Adverse Events Reporting System for instances of hearing loss and PDE-5 inhibitors.

The agency found a total of 29 postmarketing reports of sudden hearing loss, both with and without accompanying ringing in the ears, vertigo, or dizziness. In most of the cases, this involved one ear. It was either a partial or complete loss of usual hearing. In around one third of cases, the event was temporary. In the remainder, the problem was ongoing at the time of the report or the final outcome was not described, the agency noted.

Although no causal relationship has been demonstrated, the strong relationship between the use of these drugs and sudden hearing loss in these cases warrants revisions to the product labeling for this whole drug class, the FDA concluded.

[Preciouslife1]

Genetics: Conserved by evolution, but altered in cancer
Patrick Goymer

http://www.nature.com/nrc/journal/v7/n11/full/nrc2261.html

Some regions of the genome are 100% conserved between human, mouse and rat, suggesting that they have important functions. A new study shows that changes in the expression of these so-called ultraconserved regions (UCRs) are associated with various cancers.

Several recent studies have shown that, in addition to classical oncogenes and tumour suppressors, microRNAs (miRNAs) have a role in cancer. However, these are not the only type of non-coding RNA — many other parts of the genome appear to be expressed and functionally important, even though they do not encode protein. UCRs are one particular class of these whose functional importance has been demonstrated through deletion experiments in mice.

The authors used microarray profiling of UCRs in normal tissue to identify those that were transcribed — T-UCRs. More detailed study using quantitative PCR and northern blots showed that two particular T-UCRs differed significantly in their expression between normal lymphocytes and chronic lymphocytic leukaemia cells. The authors then explored whether T-UCR expression signatures could distinguish between a wide range of normal and cancer cells. Using a panel of 133 cancer samples and 40 corresponding normal controls, they showed that signatures of between 8 and 61 T-UCRs could distinguish specific cancer cells from their normal counterparts.

So what do these T-UCRs do and how are changes in their expression associated with cancer? First, the authors showed that the locations of T-UCRs are correlated with regions that have previously been shown to be associated with cancer, such as fragile sites, amplified regions and regions with a loss of heterozygosity. In one particular case, no mutations were found in the protein-coding genes in the region, suggesting that the change in the T-UCR was what promoted cancer susceptibility. Second, they showed that the expression of several T-UCRs was negatively correlated with that of certain miRNAs, and that there was a significant antisense complementarity between several miRNA–T-UCR pairs, suggesting a functional link. In four cases these interactions were confirmed in an in vitro reporter system, and several were observed to function in vivo.

Finally, the authors demonstrated the oncogenic potential of one T-UCR. They chose one of the T-UCRs that is most significantly upregulated in colon cancer, and used small interfering RNAs to downregulate it. This decreased proliferation and increased apoptosis.

The role of T-UCRs in cancer is just beginning to be explored. They are unlikely to be the last new element with a role in tumorigenesis: as geneticists discover more functional elements in their increasingly detailed annotation of the genome, cancer biologists can expect many of them to have roles as oncogenes and tumour suppressors.

References and links
ORIGINAL RESEARCH PAPER
Calin, G. A. et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 12, 215–229 (2007)

ArticlePubMedISIChemPortFURTHER READING
Esquela-Kercher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006

[Preciouslife1]

Research Highlight
Nature Reviews Cancer 7, 811 (November 2007) | doi:10.1038/nrc2265

http://www.nature.com/nrc/journal/v7/n11/full/nrc2265.html
Ageing: Falling p53 function
Sarah Seton-Rogers


SUPERSTOCK
The increased incidence of cancer with age is thought to occur because of the accumulation of mutations in cells with time, and many biological processes gradually decline in ageing organisms. Arnold Levine and colleagues asked whether the function of the tumour suppressor p53 could also decline with age and hence contribute to enhanced mutation frequency and tumorigenesis.

The authors first examined the transcriptional activity of p53 in young and old C57BL/6 mice in response to -irradiation. In the spleen, which has a high p53 response to irradiation, the mRNA levels of six p53 target genes (Cdkn1a (encoding p21), Puma, Bax, Fas, Mdm2 and Ccng 1 (encoding cyclin G1)) were consistently lower after irradiation in older mice. Similar results were observed in other tissues, indicating that this is not a spleen-specific phenomenon, and the decrease in gene induction occurred at all time points, excluding the possibility that p53-induced transcription is simply slower in older mice. Decreased p53-dependent transcription with age was also observed in two other inbred mouse strains (DBA2 and BALB/c), indicating that it is a general phenomenon in mice. A major function of p53 is to induce apoptosis, and the authors found that the number of apoptotic splenocytes in older mice of all three strains decreased following irradiation.

Interestingly, the onset of the decline in p53-dependent transcription and apoptosis was different for male and female C57BL/6 mice, occurring at 20 months in females but not until 28 months in males. Male C57BL/6 mice live 2–3 months longer than females, suggesting that decreased p53 function correlates with expected life span rather than actual age. Consistent with this hypothesis, DBA2 mice, which live for about 2 months less than C57BL/6 mice, had a decrease in p53 function at an earlier age.

How is p53 activity decreased in ageing mice? p53 protein levels were lower in older mice of all three strains; however this was not due to upregulation of the negative regulator MDM2 or the p53 ubiquitin ligases COP1 or PIRH2. So, the authors examined the kinase ataxia-telangiectasia mutated (ATM), which phosphorylates Ser18 (Ser15 in humans) to stabilize p53 following irradiation-induced DNA double-strand breaks (DSBs). Total mRNA and protein levels of ATM were reduced in older mice of all three strains, as was phosphorylation of Ser18 on p53. Furthermore, there did not seem to be a general decline in the function of all signalling pathways, as the insulin-like growth factor 1 (IGF1)–Akt and mammalian target of rapamycin (mTOR) pathways remained functional.

p53 is induced by various stress signals besides irradiation, so how general is the decreased response? Cultured splenocytes from older C57BL/6 mice (which mimicked the results of the in vivo experiments) were less responsive to etoposide and doxorubicin (which, like irradiation, induce DNA DSBs), actinomycin D (which blocks ribosomal RNA synthesis), ALLN (N-acetyl-L-leucyl-L-leucyl-L-norleucinal; which inhibits proteasome-mediated degradation) and paclitaxel (which disrupts microtubules).

Therefore, it seems that a decline in p53 function owing to reduced ATM levels occurs in aged mice. Whether a similar decline occurs in humans and whether the increased incidence of cancer with age can be attributed to it remain to be determined.

References and links
ORIGINAL RESEARCH PAPER
Feng, Z. et al. Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations. Proc. Natl Acad. Sci. USA 104, 16633–16638 (2007)

[Preciouslife1]

Trial Watch: Trial and error

http://www.nature.com/nrc/journal/v7/n11/full/nrc2266.html#Trial-and-error

Why is it that so many drugs fail at phase III? Could this failure rate be reduced by changing the design of phase II trials? This question has been addressed by Mark Ratain and colleagues in a recent publication in the Journal of the National Cancer Institute.

Phase II trials generally assess whether a new drug or treatment regimen has sufficient efficacy to warrant further trials. These trials are normally single-arm trials for which the primary outcome is complete or partial response in patients with solid tumours as assessed by RECIST (response evaluation criteria in solid tumours) guidelines. Although this might effectively select against non-efficacious drugs, it does not indicate whether a treatment should continue into a phase III trial.

So, when designing a phase II trial of the tyrosine kinase inhibitors sorafenib and erlotinib in patients with non-small-cell lung cancer, the primary endpoint chosen was changes in tumour size treated as a continuous variable instead of categorized changes in tumour size. Although randomized phase II trials are often avoided because of the number of patients needed, using changes in tumour size as a continuous variable reduces patient numbers. The size of the trial was determined by examining four previous trials with these agents and making assumptions about the likely effect of the drugs and the variability in the changes in tumour size. The resulting trial design consisted of three treatment groups (150 mg erlotinib daily with placebo; 150 mg erlotinib daily with 200 mg sorafenib twice daily; and 150 mg erlotinib daily with 400 mg sorafenib twice daily) with 50 patients in each group.

The authors conclude that treating tumour size as a continuous variable rather than categorizing the changes, along with the placebo control group, should give more useful information than a standard single-arm phase II trial.

ORIGINAL RESEARCH PAPER
Karrison, T. G., Maitland, M. L., Stadler, W. M. & Ratain, M. J.Design of phase II cancer trials using a continuous endpoint of change in tumor size: application to a study of sorafenib and erlotinib in non-small-cell lung cancer. J. Natl Cancer Inst. 99, 1455–1461 (2007)

All or nothing?
Callisto Pharmaceuticals, Inc. has completed enrolment ahead of schedule of 40 patients to its phase II clinical trial of atiprimod, a new drug to treat low- to intermediate-grade neuroendocrine carcinoma (carcinoid cancer).

What makes this small molecule interesting is that it has multiple targets and its mechanism of action is unclear. It can inhibit the secretion of vascular endothelial growth factor and interleukin 6, suppress tumour angiogenesis, induce apoptosis and inhibit phosphorylation of Akt and signal transducer and activator of transcription 3 (STAT 3). Because this trial was initiated in November 2006, some patients in the trial have been taking atiprimod, an orally bioavailable small molecule, for 11 months and most will have been given the drug for 6 months by January of next year.

WEB SITES http://www.callistopharma.com/ | http://www.clinicaltrials.gov/

[Preciouslife1]

Autophagy: Tumour or death?
Nicola McCarthy

http://investorshub.advfn.com/boards/post_new.asp?board_id=10777

Autophagy — the process of digestion of cellular organelles in order to survive periods of starvation — has been linked with cell survival and cell death, and more recently to tumorigenesis. Hong-Gang Wang and colleagues have identified another molecular player linked with all three outcomes, the BAX interacting factor BIF1.

BIF1 is a membrane-binding endophilin that is involved in the activation of the pro-apoptotic proteins BAX and BAK. When verifying its mitochondrial localization in mouse embryonic fibroblasts (MEFs), the authors noted that the pan-caspase inhibitor zVAD-fmk increased the number of MEFs that died as a result of serum starvation. Suppressing apoptosis in various cell types under conditions of cellular stress has been shown to induce autophagy, so the authors analysed cell death in BIF1 wild-type and null MEFs. They were able to conclude that BIF1 expression is required for autophagy-induced death when apoptosis is suppressed.

The authors also observed that the formation of autophagic vesicles was reduced in BIF1-depleted cells, indicating that BIF1 might be involved in this process. BIF1 was shown to associate with the autophagosome and, moreover, its N-terminal BAR domain, involved in membrane binding and curvature, was required to induce autophagosome formation. Immunoprecipitation studies in intact cells showed that BIF1 can pull down the autophagy-regulating protein beclin 1 (BECN1). BECN1 is known to interact with UVRAG, another protein involved in autophagy, and Wang and colleagues found that UVRAG acts as a bridge to facilitate that interaction between BIF1 and BECN1. The BECN1–UVRAG interaction has previously been shown to be important for activation of the lipid kinase PI3KC3, which is required for autophagosome formation, and results in this paper indicate that BIF1 regulates the activation of PI3KC3 by this complex.

Finally, the authors found that unlike Becn1 null mice, Bif1 null animals are viable, but are prone to tumour development later in life. 26 out of 29 Bif1 nulls developed tumours, compared with 3 out of 21 controls, with lymphoma being the most common tumour type. Therefore, like BECN1, BIF1 seems to be a tumour suppressor, and these results add more weight to the argument that the induction of autophagy might be a viable approach for treating and preventing cancer.

References and links
ORIGINAL RESEARCH PAPER
Takahashi, Y. et al. BIF1 interacts with beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature Cell Biol. 23 September 2007 (doi: 10.1038/ncb1634)

[Preciouslife1]

Tumorigenesis: Size is everything

Nicola McCarthy

How is tissue size regulated? This question has been occupying scientists for a long time, and although a few genetic regulators of organ size have been identified in organisms such as Drosophila melanogaster, the regulation of organ size in mammals is still perplexing. Do YAP and Yorkie hold the key?
Yorkie (Yki) is a transcriptional co-activator involved in the Hippo (Hpo) kinase pathway that suppresses tissue growth in Drosophila. Its mammalian homologue is YAP. The Hippo pathway, which is thought to be conserved in mammals, was previously shown to antagonize the function of Yki. Duojia Pan and colleagues investigated how this is achieved. By using an epitope-tagged version of Yki in Drosophila cells in vitro, the authors showed that an intact Hpo–salvador (Sav)–warts (Wts) pathway resulted in Yki phosphorylation and exclusion from the nucleus. YAP was reported to be phosphorylated by Akt at S127, and a conserved site is present in Yki at S168. Given that Wts belongs to the same kinase family as Akt, it seemed plausible that Wts could phosphorylate Yki. Several in vitro and in vivo experiments indicated that S168 is the main site through which Wts regulates Yki. For example, conditional expression of a Yki S168A mutant protein that cannot be phosphorylated resulted in overgrowth of the eye and lethality in some flies, and disruption of the Hippo pathway resulted in nuclear accumulation of Yki. Therefore the Hippo pathway regulates tissue growth by phosphorylating Yki at S168 and excluding it from the nucleus.
The authors then used the similarity between the regulation of Yki and YAP to further map the Hippo pathway in mammals. They found that phosphorylation of S127 by the Hippo pathway also regulated the nuclear localization of YAP in vitro. So can YAP regulate organ size? To answer this Pan and colleagues made a tetracycline regulatable Yap transgene that was only expressed in the liver. These mice had much larger livers than controls owing to increased cell proliferation rather than an increase in cell size. Moreover, this overgrowth was dependent on YAP, as the livers returned to normal size when the expression of the transgene was turned off. Microarray analyses indicated that YAP induces the expression of genes associated with proliferation and genes known to suppress apoptosis, a combination that proved to be tumorigenic in these mice.
An examination of human cancer cell lines showed that YAP was overexpressed in many. However, further work is needed to establish how YAP function is disrupted in human tumorigenesis. The conserved nature of these pathways in flies and mammals should aid in fully understanding the function of the Hippo pathway in the regulation of organ size and tumour development.

References and links

ORIGINAL RESEARCH PAPER

1. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007)

[Preciouslife1]

Genetics: Networks uncover new cancer susceptibility suspect

Patrick Goymer

Cancer susceptibility genes such as breast cancer 1 (BRCA1) do not function in isolation — they are parts of networks, and deciphering how these networks operate is an important step in understanding cancer progression. A new study has constructed a network for breast cancer susceptibility using various 'omic' data sets, and identified the hyaluronan-mediated motility receptor gene (HMMR) as a new susceptibility locus for the disease.
The authors sought to construct a network around four genes that are known to be associated with breast cancer: BRCA1, BRCA2, ataxia telangiectasia mutated (ATM) and checkpoint homologue (CHEK2). They used published expression data from normal cells to identify 164 other genes, the expression of which correlated with all four of their reference genes. The relevance of these genes for the BRCA-related network was confirmed by the fact that their expression was in many cases upregulated in tumours from carriers of BRCA1 mutations compared with sporadic tumours.
This list was integrated with published functional genomic data about interactions between the genes on the list. The resultant network consisted of 118 genes and proteins, with 321 direct and 545 indirect interactions. One of the most highly connected nodes in the network, and the one with the closest coexpression with BRCA1, was HMMR, which probably has a role in centrosome function.
The authors further explored the role of HMMR using a yeast two-hybrid assay, and found that HMMR interacts with several components of BRCA1 complexes. Using co-immunoprecipitation assays, the association of BRCA1 and HMMR was seen specifically as cells entered mitosis, and the authors also showed that HMMR was ubiquitylated by the BRCA1 complex and was localized to the centrosome. Knocking down either HMMR or BRCA1 caused abnormal increases in centrosome number, but this effect was abolished if the expression of both genes was inhibited simultaneously.
In the light of this functional information, the authors looked for associations between SNPs in HMMR and breast cancer susceptibility. Typing for five SNPs in several independent populations showed that two haplotypes significantly increased susceptibility to breast cancer, and that this effect was independent of BRCA1 or BRCA2 status. Interestingly, expression analysis showed that one of these haplotypes was associated with an increase in HMMR expression whereas the other was associated with a decrease. This implies that any perturbation from a precise level is detrimental.
This study comprised several components — the construction of a network model from published data, the functional molecular characterization of a candidate component of this network, and a candidate-gene population association study to demonstrate its link with cancer susceptibility. It shows the power of network modelling to generate hypotheses for both molecular and population genetics.

References and links

ORIGINAL RESEARCH PAPER

1. Pujana, M. A. et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nature Genet. 7 October 2007 (doi: 10.1038/ng.2007.2)
   • Article

FURTHER READING

1. <LI id=B2>Jensen, L. J., Saric, J. & Bork, P. Literature mining for the biologist: from information retrieval to biological discovery. Nature Rev. Genet. 7, 119–129 (2006)
   • Article
2. Badano, J. L., Teslovich, T. M. & Katsanis, N. The centrosome in human genetic disease. Nature Rev. Genet. 6, 194–205 (2005

[Preciouslife1]

Tumorigenesis: A shocking enabler of tumour growth
Sarah Seton-Rogers

http://www.nature.com/nrc/journal/v7/n11/full/nrc2262.html

The conserved heat-shock response, mediated largely by the transcription factor heat-shock factor 1 (HSF1), allows cells to adapt to stress. Although this response is crucial to protect against some diseases of ageing, including ischaemia and neurodegenerative disorders, Susan Lindquist and colleagues now show that HSF1 has an opposite role in cancer, in which it promotes tumorigenesis.

The authors first showed that Hsf1-/- mice were less susceptible to skin tumours induced by the chemical carcinogens dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) than were wild-type mice — tumour latency and survival were increased and tumour incidence and burden were reduced in Hsf1-/- mice. The authors also examined the effects of HSF1 on tumours arising in mice heterozygous for the Trp53 mutation Trp53R172H. As in the skin carcinogenesis model, tumour-free survival was increased in Hsf1-/- mice carrying this allele.

A random sampling of chemically induced skin tumours that developed in Hsf1-/- and wild-type mice showed that all had activating mutations in Hras. To further examine the effects of HSF1 on transformation by HRAS, the authors expressed an activated form of HRAS, encoded by HRASV12D, in Hsf1-/- and wild-type mouse embryonic fibroblasts (MEFs) and found that a lack of HSF1 made the MEFs resistant to HRASV12D-induced focus formation. Similar results were observed using wild-type MEFs expressing short hairpin RNAs (shRNAs) directed against Hsf1.

How does HSF1 promote tumorigenesis? The differential effects of HRASV12D on Hsf1-/- versus wild-type mice were a result of increased proliferation of the wild-type cells, rather than increased death of Hsf1-/- cells. However, expression of MYC or SV40 large T antigen enhanced death in Hsf1-/- MEFs, so depending on the oncogenic insult HSF1 seems able to promote either proliferation or survival. HSF1 might also affect signalling pathways. The authors found blunted activation of extracellular signal-regulated kinase (ERK) downstream of Ras in the absence of HSF1. Activation of protein kinase A (PKA) downstream of G-protein-coupled receptor activation was also reduced, suggesting that HSF1 can modulate at least two oncogenic signalling pathways.

Yet another effect of HSF1 on tumorigenesis might result from its role in translation. Ribosomal biogenesis normally depends on growth factors, but cancer cells can circumvent this requirement. The expression of ribosomal subunits was reduced in serum-starved Hsf1-/- or Hsf1 shRNA-expressing MEFs compared with wild-type cells, indicating that HSF1 deficiency promotes the dependency of the translational machinery on growth factors. HSF1 might also affect translation through its effects on the mammalian target of rapamycin (mTOR) pathway. Inhibition of mTOR or loss of its downstream effector p70S6K (ribosomal protein S6 kinase, 70 kDa) impairs protein translation and reduces cell size, and MEFs from Hsf1-/- mice had reduced p70S6K phosphorylation and a smaller size.

Finally, HSF1 can promote glycolysis, which occurs in most cancer cells and is beneficial for tumour growth and survival. Glucose uptake was decreased in Hsf1-/- compared with wild-type MEFs, and Hsf1-/- cells were less dependent on glucose for survival.

Is HSF1 relevant in human cancers? The authors examined human cell lines of varying malignant potential that were either transformed in the laboratory or derived from human tumours with diverse histological origins and various genetic abnormalities. In all cases, they found that the growth of tumorigenic cells was decreased by shRNA knockdown of HSF1.

HSF1 seems to act not as a classic oncogene, but as a modulator of tumorigenesis, affecting multiple pathways that allow cells with oncogenic defects to adapt and survive. Activation of HSF1 is being explored for treating ischaemic injury and some neurodegenerative diseases, and it needs to be determined whether such therapies might enhance tumorigenesis if used in the long term. Furthermore, any potential cancer therapeutics that inhibit HSF1 could possibly affect neurodegeneration and ageing. Hopefully a greater understanding of HSF1 will lead to the development of more effective therapeutics for several diseases.

References and links
ORIGINAL RESEARCH PAPER
Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007)

[Preciouslife1]

Neuronal circuits can now be seen in a multicolour 'brainbow'.
Alison Abbott
A mix of 5 colours can produce about 90 distinct shades.Courtesy of the researchers
It's not often that research results look this good. An elegant new way to visualize individual brain cells not only provides a major boost to scientists trying to understand how the brain works, but has also won one of its developers a major prize in science photography.
The method — described by neuroscientists at Harvard University in Cambridge, Massachusetts, in today’s Nature 1 — allows researchers to see more clearly how individual neurons connect with each other by colouring each one from a palette of about 90 shades. In this way they will be able to build up a detailed diagram of the brain's wiring, which will help to study how it computes.
More than a century ago, neuroscientists developed the first method of staining individual neurons — with silver chromate. Work with this technique was the basis of the Nobel Prize in Physiology or Medicine in 1906. But this could only stain neurons with one colour.
Only in the last decade have scientists improved on this technique, using genetic engineering to transfer genes for fluorescent proteins into mice such that they are expressed in neurons. But until now they could transfer no more than two florescent-protein genes at a time, lighting up the brain with two colours. “It was clear that two colours were not enough to map connections efficiently in the brain’s complex tangle of neurons,” says Joshua Sanes, one of the paper’s senior scientists.
All the colours of the rainbow


Colours show how cells intertwine.Courtesy of the researchers
Jeff Lichtman, Sanes and colleagues found a way for transgenic mice to express various mixtures of four colours of fluorescent proteins in their neurons: yellow, red, cyan, and either orange or green.
They did this by introducing a string of four colour-producing genes, controlled by a genetic system called Cre/ lox. They organized the elements of this system such that it would randomly promote the activity of just one of the colour-producing genes in vivo. Then they introduced multiple copies of the gene string into the genome of mouse embryonic stem cells, from which they developed transgenic mice.
Each neuron of the transgenic mice switched on a random number of these colour genes. The result was some 90 shades that could be seen by a researcher looking at the cells.
One neuron, for example, might switch on just red and cyan, so it would glow a pleasant mauve; a neighbour might switch on a lot of red and a bit of green and blue glow a shocking pink. They call their system the Brainbow.
This colour mixing is similar to that used by television sets, says Sanes, which produce only red, green or blue pixels but mix them to make any colour needed.
You light up my brain

Brain researchers say that they are amazed that the Harvard scientists managed to pull off such a technically difficult stunt while making it so easy to use in practice. The transgenic mice and necessary research tools are now available for other scientists to use.


"It will give those of us trying to work out how the brain computes different insights," says Karel Svoboda, a neuroscientist at the Howard Hughes Medical Institute’s Janelia Farm laboratories, in Loudoun County, Virginia. “Brainbow will allow you to trace neuronal circuits over long distances — maybe across centimetres of tissue," says Svoboda. "You can see how different neuronal circuits relate to each other in the same animal."
It’s also "very aesthetic", he says. Which is why Jean Livet — the postdoc credited with having the idea for the Cre/ lox tricks, and the paper’s first author — has just won the 2007 Olympus BioScapes Digital Imaging competition, says Sanes.

[Preciouslife1]

Merck to Settle Nearly All Vioxx Suits for $4.85 Billion

[Some analysts had pegged MRK’s Vioxx liability at $50B! At $4.85B, this settlement is small potatoes compared to what WYE paid out for fen-phen.]

http://online.wsj.com/article/SB119458553606887746.html

By HEATHER WON TESORIERO
November 9, 2007 1:07 a.m.

NEW ORLEANS -- Merck & Co. agreed to pay about $4.85 billion to settle a large portion of the claims over injuries allegedly linked to its Vioxx painkiller, according to a person familiar with the situation, after insisting for years that it would fight all 27,000 cases filed rather than compromise.

The agreement is to be announced here Friday morning where a federal judge is overseeing the litigation.

Vioxx was approved for sale in 1999 and quickly became a popular drug, with annual sales reaching $2.5 billion before the Whitehouse Station, N.J., company pulled it from the market in September 2004 amid cardiovascular safety concerns. Since then, it has won 11 cases that have gone to trial and lost five. What's more, the company won four of five cases considered to be bellwethers of how future cases would likely turn out, making the decision to settle somewhat surprising.

U.S. District Judge Elden E. Fallon, who oversees the litigation, had said following those test cases that he wanted the parties to meet to gauge where things stood.

The drug maker also got some other good omens of late. In September, New Jersey's highest court ruled that health insurers' lawsuits against Merck couldn't be consolidated into a nationwide class action, removing the company's greatest financial exposure from the Vioxx litigation. The suit sought reimbursement for as much as $9.6 billion of Vioxx purchases. And last April, a ruling by a Texas state court judge undercut the legal basis for the roughly 1,000 cases filed there.

Plaintiffs' attorneys have long said they wanted to engage in settlement talks with Merck. It is expensive to bring cases to trial and even when plaintiffs prevail, it often takes years for the suits to wind their way through the appellate process.

Merck's stock has rebounded significantly since the lows it saw at the time it withdrew Vioxx. In late 2004, the stock fell to the high $20s. On Nov. 1, its stock hit a 52-week high of $58.36.

But the company has incurred considerable costs from the litigation. In its most recent earnings statement, Merck said it spent $160 million in the third quarter for world-wide Vioxx litigation costs. It also took a charge of $70 million to shore up its litigation coffers, and in the year earlier period took a charge of $598 million. The company currently has set aside $720 million for its Vioxx legal defense costs, which doesn't include any potential damages to plaintiffs.

The withdrawal of Vioxx, which was approved to relieve arthritis and other types of pain was taken by an estimated 20 million Americans, drew questions from critics and government regulators about safety issues and marketing practices in the drug industry. Vioxx was one of three painkillers in the class of so-called Cox-2 inhibitors. Only Pfizer Inc.'s Celebrex remains on the market, and it now carries the Food and Drug Administration's strongest warning label. Bextra, also made by Pfizer, was withdrawn from the market.

Earlier this year, a regulatory panel voted against the approval of Arcoxia, Merck's follow-on Cox-2 inhibitor, which is sold abroad.

[Preciouslife1]

Reovirus Plus Radiation Act Synergistically Against Cancer
Main Category: Cancer / Oncology News
Article Date: 08 Nov 2007

http://www.medicalnewstoday.com/articles/88082.php

Since the advent of cancer therapy, clinicians and patients have sought more targeted treatments that attacked tumors while sparing normal tissues. Several viruses, including the reovirus, or Respiratory Enteric Orphan virus, have shown a strong preference for killing cancer cells vs. normal cells. These oncolytic (tumor-bursting) viruses represent an entirely new approach to cancer treatment.

Calgary-based Oncolytics Biotech has recently reported encouraging results from a U.K. Phase Ia/Ib clinical trial with its Reolysin® oncolytic reovirus formulation in combination with radiation for patients with a variety of advanced or ********************static cancers. The rationale for the trial emerged after preclinical work demonstrated that the addition of radiation enhanced the cancer-killing ability of Reolysin.
Interim results from the Phase Ia/b human study suggest this is true.

The study has treated 22 middle-aged and elderly patients with various tumor types to date. Patients were split into two groups that received either 20 or 36 Gy of radiation, along with escalating dosages of two to six injections of REOLYSIN into a target tumour. Tumors included melanomas and cancers of the colon, pancreas, ovaries, larynx, and other sites. No serious or dose-limiting side effects were noted.

Although this safety study was not designed to show tumor shrinkage, investigators noted a positive trend towards efficacy. Of the 11 patients in the Ia study, three experienced significant partial responses. Three of the 6 patients who completed the Ib trial also responded to treatment.
Typically, only 5% to 15% of patients with advanced cancer respond to conventional cancer treatments. These particular patients had cancers that either did not respond to cancer treatment, or for whom no other treatments were available.

Dr. Brad Thompson, President and CEO of Oncolytics, is encouraged by the results. "The study demonstrates that Reolysin plus radiation is quite safe at the levels administered," he said. "We are also hopeful about the anti-tumor activity data from the Phase Ia/b trials," he added. "These patients were very sick. Any improvement in their condition is cause for optimism."

What was particularly noteworthy in this trial was that patients experienced tumor responses both at the injection site and also in non-injected tumors. Oncolytics has noted this effect in earlier studies as well. This may have been caused by the reovirus traveling through the bloodstream to other tumors. It could also have been caused by an immune response which fights tumors that have not been directly infected by reovirus. This "bystander effect", caused by the priming of the immune system from the initial tumor killing by reovirus, can endure for weeks or months after treatment.

Reovirus is a double-stranded RNA virus that causes asymptomatic human infection. When it encounters cancer cells, reovirus invades and produces thousands of copies of itself, causing the cell to burst. The reovirus selectivity is based on its ability to exploit a pathway specific to cancer cells. Specifically, reovirus only infects cells that possess ras, an activated cancer signaling pathway that operates in about 70% of human cancers. Ras acts as a kind of switch to allow reovirus to invade and destroy the cell. Normal cells keep ras (the name of both a gene and its protein product) in check; cancer cells lose control over Ras, resulting in the uncontrolled growth characteristic of deadly tumors.

The Ib phase of this trial is almost complete. Oncolytics is also enrolling patients in a Phase II trial for this treatment combination. In addition, the company is testing Reolysin, alone and in combination with radiation or chemotherapy, in Phase I and Phase II human trials for several cancer types.

For more information, log on to http://www.oncolyticsbiotech.com

[Preciouslife1]

Biomarker May Be An Early Predictor Of Advanced Breast Cancer

http://www.sciencedaily.com/releases/2007/11/071105103009.htm

Researchers have identified a molecule that may be more accurate than existing biological signposts used to predict which breast cancers will develop into advanced forms of the disease.

The discovery could one day influence therapy decisions and prevent patients from unnecessarily undergoing aggressive cancer treatments.

When diagnosing breast cancer, pathologists currently look for elevated levels of three standard molecules known to make tumors grow in the breast. These molecules—estrogen receptor (ER), progesterone receptor (PR) and HER2—are used as “biomarkers” for diagnosis and individually detect only a fraction of breast cancers.

“The problem with these biomarkers is that many of them are present at some level in the normal breast,” says Georg Weber, MD, PhD, lead investigator of the new study and associate professor of pharmacy at the University of Cincinnati. “In addition, they are surface molecules that support growth so they are not necessarily a good predictor of tumor me.tastasis.”

Weber and his team have identified a molecule, osteopontin-c, that is absent from the normal breast and appears to more accurately predict breast cancer that will become me.tastatic and spread to distant organs from the original tumor site.

In normal levels, osteopontin is a protein used by the immune system to help cells move and migrate. There are three forms of osteopontin—a, b and c—which are formed by splicing, or “cutting and pasting,” ribonucleic acid (RNA) molecules to make variations of the original gene. Osteopontin-a is the normal form that helps with immune functions. Little is known about osteopontin-b, but if present its levels are very low. Osteopontin-c is the molecule Weber and his team discovered is a good biomarker of breast cancer.

In a two-year evaluation of 178 breast tumors, normal and abnormal tissue samples, they found that osteopontin-c was present in 78 percent of cancers and in 36 percent of the surrounding tissues. It was not detected at all in normal tissues.

In 56 breast cancers, 20 were positive and 36 were negative for estrogen receptor, 19 were positive and 37 were negative for progesterone receptor, and 26 were positive for HER2 with 30 negative.

“Osteopontin-c was present in a substantially higher number of breast cancers than the three biomarkers traditionally used to diagnose breast cancer,” says Weber. “We also found that the cancers containing osteopontin-c correlated with a higher tumor grade, meaning they were more likely to become aggressive cancer.”

“If we know that this molecule is not present in a patient with breast cancer, it’s more likely that we can treat them with conservative therapy rather than breast surgery, hormone therapy or chemotherapy because we know it’s less likely to me.tastasize,” he adds. “On the other hand, if we know that a patient has this molecule early in their diagnosis, we can treat it more aggressively because we know their cancer is likely to become invasive.”

The study was funded by grants from U.S. Department of Defense Breast Cancer Program and the UC cancer research program. The tissue procurement was supported by a grant from the National Institute of Health.

This research was detailed Oct. 24, 2007, in an online edition of the International Journal of Cancer. Collaborators include UC’s Mana Mirza and Elizabeth Shaughnessy, MD, John Hurley, Kristie Vanpatten and Gary Pestano of Ventana Medical Systems in Tucson, Ariz., as well as Bin He, MD, of the North Shore Medical Center in, Salem, Mass.

[Preciouslife1]

New South S.F. center to help Pfizer find next biotech cure.
Bernadette Tansey, Chronicle Staff Writer

http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2007/11/07/BUVJT4Q77.DTL&type=tech

Corey Goodman, a former biotech entrepreneur, now has the resources of the world's largest drugmaker at his fingertips.

But as the president of Pfizer Inc.'s new Biotherapeutics and Bioinnovation Center, he also shares the company's world-class headaches.

The patent rights and other protections on some of the company's blockbuster drugs - which generate a significant share of its $48 billion in annual revenue - are poised to expire. And the New York pharmaceutical giant is counting on Goodman's center, in South San Francisco, to help guide Pfizer to lucrative new partnerships on drugs that can replace those fading moneymakers.

Goodman will be seeking collaborations among the kind of struggling, venturesome and often cash-hungry biotech outfits he previously helped found. Along the way, Goodman, 56, hopes to create an independent, entrepreneurial science outfit backed by the resources of a major corporation.

The new center, he said, will help Pfizer build a product line of biologic drugs, including proteins and antibodies - the types of products that have made Genentech Inc. of South San Francisco the world's No. 2 biotechnology company, behind Amgen of Thousand Oaks in Ventura County.

Jonathan MacQuitty, a partner in the health care investment firm Abingworth Management Inc. in Menlo Park, said Pfizer's money and drug development expertise could boost the growth of small companies, "sort of like putting a flower in a hothouse.

"This will give Pfizer a window on how these (scientific) areas are developing, and also the opportunity to pounce when they want to make an acquisition," MacQuitty said.

Pfizer recently recruited Goodman, the former chief executive and co-founder of nearby Renovis, a biopharmaceutical company.

Goodman barely had time to move into his new office before Pfizer chief executive Jeffrey Kindler whisked him away on a whirlwind tour of company research sites in St. Louis; Groton, Conn.; Cambridge, Mass.; La Jolla (San Diego County); and Sandwich, England.

Kindler told him to scout out early stage research that can someday bolster Pfizer's product line, to set up biotech incubators in the Bay Area and elsewhere, and to accelerate the development of new technologies by drawing on Pfizer's deep field of experts and established labs, Goodman said.

"To me it was a dream job," said Goodman, who has deep roots in the Bay Area's top science universities as well as its biotech industry. The eminent neurobiologist has held teaching posts at Stanford and UC Berkeley, and just joined the faculty at UCSF.

Renovis and another company he helped found, Exelixis, both are located in the biotech-studded South San Francisco commercial blocks Goodman can see from his new office window. For now, his bioinnovation center is based at Rinat Neurosciences Corp., a biomedical company Pfizer acquired last year. Rinat is the first unit placed under Goodman's supervision, but he said more alliances will be announced during the next six months.

Goodman said Pfizer's relationship with Rinat will be the model for biotech alliances to come. Rinat has retained its name and core mission since it accepted Pfizer's purchase offer in 2006, he said. The company brought Pfizer a portfolio of drug candidates for acute pain, Alzheimer's disease and other diseases of the central nervous system.

The center has plenty of room to grow in Rinat's building, but Goodman said it might expand elsewhere in South San Francisco or at the sprawling new biotech complex surrounding UCSF's new campus at Mission Bay.

Pfizer hasn't revealed the eventual budget or staffing levels of its bioinnovation center, which is only one of its efforts to find the next generation of blockbuster drugs.

Pfizer already has more than 800 drug development partnerships with other companies. It devoted $7.6 billion to research and development in 2006, and spent more than $6.7 billion to acquire companies during the past three years. Under Kindler's leadership, Pfizer has been slashing its workforce and consolidating research sites to free up money for investments in potential drugs.

Among its drugs that will face generic competition soon is the cholesterol medication Lipitor, the top-selling drug in the world. It alone brings in $12 billion, or about a quarter of Pfizer's yearly revenue.

By 2011, Pfizer will lose exclusive rights to Lipitor. Patent rights on five other drugs that made up 21 percent of Pfizer's revenues last year have either expired or will expire by 2008.

This amounts to huge savings for consumers, because generic drugs can cost as little as 20 percent of the brand name price. But it sends drug companies scrambling for new sources of revenue.

Pfizer's hope to replace Lipitor with a next-generation drug was dashed in December, when the company halted studies on the experimental compound torcetrapib because of safety concerns. That failure increased the pressure on Pfizer to expand its overtures to innovative biomedical companies.

For example, Goodman said, Pfizer will pursue projects in a technology called RNA interference or RNAi, which blocks messenger molecules inside the cell that can foster disease. Pfizer will be elbowing its way in among other large drug companies that have invested in RNAi, including Merck, Novartis and Roche. "We will be a leader there," Goodman said.

Among Goodman's many responsibilities is building ties between Pfizer and the community of venture capitalists and university scientists in and outside of California. He's switching from UC Berkeley's faculty to UCSF's because the medical school's research is more closely related to the development of new treatments.

Kindler also made Goodman a member of Pfizer's Executive Leadership Team, so he'll be flying to New York frequently. As if that weren't enough to keep him busy, Goodman and his wife are expanding a sheep ranch and artisanal cheese-making operation in Marin County overlooking Tomales Bay. On weekends, he said, he can sometimes be found vaccinating sheep.

Pfizer is not a latecomer to biotech alliances, but several other drug companies have moved faster. Swiss pharmaceutical company Roche was one of the most successful, said MPM Capital general partner Luke Evnin. Roche acquired a majority stake in Genentech Inc. of South San Francisco in 1990, and Roche's revenues have swelled under a deal that gives it marketing rights to Genentech's blockbuster cancer drugs outside the United States. Evnin said Roche also draws praise for allowing Genentech to maintain its independence and entrepreneurial culture.

Pfizer's Kindler gave Goodman a measure of independence in the company hierarchy. Goodman reports directly to Kindler, rather than to the company's new head of global research and development, Martin Mackay. That could have set up an uncomfortable rivalry, Goodman said, with the research chief controlling the bioinnovation center's access to Pfizer's resources. But Goodman said Mackay has been an enthusiastic supporter of the arrangement.

Pfizer did not provide one of its executives for an interview.

While Pfizer's biotech initiatives boost its chances of bolstering revenue, they hold no guarantee. Pfizer already has suffered failures from such outside investments, including the abandonment in October of Exubera, an inhaled form of insulin. Pfizer had paid $1.4 billion in 2006 to acquire manufacturing facilities and worldwide rights to Exubera, which originated in a collaboration with Nektar Therapeutics of San Carlos.

In its drive to develop revenue sources, Pfizer is competing for deals in the risky biotech arena not only against other large drug companies but against savvy large biotech companies such as Genentech. The industry is facing drug price pressure from health insurance plans, and the Food and Drug Administration is taking a harder look at drugs submitted for approval.

Goodman is optimistic. He sees not only great potential in biotech deals, but also a reservoir of talented people in Pfizer's research establishment who are eager to explore new strategies.

"I'm sure there are going to be critics or cynics who say you can't take a major pharmaceutical company and make it more entrepreneurial," he said. "I think we can unleash a lot of that entrepreneurial spirit within Pfizer. It's a question of the culture I build."

Pfizer's vulnerable drugs
Half a dozen of Pfizer's blockbuster drugs have either recently gone off-patent or soon will

Drug Use Patent expires
Zithromax Bacterial infections 2005
Zoloft Depression 2006
Norvasc High blood pressure 2007
Zyrtec Allergies 2007
Camptosar Colon cancer 2008
Lipitor Cholesterol control 2011

Source: Pfizer 2006 financial report; Pfizer product Web sites

[Preciouslife1]

Cryo-Cell Launches C'elle, First-Ever Proprietary Menstrual Stem Cell Service

Women's Health Weekly - Nov. 15, 2007


Cryo-Cell International Inc. (BULLETIN BOARD: CCEL) ("Cryo-Cell" or the "Company"), one of the largest and most established family cord blood banks, announced its discovery of breakthrough stem cell technology and its launch of the world's first-ever service provided for women to store their own menstrual stem cells. The new service, called C'elle(SM) (pronounced "C-L"), enables women to collect menstrual flow containing stem cells, which can be cryogenically preserved in a manner similar to stem cells from umbilical cord blood and may one day serve as a potential source for promising regenerative therapies to treat heart disease, diabetes, neurological disorders like spinal cord injury, Parkinson's and Alzheimer's diseases, in addition to cosmeceutical applications such as anti-aging therapies, to name a few.
However, realistically, it may take several years for these menstrual stem cells to be developed into potential widely-available commercial therapies.
The C'elle service is based on Cryo-Cell's intellectual property, for which patent applications are pending, related to the procurement, processing, isolation and cryo-preservation of these unique menstrual stem cells (see also Cord Blood).

The unique C'elle service is being offered following Cryo-Cell's discovery of new scientific evidence that menstrual flow, which results from the shedding of the uterine lining (endometrium) during menstruation, contains millions of stem cells that have many properties and characteristics similar to those of both bone marrow and embryonic stem cells. Dr. Amit N. Patel, Director of Cardiac Stem Cell Therapies at the McGowan Institute, University of Pittsburgh Medical Center, along with other independent research laboratories, studied these menstrual stem cells, which have demonstrated the capability in vitro to differentiate into neural, cardiac, bone, cartilage, and adipose cells, and possibly other cell types. Dr. Patel's preliminary findings were presented on October 21, 2007 at TCT 2007, the annual scientific symposia of Transcatheter Cardiovascular Therapeutics, in a seminar entitled "Novel Cell Sources for Myocyte Repair and Replacement."

"This is the first discovery of such a multipotent, highly prolific and readily accessible source of stem cells -- even one menstrual cycle has the potential to produce millions of stem cells," said Dr. Stephen Noga, Director, Medical Oncology/Hematology, Alvin & Lois Lapidus Cancer Institute, and Director, Cellular Therapeutics Program, Sinai Hospital of Baltimore. "Stem cells isolated from menstrual blood may show significant promise for future use in clinical regenerative medical therapies. This brings us one step closer to tissue and organ regenerative approaches. They are adult stem cells, but they share some of the same features of embryonic stem cells in their ability to multiply rapidly and differentiate into other cell types of the body. Current research is very preliminary, but given their properties, we believe these menstrual stem cells demonstrate compelling promise to transform regenerative medicine in the coming years."

Dr. Gerald Elfenbein, a Professor of Medicine at Boston University, former director of the Cancer Center and Blood and Marrow Transplant Program at Roger Williams Medical Center, Providence, R.I., and former division chair of the Blood and Marrow Transplant Program at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla. believes the impact to the research and medical communities is significant. "I've been in the stem cell transplant world for more than three decades, and this finding follows in a long tradition of bench-to-bedside research," he said. "This discovery has the potential to offer significant benefit to the research community by accelerating the pace of study, and I look forward to seeing the possible clinical results we can achieve in the future."

The use of these unique menstrual stem cells in pre-clinical studies for human cardiovascular, diabetes and neurodegenerative regenerative therapies is under evaluation. Preliminary research related to the immunological profile of these unique menstrual stem cells suggests that in addition to the donor, these stem cells may also potentially be used to benefit other family members who are genetically related to the donor, such as perhaps a parent, sibling or child.

"Cryo-Cell's discovery of these unique menstrual stem cells and the processes associated with their procurement, processing, isolation and cryo-preservation, is an extraordinary milestone for the Company," stated Mercedes Walton, Cryo-Cell's Chairman and CEO. "We are very excited that our revolutionary new service, C'elle, based on the Company's proprietary technology, is now available to the public.
Over the past year, Cryo-Cell has made significant progress in the study of these unique menstrual stem cells and commercialization of related processing services.
The Company is pleased to collaborate with world-class researchers from many different fields of medicine to explore possible utilization of these stem cells in the development of potential breakthrough therapies that may possibly benefit millions of people in the future. In the months ahead, we eagerly anticipate emerging developments related to the Company's novel technology and innovative proprietary service."

Beginning today, the C'elle service is exclusively available from Cryo-Cell and may be used by any woman who menstruates. It is currently estimated, however, that over 100 million women in the U.S. alone experience menstrual cycles. The Company believes that the C'elle service offers women no matter what their age, with the unique opportunity to preserve "Your Monthly Miracle(SM)" while they are in good health and have access to this distinctive source of stem cells. With global advancements in stem cell research and development, the C'elle service offers a unique family healthcare asset that may potentially increase in value over time as breakthrough regenerative stem cell therapies emerge in the future. Detailed information about the C'elle service is available at www.celle.com.

[Preciouslife1]

Gene's Role In Type 1 Diabetes Discovered

http://www.sciencedaily.com/releases/2007/11/071107100917.htm

Researchers at the University of Virginia Health System have identified an enzyme thought to be an important instigator of the inner-body conflict that causes Type 1 diabetes. A chronic condition that affects nearly three million American children and adults, Type 1 diabetes is more severe than Type 2. Type 1 diabetes, also called autoimmune diabetes, arises when the body's infection-fighting white blood cells start destroying the beta-cells that produce insulin in the pancreas.

To shed light on how this conflict begins, UVa researchers focused on a single gene, 12/15-lipoxygenase (12/15-LO). This gene leads to the production of the enzyme, which appears to have an important role in the activation of white blood cells in the pancreas.

Researchers developed non-obese diabetic female mice to serve as a model of Type 1 diabetes. After turning off the 12/15-LO gene in study mice, they discovered that these mice without the enzyme were 97 percent less likely to develop diabetes than mice that had normal levels of it, according to the study, published online in the journal Diabetes (to be published in print in February 2008).

"This research is exciting because it advances our knowledge of a new gene that is involved in causing Type 1 diabetes and could pave the way for new treatments to prevent or reverse this increasingly prevalent disease," said Dr. Jerry L. Nadler, who is chief of the UVa Division of Endocrinology and me.tabolism.

UVa researchers also discovered that study mice that did not have the 12/15-LO gene and remained non-diabetic demonstrated better glucose tolerance than non-diabetic NOD mice that were matched for age. (Worse glucose tolerance is an indication of having a pre-diabetes condition). The same group of study mice also had improved beta cell mass and less severe insulitis than their non-diabetic NOD counterparts.

Insulitis is a change in the islet cells that includes a high-fluid volume and too many white blood cells. While white blood cells normally help to fight off infections, they can cause damage over time when they infiltrate the islet cells of the pancreas.

"Our findings have two practical implications," said co-author Marcia McDuffie, professor of Microbiology at UVa. "First, they help us to understand the complicated process that produces self-destructive white blood cells. This knowledge may be useful in predicting which children may be at risk for developing Type 1 diabetes before significant damage has occurred in the islets. Second, we may be able to design drugs targeting this enzyme that may help to prevent Type 1 diabetes in people at risk for the disease and also to prevent recurrence of disease in transplanted islets."

Type 1 diabetes requires insulin injections, because the body cannot produce insulin on its own.