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I wish I could come home after picking up the kids from school and have time to cook a nice meal. I long for a calm, zen-like cooking experience each day, but instead I find myself chasing after my sons who prefer to run amok, trying to keep them from raiding the refrigerator and the pantry even though I fed them a snack as soon as we got home. We had to put locks on to keep the Three Amigos from eating us out of house and home. Yesterday's meal was supposed to happen on Monday, but the events of the day and the constant distractions left me disorganized and frustrated at dinner time and I pulled out some leftover pasta sauce and boiled some spaghetti. Now there's nothing wrong with that, and in fact spaghetti with tomato sauce and/or meatballs is Michael's favorite meal, but I had a grilling recipe up my sleeve for Cinco de Mayo which I had to grudgingly postpone.
I thought I could start some of the prep for dinner on Tuesday morning, but Monday night we remembered Top Gun, our three-year-old, had a project due for school the next day and I needed to finish some prep work on that before we could do it in the morning. So Tuesday morning was spent cutting photos and pasting them memory-book style onto a piece of paper describing his favorite things, and then we wrote our story about Spike's visit (Spike is the class mascot, a stuffed kangaroo) and pasted more pictures onto that story.
After dropping the boys off at school I did a little dance in my head thinking our toddler would go down for his afternoon nap and I could do all my prep work, but that was optimistic on my part. For the second day in a row he refused to take a nap and I ended up with a cranky toddler for the afternoon. I hope he doesn't give up naps early like his oldest brother!
Michael was late getting off work and the boys demanded my total attention for the rest of the day, so I finally tossed a burger and some dogs on the grill for them and saved the fish tacos for a quiet dinner just for the two of us after we got the Three Amigos to bed! We grilled in the dark, talking about our day and the refrigerator that isn't working and debated whether to repair or replace. Mundane conversation, perhaps, but relaxing nonetheless, and it was time we had to ourselves. Michael said he loved the tacos and the salsa, and the cold beer with a lime wedge tasted pretty good after a busy day.
P.S. Don't forget about the Grilled Pizzas & Piadinas cookbook give away! Visit the original post to enter. The deadline is Sunday May 11 at 6 pm EST.
Serves 4.
grill wok or skillet (Thanks for the Christmas present, Mom & Dad!), coated with cooking spray
medium bowl or a one gallon plastic zip bag
3 medium serving bowls
liquid measuring cup
3 mahi mahi fillets, cut into chunks
1/2 teaspoon chili powder
1/2 teaspoon cumin
1/4 teaspoon cayenne pepper
1/4 teaspoon fresh ground black pepper
1/4 teaspoon sea salt
2 cups red cabbage, sliced thin
5 or 6 green onions, sliced thin
1/4 cup light sour cream
1/4 cup apple cider vinegar
1/2 teaspoon sea salt
1 mango, cut into small chunks
1 avocado, cut into small chunks
1 jalapeño, finely diced
1 red onion, finely diced
3 tablespoons finely chopped cilantro
2 limes, juiced
tortillas, corn or flour
1 red pepper, sliced thin
Monterrey jack cheese, shredded
1. Preheat the grill.
2. FISH: Stir together the spices and toss with the fish in the bowl or the zipper bag. Set aside.
3. SLAW: In the serving bowl, toss together the sliced cabbage and onions. Measure the cider vinegar in the measuring cup and add the sour cream and salt. Stir until thoroughly mixed, then pour over the cabbage and onions, and stir until the vegetables are evenly coated.
4. SALSA: In the serving bowl, toss together the mango, avocado, jalapeño, onion, and cilantro. Squeeze the limes over the bowl and stir gently.
5. GRILL: Pour the spiced fish into the lightly greased grill skillet/wok and cook over medium heat for about 5 to 7 minutes, stirring occasionally for even cooking. Fish should be slightly firm and opaque when finished.
6. SERVE: Layer your tacos in this order: Slaw, red peppers, fish, salsa, cheese. Enjoy with a cold Corona and lime.
More Recipes with Mango
[An original post from Andrea Meyers: making life delicious. All images and text copyrighted, All Rights Reserved.]
[Disclosure: This blog earns a few cents on items purchased through the Amazon.com links in posts.]


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Optional deep chair cushion with self-welt detail is covered in fade- and mildew-resistant Sunbrella acrylic in neutral stone.
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subset: commoncrawl


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Just called to book 2 nights: this Sun/Mon before we head back home to all the snow. We had stayed at POR for the first part of our trip & then staying offsite now. Really wanted to get back to the magic . But the CM said that not only was POR not available but they have zero avail at ANY resort!! Wow. Never in a million years would i have thought Disney would be at full capacity
This is the beginning of "President's Week". Some schools are off this week/some next week. I would go over to the resort and see if there isn't something available. Additionally, it is Valentine's week. Very busy time (and expensive) in the World.
They are probably offering rooms to anyone who has to fly back to the North East and can't because of the Blizzard. That plus President's week is probably putting everything at capacity, but I would call again or book through the website or secondary source.
It is totally wild to think that all of Disney is filled! Wow! Who would have ever thought that it was possible? I would LOVE to have the income from all of those rooms! I would also love to BE THERE right now!
I would have walked to the front desk to ask about extending my stay. You'd have a better chance that way.
I know it's President's Week, plus everyone here is off for Mardi Gras and everyone I know is there for that. I guess the blizzard could be playing into it also I'll be there later this week and I hope the crowds will have died down some.
There is a huge cheerleading competition going on this week at all stars as well as a big tax convention at the grand and who knows what else. It wouldn't surprise me if there wasn't availability with others extending because of snow and everything else.
Just read on another thread, how many rooms were taken up by people extending their stay because of the storm.
Presidents week is next week but many people will start arriving later this week. Expect good size crowds from Thurs all the way through next week.
check dvc resorts also...they have many rooms and some of the cheaper/less popular ones might have openings (OKW/SSR).
They have their own transportation. I should have added that I would drive to POR, then walk to the front desk.


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Best Burger in NYC?
- 15 Comments
- Follow
Hi there! we have a group of about 8 people getting together for a bday party and we want a divey FUN place with burgers and beer in East Village area. Any ideas?
Royale perhaps
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Here is a huge list of everyone's favorite burgers. They're not sorted by neighborhood but it'll give you some ideas.
Royale is on there, along with the Stoned Crow which is in Greenwich Village.
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pauls would also be a good place for a tasty burger and beer as well as mcsorley's.
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The best burger in the East Village area is @ Stand (12th & University.) Not really divey though.
If you're willing to head over to Alphabet City, I think you'll love Royale. Great burgers. Awesome beer menu. Sounds more of what you're looking for.
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Molly's, though it's further north and depending on when you get there 8 may be difficult.
re: zbs
For 8 people in a pub atmosphere with awesome burgers Royale on 10th ad C is the best choice. One of the top 2 burgers in the city (IMO) and plenty of room for a party of 8. There is a back yard that is heated as well.
re: princeofpork
Second that for all those reason and the freshest burger toppings as well.
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re: princeofpork
I finally tried Royale after all the good reviews here and can't say I was blown away. The bun was probably the best part. The fries were alright, but appeared to have been cut in half into tiny pieces. I can't see going back with all the other amazing burgers out there. Also in regards to price, if you order fries it comes to $9 which is standard. No special bargain as some have reported.
re: sugartoof
$9 with fries is still a lot better than the $18 I paid at JG Melon the other night (before tip) for a cheeseburger (no fries) and two beers. The beers at Melon come in small mugs, not pints.
It's a great burger and it's convenient to where I live, but every time I go there I feel like I've been bent over.
re: TipsyMcStagger
No doubt there are some ridiculously priced burgers (though you did get a midtown beer with yours).... the standard price for the best burgers in the city hover around $7-$12, right?
The $6 price at Royale being mentioned on this forum is just a burger, no fries, and you would have to order the extra fries or onion rings to fill up on it. Why do people get excited about the price of a bare burger anyway?
I just didn't think it compared a lot of other options in it's price range (and I'm not talking about the shake shack take out places). It's just not worth a special trip to Ave. C
re: zbs
We did 8 at the round table just by the fireplace at Molly's two weeks ago.
Such a good burger!


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One-toed amphiuma (Amphiuma pholeter)
Kingdom | Animalia |
Phylum | Chordata |
Class | Amphibia |
Order | Caudata |
Family | Amphiumidae |
Genus | Amphiuma (1) |
The one-toed amphiuma is classified as Near Threatened (NT) on the IUCN Red List (1).
Information on the one-toed amphiuma (Amphiuma pholeter) is currently being researched and written and will appear here shortly.
This information is awaiting authentication by a species expert, and will be updated as soon as possible. If you are able to help please contact:
IUCN Red List (January, 2011)


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Ever wonder what exactly the road crews are working on? We'll be featuring new traffic projects each week in this slideshow.
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Advances in molecular biology are gradually revealing the biological processes underlying the individual predisposition to breast cancer, its early development, and its progression from benign to invasive to lethal. As our understanding of cancer biology grows, so does the potential to turn that knowledge into technologies that are not limited to screening, prognosis, monitoring, or even treatment, but which inform every aspect of patient care. The three areas of biologically based technologies discussed in this chapter—cancer biomarkers, molecular profiles, and molecular imaging—hold the promise of revolutionizing breast cancer detection and management.
Instead of competing with mammography, biologically based technologies for breast cancer detection are currently poised to serve as its adjuncts. Molecular biomarkers or profiles of breast cancer will need to be linked with imaging information to define tumor size and location. Among the most important recent insights into breast cancer biology is the recognition that cancer can arise through various sequences of events, and through the actions of many genes with small but additive effects.35 While some researchers are seeking these genes (or their products) one by one, investigating the most promising candidates as potential biomarkers for breast cancer, others are examining overall patterns of gene expression associated with breast cancer risk or prognosis. Whatever the method of discovery, however, the final result is likely to reflect a highly individual molecular profile, characterized by both tumor and patient heterogeneity.
A major goal of these efforts is the development of blood tests to detect specific types of cancer. It is important to recognize, however, that the value
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Biologically Based Technologies
Advances in molecular biology are gradually revealing the biological processes underlying the individual predisposition to breast cancer, its early development, and its progression from benign to invasive to lethal. As our understanding of cancer biology grows, so does the potential to turn that knowledge into technologies that are not limited to screening, prognosis, monitoring, or even treatment, but which inform every aspect of patient care. The three areas of biologically based technologies discussed in this chapter—cancer biomarkers, molecular profiles, and molecular imaging—hold the promise of revolutionizing breast cancer detection and management.
Instead of competing with mammography, biologically based technologies for breast cancer detection are currently poised to serve as its adjuncts. Molecular biomarkers or profiles of breast cancer will need to be linked with imaging information to define tumor size and location. Among the most important recent insights into breast cancer biology is the recognition that cancer can arise through various sequences of events, and through the actions of many genes with small but additive effects.35 While some researchers are seeking these genes (or their products) one by one, investigating the most promising candidates as potential biomarkers for breast cancer, others are examining overall patterns of gene expression associated with breast cancer risk or prognosis. Whatever the method of discovery, however, the final result is likely to reflect a highly individual molecular profile, characterized by both tumor and patient heterogeneity.
A major goal of these efforts is the development of blood tests to detect specific types of cancer. It is important to recognize, however, that the value
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of such a test depends on existing options. For example, the development of a test for ovarian cancer, even one that is not highly accurate, could save many lives because there is no existing technique to detect early stage ovarian cancer. In contrast, a comparable test for breast cancer would be unlikely to save lives unless it is more sensitive or specific than mammography and gave localization information or was paired with mammography.
Recent headlines to the contrary, it will be many years—if ever—before blood tests replace mammograms. The most obvious reason is that a blood test would measure biomarkers (usually proteins) that have been released from cancerous tissue into the general blood circulation, which means they are highly diluted in the midst of a multitude of other proteins, and are a long way from their source. A blood test would have to be able to measure trace quantities of any biomarkers and, at best, a blood test would indicate that cancer was present somewhere in the body, but not where—unless the biomarkers were found only in breast tissue, which puts yet another restriction on possible tests. For example, a problem could arise if it was so sensitive that only a few cancer cells would result in a positive test. The cancer could not be physically located with current imaging technology within the breast and thus true positives could not be distinguished from false positives.
No existing blood test—for breast or any other cancer—rivals mammography as a screening method. Mammography has an acceptable sensitivity, and despite its modest specificity, it locates the tumor for definitive biopsy. Furthermore, mammograms provide richer data than would be possible from a low-dimensional biochemical assay that measures only one or a few substances; improvements described in Chapter 3 have the potential to increase the information available from mammography.
Many different biologically based approaches to detecting breast cancer are in development, but they face many of the same challenges if they are to become truly useful for improving outcomes for breast cancer patients. Certain themes recur throughout this chapter in the discussions of the different types of biologically based cancer detection technologies:
Biological methods may prove to be advantageous for screening high-risk populations, but are not likely to replace mammography.
Nonimaging biological techniques must be linked to imaging methods that can localize the cancer.
Statistical methods necessary for definitive analysis of large genomic and proteomic data sets are not yet defined or standardized.
Assays to detect cancer must account for the variability that exists among tumor types and among patients in order to be effective for widespread use.
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New technologies should be developed in conjunction with experts in the current best practices for breast cancer detection and diagnosis.
Novel diagnostic approaches need to be validated in large-scale clinical studies.
Broadly defined, a biomarker is an objectively measurable characteristic that can be evaluated as an indicator of normal biological processes, disease, or response to therapeutic intervention.15,65 The search for biomarkers of breast cancer should not be confused with the search for inherited, or germ-line, mutations that affect the likelihood of developing breast cancer. Although the discovery of such mutations is important to assess breast cancer risk and may, ultimately, lead to the identification of the causes of breast cancer, the presence of such mutations does not indicate or predict the presence of breast cancer in an individual.
Biomarkers are being sought—and some have been identified—across a wide spectrum of events in the development of breast cancer, as shown in Table 5-1. The clinical use of breast cancer biomarkers is currently limited largely to prognosis, predicting response to therapy, and monitoring patients with diagnosed malignancy, but biomarkers hold considerable potential for risk assessment, screening, diagnosis, and the identification of therapeutic targets.11,18,38,44,55,58,65 Fulfilling that potential will not be easy. There are considerable biological and technical challenges to both the discovery and development of assays to detect early events in cancer development.18,44,55
The search for cancer biomarkers is proceeding along parallel paths: the "hypothesis-driven" assessment of candidate genes or proteins and the "discovery-based" comparison of gene expression and proteomic profiles.55,58 The potential uses and limitations of bioassays based on individual biomarkers for breast cancer are reviewed in this chapter. Molecular profiles of breast cancer, as revealed by DNA microarrays and proteomic analysis, are also discussed later in this chapter.
Biomarker Assays May Complement Mammography
Research on cancer detection has long been inspired by the search for a single, specific biomarker: a molecule or compound produced at such high levels by newly malignant or premalignant cells that it could be detected in an easily obtained fluid or tissue sample. This ideal marker would appear in all patients with a specific type of cancer and be absent or below a definable threshold in individuals without the disease. Its concentration in the sampled
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TABLE 5-1 Biomarkers of Events in the Development of Breast Cancer: Their Potential Uses and Limitations
Potential Use for Biomarkers
Progress to Date
Key Limitations
Germ-line mutations27
Risk indicator
Several mutations identified; genetic testing available for BRCA1 and BRCA2
Account for only 10 percent of breast cancers
Genetic polymorphisms27,44
Risk indicator
Some candidate polymorphisms identified; thousands of single nucleotide polymorphisms (SNPs) have been mapped
Validation difficult due to genetic diversity among different ethnic populations and the need to measure cumulative effects of multiple SNPs
Somatic genetic alterations27
Risk indicator; screening; diagnosis; prognosis
Loss of heterozygosity (LOH) at several loci associated with premalignant disease, as well as early and late-stage breast cancer
Unknown which, if any, LOH events are specific to invasive or metastatic cancer
Epigenetic changes (e.g., methylation) in breast cells 14,57,67
Risk indicator; screening; diagnosis; prognosis; therapeutic target
Research correlating methylation patterns at key loci with breast cancer presence and stage
Validation will require large-scale longitudinal studies and comprehensive cancer registry data
Altered gene expression in breast cells18,25,36,67
Screening; diagnosis; prognosis; choosing therapy; monitoring outcome
Studies under way on several overexpressed and underexpressed genes in breast tumor tissue; estrogen receptor status predicts response to antiestrogen therapy
Validation will require large-scale longitudinal studies and comprehensive cancer registry data
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Changes in protein signaling pathways in breast cells36
Screening; diagnosis; prognosis; choosing therapy; monitoring outcome
Clinical trials underway in breast cancer patients before, during, and after therapy
Population heterogeneity reduces sensitivity and complicates standardization; sampling involves microdissection
Changes in individual serum markers18
Screening; diagnosis; prognosis; monitoring outcome
Preliminary findings indicate prognostic benefits of monitoring a mucin, CA 15-3, which has received FDA approval for the detection of recurrent breast cancer
Typically lack sensitivity for early malignancy and organ specificity; not elevated in all patients
Changes in serum protein/peptide profile36
Secondary screening; diagnosis; prognosis; choosing therapy; monitoring outcome
Research under way to improve ovarian cancer diagnosis
Low sensitivity and specificity; population heterogeneity
Risk indicator, prognosis, choosing therapy
Research on several angiogenesis-related receptors being conducted to develop a possible treatment
Validation will require large-scale longitudinal studies. Main focus is currently on developing therapeutics
Invasion and metastasis18,25,36,67
Candidate proteases and inhibitors have been identified; prognostic benefit of urokinase plasminogen activator for node-negative breast cancer confirmed in large prospective randomized trial
Lack of effective therapy for metastatic breast cancer
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The CA 15-3 protein is a member of the family of proteins known as mucins, whose normal function is cell protection and lubrication. It plays a role in reducing cell adhesion and is found throughout the body. Elevated levels in breast cancer tissue may be involved in metastasis. CA 15-3 levels can also be elevated in patients with other cancers (lung, colorectal, ovarian, pancreatic) or because of hepatitis or cirrhosis of the liver.
fluid would increase or decrease as the cancer progresses or regresses and could be determined by a simple, reliable, inexpensive assay.
Individual biomarkers currently in clinical and experimental use fall far short of this ideal, however. (See Table 5-1 for a summary of potential issues and limitations of biomarkers for specific events in the development of breast cancer.) Most are synthesized by normal as well as malignant tissues and are only rarely elevated in premalignant or early stage disease. For example, in cancerous breast tissue high levels of the protein CA 15-3 are produced, but usually not until the cancer has reached an advanced stage (Box 5-1).18 Few of the biomarkers in use today are found among all patients with a particular type of cancer, and with the exception of prostate specific antigen, none are organ-specific.18
Absent an ideal biomarker, it is likely that any biomarker-based assay used as a primary screen for breast cancer in normal-risk populations will produce significant numbers of false positives. However, biomarker-based screening may prove to be a practical means of screening women at high risk for breast cancer for premalignant disease and/or occult cancer. Such an assay could detect clusters of proliferating cells at a preclinical stage, as well as cell clusters that may never require treatment. With the discovery of additional or better markers, bioassays may eventually be developed that not only detect the presence of breast cancer or precancer, but also predict clinical course.
As with mammographic screens, the performance of a biomarker assay should increase as additional time points are taken, particularly if the marker(s) reflect disease burden. This is true of existing biomarker assays for prostate, ovarian, and colon cancer. Therefore, although it may be unreasonable to expect that a single assay measurement can replace mammographic screening, multiple measurements taken over time that show a consistent rise in value could be indicative of an enlarging mass. This type of algorithm is likely to be the first implementation for biomarkers in breast cancer screening.
Biomarker assays could also be used to aid the decision-making process
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for biopsy following a suspicious mammogram, if the bioassay reduced the number of false positives (increased specificity) without sacrificing sensitivity. Reliance on such an assay in cases of questionable mammographic results (for example, BI-RADS® 3-4) would be prudent only if the positive predictive value of the assay is extremely high, particularly when the result is to forgo biopsy. This is especially critical in the United States, where biopsy is the current standard of care for virtually every suspicious lesion. Bioassays may also be performed on the sample of suspicious cells obtained at biopsy in order to inform treatment decisions, but such tests will not supplant pathological examination of the biopsied tissue sample for the primary diagnosis.
As long as biomarkers continue to have low sensitivity and specificity, their use in primary diagnosis will be limited, and histological examination of biopsied tissue will remain the gold standard. But even then, biomarkers are likely to be useful as adjunct to other procedures, including:
Differential diagnosis or prognosis, such as distinguishing among types of ductal carcinoma in situ;
Assistance in the choice of therapy and evaluation of its outcome; or
Monitoring patients with ongoing disease before or after therapy.
Results of preliminary studies suggest that pre-operative serum levels of CA 15-3 are as good, if not better, predictors of patient outcome than traditional measures such as tumor size and nodal status.18 Tissue levels of estrogen and progesterone receptors and the erbB2 receptor, as determined by immunohistochemical analysis, are considered in the selection of therapy.18,42 CA 15-3, approved in 1997 by the Food and Drug Administration (FDA) for the detection of recurrent breast cancer, may also prove useful in monitoring response to therapy for metastatic breast cancer.18
Roadblocks to Biomarker Discovery and Development
The path to biomarker-based assays for breast cancer, and particularly for the early detection of the disease, is far from smooth. The considerable challenge of identifying highly sensitive and specific screens that rival the effectiveness of mammography is made more difficult by biological heterogeneity among humans, as well as among cancers, and even among different cell populations within a single tumor.55 A successful bioassay for breast cancer will need to overcome variability associated with cancers of different histologic types, expression patterns within histologic types, additional (noncancerous) patient conditions, and intrinsic human biochemistry. For now, as noted by Kenneth Pritzker, "our conceptual framework of
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cancer biology remains inadequate to recognize the ideal or optimal biomarker for most cancers."55
Guiding principles for the validation of promising biomarkers have been developed by the National Cancer Institute's (NCI's) Early Detection Research Network (Box 5-2). Shown in Table 5-2, these principles define a process for selecting biomarkers with sufficient positive predictive value that they can be used for population screening.44 Navigating this process will require extensive and unprecedented collaboration among industry,
Early Detection Research Network
The NCI's Early Detection Research Network (EDRN) was founded in 2000 to facilitate biomarker discovery and validation through the collaboration among government, academia, and industry. The EDRN was established to set standards for the development and evaluation of biomarkers and guide the process of biomarker discovery in an effort to produce a useful population-screening tool.
The goals of the EDRN include:
Development and testing of promising biomarkers or technologies
Evaluation of promising, analytically proven biomarkers or technologies
Collaboration among academic and industrial leaders in molecular biology, molecular genetics, clinical oncology, computer science, public health, and clinical application for early cancer detection
Collaboration and rapid dissemination of information among awardees
The research network consists of three components:
Biomarker Discovery Laboratories are responsible for the development and characterization of new biomarkers or the refinement of existing biomarkers. There are currently 18 facilities involved in this research.
Biomarker Validation Laboratories serve as a network resource for clinical and laboratory validation of biomarkers, which includes technological development, quality control, refinement, and high throughput. The EDRN includes three validation facilities.
Clinical Epidemiological Centers conduct clinical and epidemiological research regarding the clinical application of biomarkers. There are nine facilities responsible for this research.
A fourth component, the Data Management and Coordinating Center located at the Fred Hutchinson Cancer Research Center, is responsible for coordinating the EDRN research activities in order to develop a common database for network research.
For more information see: http://www3.cancer.gov/prevention/cbrg/edrn/.
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TABLE 5-2 Guiding Principles Used in Biomarker Validation44
Phase 1: Preclinical exploratory
Promising directions identified
Phase 2: Clinical assay and validation
Clinical assay detects established disease
Phase 3: Retrospective longitudinal
Biomarker detects preclinical disease and a "screen positive" rule defined
Phase 4: Prospective screening
Extent and characteristics of disease detected by the test and the false referral rate are identified
Phase 5: Cancer control
Impact of screening on reducing burden of disease on population is quantified
NOTE: The phases of research are ordered according to the strength of evidence that each phase provides in favor of the biomarker, from the weakest to the strongest. In general the results of earlier phases are necessary to design later phases. In some cases, where discovery of the biomarker establishes the method of detection, such as surface-enhanced laser desorption, then Phase I is skipped.
academia, and government, each of which controls resources essential to the development of clinically significant biomarkers.44,66 New legislation may be needed to provide incentives for cooperation between the pharmaceutical industry, which has identified hundreds to thousands of potential biomarkers for early cancer detection, and medical schools and research institutes possessing tissue banks, cell lines, and other reagents necessary to test these candidates.44 Increased effort is being made to sample tissues with precancerous and early stage disease due to their crucial role in testing biomarkers for cancer screening; such specimens are currently underrepresented in tissue banks.42
Once a promising biomarker is identified, researchers must address the technical challenges of developing a viable assay. The procurement, handling, and storage of fluid or tissue sample warrants careful consideration, because minor differences in these procedures may introduce systematic but unknown biases. However, it will be difficult to specify precise parameters for handling samples until the effects of inconsistencies on a given bioassay can be determined.
Further progress toward biomarker-based screening will require large-scale, longitudinal studies to evaluate the ability of a given screen to reduce cancer deaths and/or increase survival. Existing cancer registry data are woefully inadequate for this purpose, but more extensive information gathering may be hampered by the Health Insurance Portability and Account-
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ability Act (HIPAA) and other legislation to protect patient confidentiality. (For more about HIPAA, see Chapter 6.) There is also a need to define statistical and inferential criteria for the evaluation of biomarker candidates for cancer screening, so that their efficacy can be measured against competing technologies.65 This comparison will ultimately hinge on the ability of the candidate technologies to reduce cancer mortality through the early detection of treatable disease.
If serum markers are shown to have promise in breast cancer studies such as these, the concept that a blood test can actually reduce cancer mortality should ultimately be evaluated in a randomized trial with cancer mortality as the endpoint, as was required in the pioneering studies of radiologic screening using mammography. Such a study would require resources similar to the mammography trials, namely tens of thousands of participants and lengthy follow-up. Methodologic issues in evaluating breast cancer screening tests are further discussed in Chapter 6.
Until the early 1990s, the search for cancer biomarkers proceeded through the one-by-one investigation of candidate genes and proteins. The advent of high-throughput techniques capable of screening thousands of genes and, more recently, proteins, has made possible broad comparisons of cancerous and normal cells, revealing new biomarker candidates and introducing the possibility that patterns of gene expression or protein profiles could themselves serve as cancer biomarkers.51,58,69 DNA microarrays, consisting of thousands of DNA oligonucleotides (short sequences of DNA) or cDNAs (complete gene sequences of DNA reverse-transcribed from RNA templates) spotted in fixed locations are used to screen samples via hybridization (joining of two complementary strands of nucleic acid). Various applications of this technique can identify cancer-related changes in gene activity and reveal qualitative and quantitative variations in genomic DNA that occur during tumor formation.
Additional high-throughput methods focus on cancer-induced changes in protein pathways and populations, both within the tumor cell and at the tumor-host interface.37,51 These techniques scan the proteome—the protein equivalent of the genome—of affected cells and tissues for cancer biomarkers. Protein microarrays, which are an analogous technology to DNA microarrays, enable researchers to screen many proteins simultaneously for function and amplification.69 Serum proteomic profiling, the analysis of disease-related changes in proteins circulating in the blood, reveals patterns that may ultimately be used to detect cancer, identify therapeutic targets, and monitor response to therapy.51
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Expression Profiles of Breast Cancer
The disruption of cell growth and survival pathways that lead to cancer occurs through multiple, cumulative genetic and epigenetic changes that in turn alter gene expression.2 While all breast tumors reflect changes common to malignant tissue, such as disordered cell cycle control, apoptosis (programmed cell death), adhesion and motility, and angiogenesis (new blood vessel formation), each tumor presents a unique pattern of gene expression (reviewed by Chung and colleagues in 2002).13 By classifying tumors according to their expression profiles, as revealed by microarrays, researchers hope to create a taxonomy that will improve prognosis and better predict each patient's response to available therapies.13,28
Expression microarrays can analyze gene expression levels in a single sample or compare the expression of thousands of genes between two different cell types or tissue samples, such as malignant and normal breast tissues. Although the technology is still in its infancy, expression-based classifications for many types of tumors, including breast cancers, have already been developed through microarray analysis.1,13,81 For example, researchers identified five distinct subtypes of breast tumors derived largely from patients with infiltrating ductal carcinoma.49,63 This approach to detecting tumor classes based on a priori similarities in expression signature is known as "unsupervised" analysis.
A contrasting approach, "supervised analysis," directly examines the relationship between gene expression profiles and a clinically determined variable, such as breast cancer prognosis. Van't Veer and colleagues determined expression patterns of 98 primary breast tumors from lymph node-negative patients less than 55 years of age using oligonucleotide microarrays of 25,000 genes.74 Based on the clinical outcome of these patients, the researchers identified a set of 70 genes with expression patterns that closely predicted patient prognosis. A poor prognosis was associated with increased expression of genes associated with cell cycle control, invasion, angiogenesis, and signal transduction. A subsequent study tested the 70-gene prognosis profile in microarrays from 295 patients under age 53 with primary breast cancers with and without lymph node involvement. In this group of patients, the prognosis profile outperformed other standard criteria—including age, tumor size and histology, and the involvement of axillary lymph nodes—in predicting outcome.73 The next step should be to conduct studies in larger and more representative groups of breast cancer patients to determine whether these encouraging initial results prove to be reliable in clinical practice.30 However, despite the lack of evidence from true prospective clinical trials, versions of this test (Oncotype DX) are already on the market in the United States and The Netherlands. The test became available in the United States in early 2004 without having been approved by the
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range of isotopes, is currently used in functional imaging.42 PET is more adaptable to molecular imaging, however, because the positron-emitting isotopes it employs are more easily incorporated into probes than the gamma-emitting isotopes visualized by SPECT.41
"It is clear that the first gene imaging to obtain FDA approval will be with PET, because the imaging probes are used in such low amounts that they will not produce pharmacologic or physiologic effects," according to Michael Phelps, chair of molecular and medical pharmacology at the University of California at Lost Angeles.9 PET imaging probes are also relatively easy to construct, because drugs or existing molecules known to interact with a specific target can be modified with a radiolabel with minimal perturbation.41 But even if a PET-based molecular imaging technology gains clinical approval in the near future, it is not likely to be widely adopted without the introduction of less-expensive PET scanners with better resolution and sensitivity.12
Another development likely to boost the clinical value of molecular imaging with PET is the advent of "multimodality" imaging systems combining PET scans—which do not clearly reveal the anatomy of regions of probe uptake—with high-resolution x-ray computed tomography (CT) imaging.12 PET/CT scanners are already in clinical use for functional imaging.12,41,71 Work is also under way to develop combined PET and MRI; however, although MRI provides better soft-tissue contrast than CT, it will be more technically challenging to integrate with PET. Researchers are exploring additional combinations of optical, radiological, MRI, and CT techniques capable of producing truly multimodal images.6,29,41
Functional MRI was introduced as an imaging technique in the 1970s, but was not widely used to detect breast cancer until the late 1990s.19 Although orders of magnitude less sensitive than PET or optical techniques, molecular resonance has attracted the attention of molecular imaging researchers because of its higher spatial resolution and simultaneous depiction of molecular and anatomical information.9,41 Antibody- and protein-based MRI probes have been used to visualize cell-surface molecules including cancer antigens and a protein associated with apoptosis.23,31,41,59,83 Novel cancer therapies containing gadolinium, a paramagnetic species commonly used in magnetic resonance applications, could be tracked with MRI to image tumors and monitor their uptake of the labeled drugs over the course of treatment.19 Activatable MRI agents for visualizing intracellular processes are possible, but only if the large target-binding molecules used in current probes can be replaced by smaller ones or made penetrable to cell membranes.9 This constraint, for example,
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challenges work in progress on an MRI-based reporter system employing the intracellular enzyme beta-galactosidase.53
Optical Imaging
Optical imaging will be widely adopted because its capabilities exceed those of other imaging technologies, according to Ralph Weissleder, director of the Center for Molecular Imaging Research at Massachusetts General Hospital.9 By identifying cancer-related alterations in gene expression, optical imaging will permit early diagnosis, "perhaps before morphological or clinical signs of disease can be seen," he says. Yet, as abnormalities are detected earlier, confirming the presence of cancer for a definitive diagnosis will become more difficult. Optical technology presents the possibility of using multiple probes, each with a distinct spectrum, to monitor several events or molecular species simultaneously.41,77 Promising optical techniques for molecular imaging feature targeted bioluminescent probes, near-infrared (IR) fluorochromes (including activatable probes), and red-shifted fluorescent proteins.41,80
Bioluminescent probes emit light that is essentially free of background, and are therefore attractive because they can be detected at very low concentrations.41 However, viable technology has yet to be developed for bioluminescent imaging in the human body, and this strategy would still require injecting mass levels of substrates, such as D-Luciferin, into the body.41 Fluorescent probes have higher background, but offer two advantages: they can be used as reporters in both live and fixed tissues, and they can often be visualized without the addition of a substrate.64
Fluorescent probes that emit in the near IR have maximal tissue penetration and minimal background fluorescence.41 An activatable near-IR probe has been used in vivo to monitor activity of cathepsin D, an extracellular protease that is overexpressed in many tumors.41,53,68 Fluorescence-mediated tomography, an approach that is still in its infancy, is being developed to penetrate further than is possible with existing near-IR methods.41,46,47 Multimodality probes that are capable of fluorescence and bioluminescence are also under active investigation.
Multidisciplinary Research Is Key to Bringing Molecular Imaging to the Clinic
A review article by Massoud and Gambhir (2003) identifies the following goals for molecular imaging, leading from the research laboratory to the clinic:
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To develop noninvasive in vivo imaging methods that reflect specific cellular and molecular processes, such as gene expression and protein-protein interactions
To monitor multiple molecular events in concert
To follow trafficking and targeting of cells
To optimize drug and gene therapy
To image drug effects at the molecular and cellular level
To assess the molecular pathology of disease progression
Meeting these goals and translating that achievement into rapid, reproducible and quantitative clinical technologies will be a critical step toward the molecular management of cancer.
Many basic questions remain to be answered in the course of developing and refining molecular imaging technologies. Overcoming the theoretical and practical challenges of biocompatibility, barriers to probe delivery, and signal amplification will require continued research.40,41 Investigators are concentrating their efforts on selecting appropriate cellular and subcellular imaging targets, probing the development and delivery, amplification strategies for targets at nanomolar to picomolar concentrations, and the development of high-resolution, real-time imaging systems that can ultimately be used in humans.41,77,80
If the potential of molecular imaging is fulfilled, imaging will influence all aspects of cancer care, from diagnosis to treatment evaluation, and will play an increased role in the development of new molecular therapies. Researchers are already looking beyond the previously described imaging technologies to the design of molecular biosensors that can be injected into the bloodstream to find and destroy cancer cells. Advances such as these can only be achieved through collaborative, multidisciplinary research that brings together molecular and cellular biologists, imaging scientists, nanotechnologists, and cancer clinicians. Consequently, a key online resource, Molecular Imaging Central, has been created to provide links among the various areas of research in molecular imaging, background information on different types molecular imaging, as well as highlighting the latest research findings. Supporting agencies for such research include the NCI, which funds a variety of molecular imaging initiatives (see Box 5-4). Bridging these disparate fields is perhaps the greatest challenge to the development of molecular imaging, but one which, if met, could establish a new research paradigm for the advancement of molecular medicine.
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National Cancer Institute Support for Molecular Imaging Research43
The following NCI initiatives foster advances in functional and molecular imaging:
In Vivo Cellular and Molecular Imaging Centers: Bring together experts from diverse scientific and technological backgrounds to conduct multidisciplinary research on cellular and molecular imaging in cancer. Five Centers established as of 2002; support provided for 14 potential sites, including a site for researching functional imaging of low-activity genes.
Novel Imaging Technologies Program: Supports collaboration of academic scientists with industry and foreign institutes to create unique imaging technology, including the next generation of PET/CT scanner for improved localization and evaluation of difficult-to-locate cancers and therapeutic monitoring.
Clinical Imaging Drugs and Enhancers Program: Fosters the development of new imaging contrast agents and molecular probes to improve cancer diagnosis and treatment. Several agents or probes currently in development for measuring blood vessel formation and cell death, evaluating cell growth, and enhancing visualization of various cancers.
Molecular Imaging Database (MOLI): A publicly available imaging database intended to help researchers develop new imaging agents and to help clinicians find existing agents for imaging specific cancers. The database is expected to be released in mid-2004.
Clinical Trial Cooperative Groups: Networks of healthcare professionals affiliated with medical schools, teaching hospitals, and community-based cancer treatment centers who encourage movement of promising imaging advances from discovery and development to clinical use (e.g., American College of Radiology Imaging Network).
Cancer Therapy Evaluation Program: Exploring the use of imaging as a biomarker or surrogate marker for cancer, instead of biopsy, to monitor treatment effectiveness.
Mouse Models of Human Cancer Consortium: Includes researchers who are developing novel imaging modalities for use in preclinical studies.
Small Animal Imaging Resource Program: Resource to allow scientists from different disciplines to use small animal imaging technology, including molecular imaging.
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Innovative in vitro diagnostics, such as tests for genetic susceptibility to various diseases, pose a new spectrum of regulatory challenges. These include overcoming both the inexperience of the FDA with such cutting-edge technology and the inexperience of the budding companies that are developing it, as well as narrowing down the complex genetic data being generated, and providing uniformity in analysis and testing.
The FDA is currently in a learning mode about genomics and proteomics. These methods use patterns in the activation of specific genes or production of specific proteins to help determine the diagnosis, prognosis, or risk of developing various diseases. New products from these endeavors have emerged in significant numbers only in the past decade.
In the past 3 years, the agency has had about 50 presentations about this technology from industry, academia, or the government. The FDA's in vitro diagnostics office has an internal "Omics" working group that has met periodically over the last 3 years to discuss new developments in the field and to interact with their counterparts in the FDA's Center for Drug Evaluation and Research, and the agency released a guidance document for pharmacogenetics and pharmacogenomics in November 2003.
Hundreds or thousands of results are generated by genomic and proteomic tests for each specimen as opposed to one result per sample in the conventional diagnostic tests that the FDA is used to seeing. Regulation of these array tests will be much easier if manufacturers of genomic or proteomic tests can reduce the amount of data required for a given diagnostic determination. Regulatory submissions for such diagnostics include imprecise measurements of every analyte and a lack of standardization in the analysis approach. These technologies are so new that clear standards have not yet emerged, which means that the FDA must not only conduct its usual evaluation for adherence to established methodological and analytic standards, but it must evaluate the validity of new methods as they are evolving.
The biological revolution in breast cancer detection and management is under way, but it is likely to proceed slowly and by degrees. Significant progress has been made toward the identification of key breast cancer biomarkers, as well as aggregate profiles of breast cancer in the genome, transcriptome, and proteome; the theoretical promise of molecular imaging is beginning to be realized in animal models. When molecular medicine for breast cancer first enters the clinic, it will most likely come in the form of techniques to monitor therapeutic response and recurrence. The use of
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molecular screening technologies, such as blood tests for routine screening of normal-risk, symptom-free women, likely lies in the more distant future. Measures of recurrence or response to therapy are intrinsically easier to develop than screening tests, because each woman can serve as her own reference point for changes that can be measured over days or months. In contrast, a screening test needs to provide interpretable results based on a single time point.
Even further in the future, researchers envision individualized management of each case of breast cancer, based on its specific molecular characteristics. "We'll have a roadmap, a wiring diagram of the deranged cellular circuitry of each patient's cancer, not just a named diagnosis, but a molecular profile," according to Lance Liotta of the NCI. "Instead of choosing therapy by a category of disease, we'll use combination therapy tailored to the individual molecular profile of the tissue, the tumor microenvironment, and the cancer. Instead of single targets and single therapeutic agents, we'll have multiple targets all along the length of key signal transduction pathways, both intracellular and extracellular, at the tumor-host interface. And finally, instead of determining efficacy by waiting for a change in tumor size or recurrence, we'll have direct monitoring of cellular targets before, during, and after therapy by biopsy—or ideally by molecular imaging or serum proteomics—to monitor changes that are going on in the tissue microenvironment following treatment." However, the nonimaging biological techniques must be linked to additional procedures that can localize the cancer and examine its pathology. In addition, the problem of a test being too sensitive—detecting cancer before it could be physically located with current imaging technology—could be traumatic for patients. True positives would thus be indistinguishable from false positives and create a high level of anxiety among women with a positive test.
Fulfilling the potential of molecular medicine for breast and other cancers will require collaboration between molecular biologists and scientists from a broad spectrum of disciplines. It will fall to epidemiologists and biostatisticians to guide the rational design of biologically based cancer diagnostics, to establish their significance and reproducibility, and, in the case of clinical epidemiologists, to adapt them for routine clinical use.56 Ultimately, they will have to develop standardized statistical methods for analysis of large genomic and proteomic data sets. Once these new biologically based detection and diagnostic tools have been developed, they will need to be tested for safety and effectiveness beyond the research setting in multicenter clinical trials. Yet, a lack of regulatory standards for the validation of novel diagnostic tests may hinder clinical trials by making them more difficult to design and the results more challenging to interpret. Finally, these tools will not be used in isolation but will become part of an arsenal of tools—each with distinctive capacities and caveats. Developing
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evidence-based systems for integrating this new technology will require attention at all levels of the health care system—physicians, payers, purchasers, and patients.
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83. Zhao M, Beauregard DA, Loizou L, Davletov B, Brindle KM. 2001. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med 7(11):1241-1244.


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BrightonandHoveJobs.com are currently Sussex's naming rights partner for The BrightonandHoveJobs.com County Ground.
BrightonandHoveJobs.com has rapidly become the local hub for all of the city's best jobs and employment challenges.
Representing the city of Brighton & Hove and all of its commutable areas, BrightonandHoveJobs.com has been created to become the city's one stop shop for all local job opportunities, employment, volunteering and training information.
Sussex cruised to an eight-wicket win over Northamptonshire at Arundel to consolidate their place at the top of Group C in the Clydesdale Bank 40. ..
read more »Sussex Sharks will finally get back into Clydesdale Bank 40 action today when they face Northamptonshire Steelbacks at Arundel Castle (1.45pm star..
read more »


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Twenty years later, we still mourn, still remember and still wonder what could have been.
On July 27, 1993, just as he was entering the prime of his career, former Celtics forward Reggie Lewis was taken away far too soon. On a warm afternoon, he went to shoot some hoops with a friend on a court at Brandeis University. About an hour in, suddenly, he collapsed, struggling to breathe and gasping for air. Revival efforts were unsuccessful, and he was later pronounced dead. He was only 27 years old.
Lewis had the world at his fingertips. Only six seasons into his NBA career, he had already made a name for himself, amassing just short of 8,000 points. He became the first — and to this day, only — player in Celtics history to record 100 rebounds, assists, steals and blocks in a single season. He was named Celtics captain the season after Larry Bird retired and he was named an All-Star in 1992. All things considered, he was supposed to be the one to usher the Celtics into a new era of greatness.
The initial shock of his untimely death eventually subsided, but the pain still remains for many. Lewis proved so much during his six-year career in Boston, yet had so much more to accomplish. His No. 35 will live on forever in the Garden rafters, a testament to his undeniable talent, but just another reminder of what could have been.
Click the link below to read through a timeline of Lewis' career.
Photo via Twitter/@berry_34
© 2015 New England Sports Network. All Rights Reserved. All photos © 2015 Associated Press and NBA photos © 2015 Getty Images unless indicated. Any commercial use or distribution without the express written consent of Associated Press is strictly prohibited.
All sports statistics © 2015 STATS LLC unless indicated. Any commercial use or distribution without the express written consent of STATS LLC is strictly prohibited.
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You get all dressed up and then this happens...
If you think the red carpet is just a place to strut your stuff, the jokes on you! See what happens when pranksters take to the carpet.
Ciara arrives at Valentino Fashion Show during Paris Fashion Week when none other than red carpet prankster Vitalii Sediuk surprised her!
Photo: Getty Images
Photo: FameFlyNet
Photo: Splash News
Photo: YouTube
Photo: TMZ
Welcome Baby Princess!
40 Beautiful Photos of Enrique Iglesias
Kentucky Derby Chic


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Why does America care about Egypt so much?
America and Egypt seems like an odd couple but they are forever inextricably linked. (photo for illustrative purposes only)
Top Ten Ways Egypt Actually Does deeply Matter to the United States
There more reasons than just the Suez canal that America wants to stay in cahoots with whatever powers may be in control of Egypt.
Source: Informed Comment
Lebanese national basketball team suspended for four years
Annahar just posted a few minutes ago that the FIBA has suspended the Lebanese national team from participating in international tournaments for four years!
Wasn't basketball the only somehow successful sport in this country?
Wasn't basketball the only somehow successful sport in this country?
Source: Plus 961
Oil spills from stricken tanker off Mukalla coast
For the last eight days or so, a stricken, 600 tonne old oil tanker has been leaking crude oil and several slicks were visible along the Mukalla and other parts of Hadhramout coast.
Source: Out of Hadhramout
Saudi Arabia: Gender Segregation
A picture speaks a thousand words and this shot of a cafe in Saudi speaks ten thousand.
Source: Susie's Big Adventure
Well hear me well, yes Beirut is a gay haven for me, I'm living my life superbly, it gave me freedom, Beirut gave freedom to all its seekers.
Source: The Angry Tinkerbell


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Bu-lat-lat (boo-lat-lat) verb: to search, probe, investigate, inquire; to unearth facts
Vol. VI, No. 34 Oct.1 - 7, 2006 Quezon City, Philippines
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Melo Commission a 'Whitewash,' Victims' Kin Say
BY BULATLAT Posted 7:40 p.m., Oct. 2, 2006
Families of victims of political killings and abductions called the investigation by the Melo Commission a "whitewash" meant to clear the Armed Forces of the Philippines (AFP) and the Arroyo administration of culpability in the human rights abuses.
Evangeline Hernandez, spokesperson of Hustisya (Justice), said, "The Commission's mandate is like a marshmallow – sweet on the outside but empty. It will never give us justice."
Hernandez is the mother of Benjaline Hernandez, Southern Mindanao deputy secretary-general of Karapatan (Alliance for the Advancement of People's Rights) who was slain in Davao in 2002 by soldiers and paramilitia.
Erlinda Cadapan, mother of abducted University of the Philippines (UP) student Sherlyn Cadapan, said the Melo Commission preferred to hear the side of the perpetrators, who merely denied having anything to do with the killings and abductions.
Cadapan said the victims' families were "armed" with evidence and witnesses but the commission has yet to get their side.
At an Oct. 2 press conference in Quezon City, convenors of Hustisya put their thumbs down in front of a "gravestone" bearing the number of victims of political killings and abductions, which was being painted white by an activist masked as President Gloria Macapagal-Arroyo in military jacket.
Hernandez said they would participate in the commission's investigation on the condition that the standards set by the Amnesty International (AI) were followed. In a memorandum to Arroyo, AI set standards for an independent investigation, which include having a victim-centered investigation, and the expansion of the commission members.
Jocelyn Javier, spokesperson of Mothers and Relatives Against Tyranny (Martyr), was also present at the press conference. Her husband Armando Javier, Jr. was killed in their home in Cuyapo town, Nueva Ecija province a year ago.
Javier said a year after her husband was killed, she has yet to get justice, and is herself being pursued by military men.
Karapatan public information officer Ruth Cervantes said the Melo Commission sent her group an invitation only on its fourth hearing. Cervantes said the commission asked Karapatan to "convince" the victims' families to participate in the investigation.
"Mahirap naming gawin iyan dahil nakikita namin na patungong whitewash ang nangyayari" (That is hard for us to do because we see that the developments are headed toward a whitewash), she said.
Cadapan said that the commission could show its sincerity by observing the hearings at the Court of Appeals for the petition for habeas corpus of nine victims of forced disappearances.
"Nasa seventh hearing na kami. Kung sana dumalo doon ang mga miyembro ng Melo Commission, at doon mismo makita nila ang pagsisinungaling ng mga military" (We are now on the seventh hearing. We wish the members of the Melo Commission would attend the hearing and see for themselves how the military lies), she said. Bulatlat
© 2006 Bulatlat ■ Alipato Media Center
Permission is granted to reprint or redistribute this article, provided its author/s and Bulatlat are properly credited and notified.


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