Google's Transparency Report has sometimes supplied an unsettling level of detail as to what companies and governments want to know. Americans won't feel much more comfortable now that Google has added the FBI's National Security Letters to the mix. The investigative branch wants the numbers vague for secrecy's sake, but curious residents at least have access to annual data that shows the range of requests for information and roughly how many users were affected -- in this case, about 1,000 to 2,000 Google account holders every year since 2009. Google is quick to note that it does what it can to narrow the scope of requests and require search warrants for anything private. We're slightly reassured by that extra line of defense, although the Transparency Report's addition is still a reminder that the government is watching some of us.
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The powerful master regulatory transcription factor called Bcl6 is key to the survival of a majority of aggressive lymphomas, which arise from the B-cells of the immune system. The protein has long been considered too complex to target with a drug since it is also crucial to the healthy functioning of many immune cells in the body, not just B cells gone bad.
But now, in the journalNature Immunology, researchers at Weill Cornell Medical College report that it is possible to shut down Bcl6 in the cancer, known as diffuse large B-cell lymphoma (DLBCL), while not affecting its vital function in T cells and macrophages that are needed to support a healthy immune system.
"The finding comes as a very welcome surprise," says the study's lead investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
"This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized," says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
If Bcl6 is completely inhibited, patients might suffer from systemic inflammation and atherosclerosis. Weill Cornell researchers conducted this new study to help clarify possible risks, as well as to understand how Bcl6 controls the various aspects of the immune system.
DLBCL is the most common subtype of non-Hodgkin lymphoma -- the seventh most frequently diagnosed cancer -- and many of these patients are resistant to currently available treatments.
"Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies," Dr. Melnick says. "Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs."
In fact, the findings in this study were inspired from preclinical testing of two Bcl6-targeting agents that Dr. Melnick and his Weill Cornell colleagues have developed to treat DLBCLs. These experimental drugs are RI-BPI, a peptide mimic, and the small molecule agent 79-6.
Dr. Melnick says the discovery that a master regulatory transcription factor can be targeted offers implications beyond just treating DLBCL. Recent studies from Dr. Melnick and others have revealed that Bcl6 plays a key role in the most aggressive forms of acute leukemia, as well as certain solid tumors.
Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are the equivalent of the CPU of a computer ? their actions regulate thousands of genes in different kinds of cells. For example, Bcl6 can control the type of immune cell that develops in the bone marrow -- playing many roles in the development of B cells, T cells, macrophages and other cells -- including a primary and essential role in enabling B-cells to generate specific antibodies against pathogens.
"When cells lose control of Bcl6, lymphomas develop in the immune system. Lymphomas are 'addicted' to Bcl6, and therefore Bcl6 inhibitors powerfully and quickly destroy lymphoma cells," Dr. Melnick says.
The big surprise in the current study is that rather than functioning as a single molecular machine, Bcl6 instead seems to function more like a Swiss Army knife, using different tools to control different cell types. This multi-function paradigm could represent a general model for the functioning of other master regulatory transcription factors.
"In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type," Dr. Melnick says. "For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer. You don't need to eliminate the whole knife," he says. "In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need."
Prior to these study results, it was not known that a master regulator could separate its functions so precisely.
"Now we know we can take out a specific tool -- to shut down a specific part of the protein -- that causes the disease we want to treat."
Researchers hope this will be a major benefit to the treatment of DLBCL and perhaps other disorders that are influenced by Bcl6 and other master regulatory transcription factors.
###
Weill Cornell Medical College: http://www.med.cornell.edu/index.html
Thanks to Weill Cornell Medical College for this article.
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Studies advance knowledge of HIV impact on hepatitis C infection and genes that may thwart HCVPublic release date: 4-Mar-2013 [ | E-mail | Share ]
Contact: David March dmarch1@jhmi.edu 410-955-1534 Johns Hopkins Medicine
Infectious disease experts at Johns Hopkins have found that among people infected with the hepatitis C virus (HCV), co-infection with HIV, speeds damage and scarring of liver tissue by almost a decade.
In a second study of HCV infection, the Johns Hopkins research team participated in the discovery of two genetic mutations that make it more likely that patients' immune systems can rid the body of HCV. Both studies are described in articles published online in February ahead of print in the journal Annals of Internal Medicine.
"Our latest study results suggest that HIV might promote aging and disease progression in people with HCV," says infectious disease specialist and senior investigator, David L. Thomas, M.D., M.P.H. Thomas, who is the Stanhope Bayne-Jones Professor and director of infectious diseases at the Johns Hopkins University School of Medicine and a professor at the university's Bloomberg School of Public Health, says that among 1,176 study participants, those co-infected with HCV and HIV showed the same severity of liver fibrosis and cirrhosis as those who were infected only with HCV but were 9.2 years older. All study participants were current and former intravenous drug users from Baltimore whose health and disease progression were being monitored with bi-monthly check-ups and liver tissue samples taken from 2006 to 2011.
The United States Centers for Disease Control and Prevention estimates that a quarter of the 3.2 million Americans chronically infected with HCV are also infected with HIV.
"There has been a growing hypothesis that HIV may accelerate the aging process, resulting in an earlier onset of chronic disease, including cancer, cardiovascular and liver disease. Until now, there have not been strong data to support this theory," says study lead investigator and infectious disease epidemiologist Gregory Kirk, M.D., Ph.D., M.P.H.
"There has been concern that increased chronic diseases in people aging with HIV may simply reflect their greater exposure to alcohol, tobacco or illicit drugs," adds Kirk, an associate professor at the Johns Hopkins Bloomberg School of Public Health. "Importantly, this investigation showed an increased severity of liver disease among people with HIV compared to people without HIV but whose pattern of smoking, alcohol drinking and illicit drug use was very similar."
"Co-infected patients may have to be monitored more closely for worsening liver disease, and may require earlier and more aggressive treatment than people without HIV infection," adds study co-investigator and epidemiologist Shruti Mehta, Ph.D., M.P.H. Although the reason for the accelerated rate of liver disease with HIV is unclear, the study results suggest that HIV and aging may share common mechanisms of immune activation that speed up HCV disease progression, says Mehta, an associate professor at the Bloomberg School of Public Health. Mehta and Kirk are both co-principal investigators of the long-term monitoring of the Baltimore group, known as the ALIVE cohort, which is short for the AIDS Linked to the IntraVenous Experience study.
The second study is believed to be the largest genetic investigation ever conducted of people infected with HCV. In it, researchers at 13 medical centers in five countries, including Thomas' Johns Hopkins team, analyzed nearly 800,000 differences in the genetic code among 919 people whose immune systems showed antibody evidence of having successfully fought off HCV infection, and another 1,482 people who became infected with the disease.
Lead study investigator and genetic epidemiologist Priya Duggal, Ph.D., M.P.H., says 40 percent of people exposed to HCV, predominantly of white and Asian ancestry, "spontaneously fight off infection" without any need for drug therapy, suggesting a genetic basis to risk of infection.
The international team's analysis showed that 15 percent of study participants who failed to become infected with HCV had either or both of two genetic variants, one near the gene for interleukin-28B and the other near the genes for HLA class II. Duggal, an assistant professor at the Bloomberg School of Public Health, says this information may help explain "with a relatively high degree of genetic certainty" why racial differences exist among those who do become infected. However, she cautions that further research is needed to determine the full impact of these genetic variants on preventing and treating HCV in people of different ethnicities.
Thomas says the findings may help physicians predict the people who are most likely to self-recover from exposure to HCV, and those who will most likely require aggressive treatment right away.
HCV infection is the nation's leading cause of liver failure, liver cancer and liver transplantation. The disease, transmitted by contact with blood and other bodily fluids of an infected person, and through sexual activity, injection drug use or sharing of personal care items, kills more than 10,000 Americans annually. An estimated 185 million people worldwide are infected with HCV.
###
Funding support for both studies was provided by the U.S. Public Health Service; National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases, both members of the National Institutes of Health; the Office of AIDS Research and the Intramural Research Programs, which are also part of the National Institutes of Health; and the Frederick National Laboratory for Cancer Research. Corresponding grant numbers are R01-1013324, R01-DA-033541, R01-DA-016078, R01-DA-04334, R01-DA-12568, U19-AI-088791 and AI-082630, and the contract number is HHSN-261-2008.
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Studies advance knowledge of HIV impact on hepatitis C infection and genes that may thwart HCVPublic release date: 4-Mar-2013 [ | E-mail | Share ]
Contact: David March dmarch1@jhmi.edu 410-955-1534 Johns Hopkins Medicine
Infectious disease experts at Johns Hopkins have found that among people infected with the hepatitis C virus (HCV), co-infection with HIV, speeds damage and scarring of liver tissue by almost a decade.
In a second study of HCV infection, the Johns Hopkins research team participated in the discovery of two genetic mutations that make it more likely that patients' immune systems can rid the body of HCV. Both studies are described in articles published online in February ahead of print in the journal Annals of Internal Medicine.
"Our latest study results suggest that HIV might promote aging and disease progression in people with HCV," says infectious disease specialist and senior investigator, David L. Thomas, M.D., M.P.H. Thomas, who is the Stanhope Bayne-Jones Professor and director of infectious diseases at the Johns Hopkins University School of Medicine and a professor at the university's Bloomberg School of Public Health, says that among 1,176 study participants, those co-infected with HCV and HIV showed the same severity of liver fibrosis and cirrhosis as those who were infected only with HCV but were 9.2 years older. All study participants were current and former intravenous drug users from Baltimore whose health and disease progression were being monitored with bi-monthly check-ups and liver tissue samples taken from 2006 to 2011.
The United States Centers for Disease Control and Prevention estimates that a quarter of the 3.2 million Americans chronically infected with HCV are also infected with HIV.
"There has been a growing hypothesis that HIV may accelerate the aging process, resulting in an earlier onset of chronic disease, including cancer, cardiovascular and liver disease. Until now, there have not been strong data to support this theory," says study lead investigator and infectious disease epidemiologist Gregory Kirk, M.D., Ph.D., M.P.H.
"There has been concern that increased chronic diseases in people aging with HIV may simply reflect their greater exposure to alcohol, tobacco or illicit drugs," adds Kirk, an associate professor at the Johns Hopkins Bloomberg School of Public Health. "Importantly, this investigation showed an increased severity of liver disease among people with HIV compared to people without HIV but whose pattern of smoking, alcohol drinking and illicit drug use was very similar."
"Co-infected patients may have to be monitored more closely for worsening liver disease, and may require earlier and more aggressive treatment than people without HIV infection," adds study co-investigator and epidemiologist Shruti Mehta, Ph.D., M.P.H. Although the reason for the accelerated rate of liver disease with HIV is unclear, the study results suggest that HIV and aging may share common mechanisms of immune activation that speed up HCV disease progression, says Mehta, an associate professor at the Bloomberg School of Public Health. Mehta and Kirk are both co-principal investigators of the long-term monitoring of the Baltimore group, known as the ALIVE cohort, which is short for the AIDS Linked to the IntraVenous Experience study.
The second study is believed to be the largest genetic investigation ever conducted of people infected with HCV. In it, researchers at 13 medical centers in five countries, including Thomas' Johns Hopkins team, analyzed nearly 800,000 differences in the genetic code among 919 people whose immune systems showed antibody evidence of having successfully fought off HCV infection, and another 1,482 people who became infected with the disease.
Lead study investigator and genetic epidemiologist Priya Duggal, Ph.D., M.P.H., says 40 percent of people exposed to HCV, predominantly of white and Asian ancestry, "spontaneously fight off infection" without any need for drug therapy, suggesting a genetic basis to risk of infection.
The international team's analysis showed that 15 percent of study participants who failed to become infected with HCV had either or both of two genetic variants, one near the gene for interleukin-28B and the other near the genes for HLA class II. Duggal, an assistant professor at the Bloomberg School of Public Health, says this information may help explain "with a relatively high degree of genetic certainty" why racial differences exist among those who do become infected. However, she cautions that further research is needed to determine the full impact of these genetic variants on preventing and treating HCV in people of different ethnicities.
Thomas says the findings may help physicians predict the people who are most likely to self-recover from exposure to HCV, and those who will most likely require aggressive treatment right away.
HCV infection is the nation's leading cause of liver failure, liver cancer and liver transplantation. The disease, transmitted by contact with blood and other bodily fluids of an infected person, and through sexual activity, injection drug use or sharing of personal care items, kills more than 10,000 Americans annually. An estimated 185 million people worldwide are infected with HCV.
###
Funding support for both studies was provided by the U.S. Public Health Service; National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases, both members of the National Institutes of Health; the Office of AIDS Research and the Intramural Research Programs, which are also part of the National Institutes of Health; and the Frederick National Laboratory for Cancer Research. Corresponding grant numbers are R01-1013324, R01-DA-033541, R01-DA-016078, R01-DA-04334, R01-DA-12568, U19-AI-088791 and AI-082630, and the contract number is HHSN-261-2008.
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Mar. 3, 2013 ? Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how the most common genetic mutations in familial Parkinson's disease damage brain cells. The study, which published online today in the journal Nature Neuroscience, could also open up treatment possibilities for both familial Parkinson's and the more common form of Parkinson's that is not inherited.
Parkinson's disease is a gradually progressing disorder of the nervous system that causes stiffness or slowing of movement. According to the Parkinson's Disease Foundation, as many as one million Americans are living with the disease.
The most common mutations responsible for the familial form of Parkinson's disease affect a gene called leucine-rich repeat kinase-2 (LRRK2). The mutations cause the LRRK2 gene to code for abnormal versions of the LRRK2 protein. But it hasn't been clear how LRRK2 mutations lead to the defining microscopic sign of Parkinson's: the formation of abnormal protein aggregates inside dopamine-producing nerve cells of the brain.
"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein -- the main component of those protein aggregates that gunk up nerve cells in Parkinson's patients," said study leader Ana Maria Cuervo, M.D., Ph.D., professor of developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases at Einstein.
The name for the disrupted disposal process is chaperone-mediated autophagy (the word "autophagy" literally means "self-eating"). It involves specialized molecules that "guide" old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.
"We showed that when LRRK2 inhibits chaperone-mediated autophagy, alpha-synuclein doesn't get broken down and instead accumulates to toxic levels in nerve cells," said Dr. Cuervo.
The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson's with LRRK2 mutations, and neurons derived from the skin cells of Parkinson's patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers' discovery.
"We're now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease," said Dr. Cuervo. "We've started to analyze some chemical compounds that look very promising."
Dr. Cuervo hopes that such treatments could help patients with familial as well as nonfamilial Parkinson's -- the predominant form of the disease that also involves the buildup of alpha-synuclein.
Dr. Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as Huntington's disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr. Cuervo is co-director of Einstein's Institute of Aging Research.
The paper is titled "Interplay of LRRK2 with chaperone-mediated autophagy." In addition to Dr. Cuervo, other Einstein contributors include Samantha J. Orenstein, a graduate student who performed most of this study as part of her Ph.D. thesis; Inmaculada Tasset, Ph.D.; Esperanza Arias, Ph.D.; and Hiroshi Koga, Ph.D., all members of Dr. Cuervo's group. Additional co-authors are: Sheng-Hang Kuo Ph.D., David Sulzer Ph.D., Etty Cortes, M.D., and Lawrence S. Honig, M.D. (Columbia University, NY); William Dauer, M.D., (University of Michigan, Ann Arbor, MI); Irene Fernandez-Carasa and Antonella Consiglio, Ph.D., (University of Barcelona, Barcelona Spain); and Angel Raya, M.D., Ph.D., (Institucio Catalana de Recerca I Estudies Avancas, Barcelona, Spain).
This work was supported by grants from the National Institute on Aging (AG031782 and AG08702), the National Institute of Neurological Disorders and Stroke Udall Center of Excellence both part of the National Institutes of Health; The Rainwaters Foundation, The Beatrice and Roy Backus Foundation, JPB Foundation; Parkinson's Disease Foundation; Fondazione Guido Berlucchi; Centers for Networked Biomedical Research; Ministry of Economy and Competitiveness; a Hirschl/Weill-Caulier Career Scientist Award; and a gift from Robert and Renee Belfer.
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The above story is reprinted from materials provided by Albert Einstein College of Medicine of Yeshiva University.
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Journal Reference:
Samantha J Orenstein, Sheng-Hang Kuo, Inmaculada Tasset, Esperanza Arias, Hiroshi Koga, Irene Fernandez-Carasa, Etty Cortes, Lawrence S Honig, William Dauer, Antonella Consiglio, Angel Raya, David Sulzer and Ana Maria Cuervo. Interplay of LRRK2 with chaperone-mediated autophagy. Nature Neuroscience, 03 March 2013 DOI: 10.1038/nn.3350
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
The Minnesota Parental Leave Act (MPLA) provides up to six weeks of leave for childbirth and recovery or adoption. Employees who take leave are entitled to reinstatement.
It also includes a provision for extending parental leave, stating that leave ?may not exceed six weeks, unless agreed to by the employer.? Until now, it remained up in the air what should happen to the reinstatement right if the employer agreed to a longer leave.
According to a recent decision, if the employer agrees to a specific return date, that not only extends the leave, but also the right to reinstatement.
Recent case: Anastasia was working for Old Dominion Freight Lines when she became pregnant and requested MPLA leave. Because her doctor recommended she take eight weeks to recover, she emailed her manager and asked to ?come back to work on the 9th as long as that works with you.?
He responded, ?Nov. 9 will work.? That meant Anastasia?s leave would last about a week longer than the six weeks specified in the MPLA.
Anastasia never returned to work because she was fired a few days be??fore she was set to come back. She sued, alleging failure to reinstate under the MPLA.
Old Dominion argued that it had merely extended her leave, but that Anastasia lost the right to return to her job after six weeks had passed.
The court disagreed. It said that if an employee can prove she asked for more time off and got a specific return date approved, that approval also extends reinstatement rights. Otherwise, employees who rely on their employer?s agreement to extend leave would lose the very thing they were seeking?a longer break before returning to a guaranteed job. (Kersten v. Old Dominion Freight Lines, No. 11-1036, DC MN, 2012)
Final note: In addition to deciding whether the right to reinstatement can be extended by agreement, the court also considered another important aspect of the MPLA: Whether someone on MPLA leave can be refused reinstatement if she would have lost her job anyway due to ?the good faith operation of a bona fide layoff and recall system.?
In this case, Old Dominion ex??plained that while Anastasia was recovering from childbirth, the company?s financial condition changed, necessitating a layoff. Anastasia was picked for termination because she was the least senior full-time em??ployee. The railroad claimed it had a ?standard operating procedure? requiring the least senior employees to go when the budget got tight.
Unfortunately for Old Dominion, that wasn?t a written policy. Plus, when questioned, a company representative testified that employees who were terminated never got a chance to return.
In his words, ?[W]e terminate. We don?t lay off. We don?t leave that possibility that they may come back.?
The court reasoned that the informal, unwritten policy couldn?t be a bona fide layoff and recall system since no recall was possible. That meant Anastasia?s termination violated the MPLA. That?s in sharp contrast to the FMLA, which allows termination if the employer can show it would have dismissed the employee for reasons unrelated to the FMLA.
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It also includes a provision for extending parental leave, stating that leave ?may not exceed six weeks, unless agreed to by the employer.? Until now, it remained up in the air what should happen to the reinstatement right if the employer agreed to a longer leave.