Friday, April 13, 2012
Epigenetics does not mean that thinking makes it so : Respectful Insolence
Epigenetics does not mean that thinking makes it so : Respectful Insolence
".....The not-so-subtle implication is that the reason one gets sick is because of one's habits. Of course, there are a lot of lifestyle diseases, but the implications goes beyond the sensible, science-based observation that obesity and lack of exercise increase the risk of certain diseases, into the realm of stating that if you just eat the right foods and do the right exercises you'll never get sick.
Utter nonsense, of course.
There's also a dark side to this sort of thinking, and that's the flip side of the argument. If you can nearly completely control the state of your health by what you eat and do, the not-so-subtle implication is that if you get sick it must be your fault. After all, if we have complete control over our health through our lifestyle, then it follows that if you're sick, you must be doing something wrong....."
"The latest way that quacks are trying to push the idea that you have near total control over your health is by abusing new findings in epigenetics. Epigenetics is the study of heritable changes in gene expression or phenotype that are not caused by changes in the underlying gene sequence........ It's a fascinating area of research, because it suggests that gene expression can be altered longer than transiently by environmental influences. Of course, given that organisms and biology are affected by environmental influences, this is almost a trivial observation; the power of epigenetics is that it can explain how such changes in gene expression can come about.....
Ginkgo May Sensitize Ovarian Cancer Cells to Cisplatin: Antiproliferative and Apoptosis-Inducing Effects of Ginkgolide B on Ovarian Cancer Cells
Ginkgo May Sensitize Ovarian Cancer Cells to Cisplatin: Antiproliferative and Apoptosis-Inducing Effects of Ginkgolide B on Ovarian Cancer Cells:
Ginkgolide B (GB), the primary active component of Ginkgo biloba extracts, may have antitumor properties. The objective of this study was to determine the effects and possible mechanisms of GB in ovarian cancer cells. In this study, human ovarian cancer cell lines (SKOV3 and CAOV3) were treated with different concentrations of GB alone or in combination with Cis-diaminodichloroplatinum (CDDP). .......Furthermore, GB had significantly less cytotoxicity than CDDP in normal human ovarian surface epithelial cells. This study suggests that GB can be proposed as an effective antiproliferative and apoptosis-inducing agent with interesting translational application in ovarian cancers, used in addition to conventional chemotherapy.
The transcription factor FOXL2: At the crossroads of ovarian physiology and pathology
The transcription factor FOXL2: At the crossroads of ovarian physiology and pathology: Publication year: 2012
Source:Molecular and Cellular Endocrinology
FOXL2 is a gene encoding a forkhead transcription factor. Its mutations or misregulation have been shown to cause the blepharophimosis–ptosis–epicanthus inversus (BPES) syndrome and more recently have been associated with the development of Ovarian Granulosa Cell Tumors (OGCT). BPES is a genetic disorder involving mild craniofacial abnormalities often associated with premature ovarian failure. OGCTs are endocrine malignancies, accounting for 2–5% of ovarian cancers, the treatment of which is still challenging.
In this review we summarize recent data concerning FOXL2 transcriptional targets and molecular partners, its post-translational modifications, its mutations and its involvement in newly discovered pathophysiological processes. In the ovary, FOXL2 is involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and cell proliferation. Interestingly, one of the main roles of FOXL2 is also to preserve the identity of ovarian granulosa cells even at the adult stage and to prevent their transdifferentiation into Sertoli-like cells. All these recent advances indicate that FOXL2 is central to ovarian development and maintenance. The elucidation of the impact of FOXL2 germinal and somatic mutations will allow a better understanding of the pathogenesis of BPES and of OGCTs.
Foundation for Women’s Cancer Announces 2011-2012 Research Grant Awardees - Press Release - Digital Journal
Foundation for Women’s Cancer Announces 2011-2012 Research Grant Awardees - Press Release - Digital Journal
Florence and Marshall Schwid Ovarian Cancer Research Grant: Petar Jelinic, PhD, Sloan Kettering Institute for Cancer Research
open access: Editorial: Molecular Scores to Predict Ovarian Cancer Outcomes: A Worthy Goal, but Not Ready for Prime Time
Molecular Scores to Predict Ovarian Cancer Outcomes: A Worthy Goal, but Not Ready for Prime Time
"... The premature application of inadequately validated biomarkers may adversely impact the successful implementation of individualized therapies."
open access: A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy (serous)
A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy
Patient Samples
We extracted clinical data for 511 patients with serous ovarian cystadenocarcinoma from The Cancer Genome Atlas (TCGA) database (44) website (http://tcga-data.nci.nih.gov) on February 17, 2011, representing the largest available dataset of epithelial ovarian cancer gene expression profiles (see Supplementary Table 2, available online, for further details on which ovarian cancer samples were included in this study). These were all the patients for whom full sets of tumor gene expression data were available for download.....Table 1
Clinicopathologic characteristics of ovarian cancer patients in The Cancer Genome Atlas (TCGA) dataset*
Table 2
Table 2
Genes in platinum-specific DNA repair pathways that were used to construct the score*
(For each gene, “high” means higher than median gene expression was
associated with improved overall survival in The Cancer
Genome Atlas dataset, and “low” means higher
than median gene expression was associated with worse overall survival
~~~~~~~~~~~~~~
CONTEXT AND CAVEATS
Prior knowledge
At present, there are no
effective prognostic tools for prediction of response in ovarian cancer
patients, a majority of whom
are diagnosed with an advanced stage
(stages III and IV) and undergo surgical debulking followed by and
platinum-based chemotherapy.
Study design
Gene expression data was
extracted from The Cancer Genome Atlas (TCGA) database for patients with
advanced ovarian cancer,
and a molecular score was developed by
focusing exclusively on the genes involved in platinum-induced DNA
damage repair pathways.
Patients were divided into low (0–10) and
high (11–20) scores, and the prognostic value of the score for overall
survival,
recurrence-free survival, and
progression-free survival was assessed. Data were validated in two
independent datasets.
Contribution
Patients with high scores showed
statistically significant associations with improved overall survival
compared with patients
with low scores. The score was predictive
of overall survival, recurrence-free survival, and progression-free
survival in
ovarian cancer patients who received
first-line platinum-based chemotherapy.
Implication
This score has the potential to become an important prognostic tool to determine whether advanced-stage ovarian cancer patients
will benefit from first-line platinum-based chemotherapy.
Limitation
The score has not been tested prospectively in a clinical trial.
20 Great Challenges (of health and medicine): Votes are in! | TEDMED Blog
20 Great Challenges: Votes are in! | TEDMED Blog
20 Great Challenges: Votes are in!
The Top 20 Great Challenges:
#22. Inventing Wellness Programs
#34. The Caregiver Crisis
#19. The Role of the Patient
#2. The Obesity Crisis
#1. Achieving Medical Innovation
#8. Managing Chronic Diseases
#18. Medical Communication
#26. Reducing Childhood Obesity
#3. Making Prevention Popular
#9. End-of-life Care
#51. Causes of Sleep Deprivation
#15. Impact of Poverty on Health
#12. Faster Adoption of Best Practices
#32. Impact of Stress
#4. Future of Personalized Medicine
#33. Promoting Active Lifestyles
#10. Preparing for Dementia
#16. Addressing Healthcare Costs
#39. Whole-Patient Care
#23. Eliminating Medical ErrorsThroughout the year, the Great Challenges Program will generate a lively national dialog on the 20 Challenges chosen by the TEDMED community. The program will include TV-style interviews with leaders across fields, a series of webinars on each of the 20 Great Challenges, and the opportunity for TEDMED community members to add their voice.
Thursday, April 12, 2012
abstract: Validating the Impact of a Molecular Subtype in Ovarian Cancer on Outcomes – A Study of the OVCAD Consortium - Pils - Cancer Science - Wiley Online Library
Validating the Impact of a Molecular Subtype in Ovarian Cancer on Outcomes – A Study of the OVCAD Consortium - Pils - Cancer Science -
Abstract
The
majority of patients with epithelial ovarian cancer (EOC) is diagnosed
at advanced stage and has a poor prognosis. A small proportion of these
patients though will survive while others die very quickly.
Clinicopathological factors do not allow precise identification of these
subgroups. Thus we have validated a molecular subclassification as new
prognostic factor in EOC.
One hundred
ninety-four patients with stage II to IV EOC were characterized by
whole-genome expression profiling of tumor tissues and classified using a
published 112 gene-set, derived from a FIGO stage directed supervised
classification approach.
The 194 tumor
samples were classified into two subclasses of 95 (subclass 1) and 99
(subclass 2) tumors, grouping all 9 FIGO II tumors in subclass 1
(p=0.001). Subclass 2 (54% of advanced stage tumors) correlated
significantly with peritoneal carcinomatosis and non-optimal debulking.
Patients with subclass 2 tumors had a worse overall survival in both
histological subtypes both, univariate (HRs 3.17 (serous) and 17.11
(non-serous), p≤0.001) and in models corrected for relevant
clinicopathologic parameters (HRs 2.87 (serous) and 12.42 (non-serous),
p≤0.023). Significance analysis of microarrays revealed 2,082 genes
differentially expressed in advanced grade serous tumors of both
subclasses and the focal adhesion pathway as the most deregulated
pathway.
In this validation study we
showed that in advanced-stage serous ovarian cancer two approximately
equally large molecular subtypes exist, independent from classical
clinocopathological parameters presenting with highly different whole
genome expression profiles and an impressively different overall
survival. Similar results were obtained in a small cohort of patients
with non-serous tumors.
Does Estrogen-Only HRT Decrease Breast Cancer Risk? Nationally Recognized Endocrinologist Dr. Marina Johnson Weighs In
Does Estrogen-Only HRT Decrease Breast Cancer Risk? Nationally Recognized Endocrinologist Dr. Marina Johnson Weighs In
"....So here's Dr. Johnson's take-home message: "You don't need to delay starting HRT if you choose natural estradiol and progesterone over synthetic estrogens and progestins. Don't endure symptoms like hot flashes, insomnia, anxiety, depression, sexual dysfunction, mental confusion, and weight gain. Start HRT within 10 years of menopause for the most protection against Heart Disease, Alzheimer's and Osteoporosis.
"Avoid the increased heart attacks and strokes seen in WHI by choosing topical estrogen in the form of patches, gels, creams and mists that are available at any drug store. Pharmaceutical natural hormones (also called bioidentical hormones) are superior to compounded bioidentical hormones because they are required to meet higher standards for quality control and efficacy."
Read more in Dr. Johnson's book, "Outliving Your Ovaries: An Endocrinologist Weighs The Risks And Rewards Of Treating Menopause With Hormone Replacement Therapy" (http://www.outlivingyourovaries.com) (Eyesong Publishing, February 2011), which is available in paperback, e-book and can be shipped internationally. Use coupon code BZCWJDM5 for $5 off of the retail price with purchase at http://www.buydrmarinajohnsonbook.com.
Dr. Marina Johnson, a pharmacist and UCLA/USC-trained physician, is board-certified in Endocrinology and Internal Medicine.
Current Drug Shortages: Etoposide solution for injection (updated)
Current Drug Shortages: Etoposide solution for injection (updated):
Bedford Laboratories has 100mg/5ml available in limited quantities. Once this supply is depleted, the next estimated release dates are unknown. All other presentations are out os stock and the company cannot estimate a release date. Production is pending as capacity permits. Availability of products is updated on the Bedford Laboratories website. Etoposide Injection 20 mg/mL; 5 mL; 53776 vials in stock; approximately 45000 vials will be in warehouse by the 3rd week of this month.
CMAJ: Young women with breast cancer genes face tough choices (8th part of a series in genetic testing - see links)
CMAJ: Young women with breast cancer genes face tough choices
Editor’s note: Eighth of a multipart series on genetic testing.
Part 1: Separating hype from reality in the era of the affordable genome (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4143).
Part 2: Popping the genetics bubble (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4142).
Part 3: Who should hold the keys to your DNA? (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4141).
Part 4: A race-based detour to personalized medicine (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4133).
Part 5: Race and genetics in the doctor’s office (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4134).
Part 6: Predisposed to risk but not change (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4157).
Part 7: Unhealthy behaviours influenced by genes and environment (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4162).
abstract: Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases.
Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases.:
J Med Genet. 2012 Apr 6;
Abstract
Background
Alterations in telomere maintenance mechanisms leading to short telomeres underlie different genetic disorders of ageing and cancer predisposition syndromes. It is known that short telomeres and subsequent genomic instability contribute to malignant transformation, and it is therefore likely that people with shorter telomeres are at higher risk for different types of cancer. Recently, the authors demonstrated that the genes BRCA1 and BRCA2 are modifiers of telomere length (TL) in familial breast cancer. The present study analysed TL in peripheral blood leucocytes of hereditary and sporadic ovarian cancer cases, as well as in female controls, to evaluate whether TL contributes to ovarian cancer risk.
Methods
TL was measured by quantitative PCR in 178 sporadic and 168 hereditary ovarian cases (46 BRCA1, 12 BRCA2, and 110 BRCAX) and compared to TL in 267 controls.
Results
Both sporadic and hereditary cases showed significantly shorter age adjusted TLs than controls. Unconditional logistic regression analysis revealed an association between TL and ovarian cancer risk with a significant interaction with age (p<0.001). Risk was higher in younger women and progressively decreased with age, with the highest OR observed in women under 30 years of age.
Conclusion
These findings indicate that TL could be a risk factor for early onset ovarian cancer.
abstract: Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer
Assumptions of Expected Benefits in Randomized Phase III Trials Evaluating Systemic Treatments for Cancer
Background In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (δ) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably δ approximates the observed benefit (B) in RCTs that evaluated cancer treatment.
Conclusions Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of δ. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem.
Stem Cell Network Blog: 35 reasons to like stem cells - images and art/voting open on FB "Cells I See"
Blogger's Note: the FB art/images are fabulous - take a look/vote if you wish
Stem Cell Network Blog: 35 reasons to like stem cells
April 12, 2012
35 reasons to like stem cells
by Lisa Willemse
2010 Cells I See winner: The Beauty of Pluripotency by Kamal Garcha
We were content to keep it this way, until we realized that we were, in essence, hiding some of the most incredible stem cell images we've ever seen. Prompted by interest from the Ontario Science Centre, we installed a small exhibit in their museum and the response was incredible. Most people had no idea what stem cells looked like and were amazed at their beauty and complexity. The overriding message was that people are interested not just in the science of stem cells, but in stem cell images and art.
In response, Cells I See has gone social -- we've opened up the 2012 voting to the world. Anyone with a Facebook profile can participate by "liking" any of the 35 entries in this year's contest. Of course, we invite you to share it with your friends and colleagues as well -- the images are breathtaking, displaying a range of cell types, colours and patterns.
But don't take my word for it, go see them for yourself.
abstract: Preoperative assessment of peritoneal carcinomatosis: intraindividual comparison of 18F-FDG PET/CT and MRI
Preoperative assessment of peritoneal carcinomatosis: intraindividual comparison of 18F-FDG PET/CT and MRI:
Conclusion
With high diagnostic accuracy for PC of both, MRI and PET/CT, PET/CT provides better diagnostic accuracy and especially better
NPV.
open access: A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome - study of 19 BRCA carriers
A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome
".....ShaRIT strives to ease the “burden of the messenger” and decrease the possibility of mis-communicating and misinterpreting
important medical information to their relatives."
Wednesday, April 11, 2012
Current Drug Shortages: Ondansetron Injection 2 mg/mL (updated) discontinued manufacturing
Current Drug Shortages: Ondansetron Injection 2 mg/mL (updated):
Apotex has discontinued the manufacturing of Ondansetron Injection.
Medscape: Oncologists Are Not Health Economists, Suggests Survey (U.S. & Canadian physician survey)
Oncologists Are Not Health Economists, Suggests Survey
"Interestingly, responses to the clinical scenario did not significantly differ between American and Canadian oncologist."
Faults seen in cancer study funding | Reuters
Faults seen in cancer study funding | Reuters
NEW YORK |
(Reuters
Health) - It's well-known that clinical trials of cancer treatments
often can't cover their costs. But a new study suggests that
government-funded trials could take at least one cue from those backed
by drug companies.In 2010, the Institute of Medicine (IOM) released a report saying that the U.S. system for conducting cancer clinical trials was approaching a "state of crisis" (see Reuters story of April 10, 2010).
The IOM -- an expert panel with federal support -- said the National Cancer Institute's Clinical Trials Cooperative Group program was inefficient, bogged down by red tape and underfunded.
The NCI program includes a number of collaborative groups -- academic cancer centers, researchers and community doctors that work together to conduct trials on cancer treatment. Altogether, the program involves more than 3,100 institutions in the U.S., Canada and Europe.
In the new study, researchers at one Canadian cancer center focused specifically on the timing of cancer clinical trial funding.
With cooperative group trials, funding typically comes as a "modest payment up front" for each patient enrolled, explained lead researcher Dr. Hsien-Yeang Seow of McMaster University and the Juravinski Cancer Center in Hamilton, Ontario.
Trials done by the drug industry, on the other hand, dole out money over time, as patients hit certain "milestones" -- like during treatment, and as they come back for follow-up visits after treatment ends.
Seow's
team looked at 97 clinical trials done at its center in recent years.
Two-thirds of those studies were cooperative group trials, including
some with NCI funding, while the rest were industry-sponsored.
Those included early- and late-stage trials of treatments for cancers including breast, lung and stomach cancer.
The
researchers found that the cooperative group trials quickly began to
lose money after the initial stages because the funds were all spent
early on. That leaves nothing for study patients' follow-up, which can
last for years.
The industry trials, in contrast, had more money going in than out at multiple time points -- though any net income typically disappeared during longer term follow-up.
What's more, Seow's team found, its center had fallen into a pattern of starting new clinical trials in order to pay for patients' follow-up in the older, ongoing trials.
Seow likened it to a "Ponzi scheme" -- albeit an unintentional and legal variant.
"In order to stay afloat," Seow explained in an interview, "we have to start new trials and recruit new patients."
The money from that new-patient accrual then goes to "pay down the deficit" of earlier trials. "Obviously, that's not sustainable," Seow said.
One way to help with the larger issue of sustaining cooperative group trials could be to switch from "up front" payment, according to Seow.
The author of an editorial published with the study in the Journal of Clinical Oncology agrees. "Perhaps it is time to consider more closely following the pharmaceutical industry model of progress payments," writes Dr. David M. Dilts, of the Knight Cancer Institute in Portland, Oregon.
That, he adds, could help stop the "robbing Peter to pay Paul" habit of using new trials to fund old ones.
FUNDING GAP
An alternative for individual cancer centers would be to take part in fewer and fewer cooperative group trials, and more industry-funded ones.
A recent survey of centers in the NCI cooperative program suggested that is happening: one-third said they were going to limit their participation in NCI-funded trials in the future.
But non-industry trials are vital, Seow pointed out. Drug company studies may bring us the "next blockbuster drug," he noted, but the cooperative group trials help answer the bigger questions of how to improve cancer patients' overall care.
This new analysis, Seow said, looks at just one aspect of the larger, complicated issue.
The 2010 report from the IOM recommended an overhaul of the NCI cooperative group program. Many of its suggestions focused on efficiency: the process of simply designing a trial, for example, is lengthy and cumbersome -- taking an average of two years to complete.
It also called for more funding. The NCI's payment-per-patient has not changed in a decade, standing at about $2,000. But the actual cost is thought to be closer to $6,000, Dilts points out in his editorial.
The NCI has said it plans to boost that reimbursement to $4,000, at least to "high performance" centers that enroll a large number of patients in clinical trials.
In an email to Reuters Health, a spokesperson for the organization said it recognizes the need for more funding going to individual study sites.
But centers may still end up spending the money up front, Dilts notes -- especially with today's trend of doing expensive genetic testing of patients. That's done because researchers are increasingly trying to develop treatments that are "personalized" to patients' genetic makeup.
So there still may be no money left over for years of patient follow-up.
Another option, Seow said, is to finally close some of the long-running "mega-trials" that are no longer generating useful information.
But the wider problem will ultimately need multiple solutions, according to Seow.
"There have been remarkable breakthroughs in cancer therapies," he said. "But there's a state of crisis in clinical trials right now, and there are many reasons for it."
SOURCE: bit.ly/GSkEGD Journal of Clinical Oncology, online March 26, 2012.
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