How to identify drugs that work best for each patient

Implantable device could allow doctors to test cancer drugs in patients before prescribing chemotherapy.

More than 100 drugs have been approved to treat cancer, but predicting which ones will help a particular patient is an inexact science at best.

A new device developed at MIT may change that. The implantable device, about the size of the grain of rice, can carry small doses of up to 30 different drugs. After implanting it in a tumor and letting the drugs diffuse into the tissue, researchers can measure how effectively each one kills the patient’s cancer cells.

Such a device could eliminate much of the guesswork now involved in choosing cancer treatments, says Oliver Jonas, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and lead author of a paper describing the device in the April 22 online edition ofScience Translational Medicine.

“You can use it to test a patient for a range of available drugs, and pick the one that works best,” Jonas says.

The paper’s senior authors are Robert Langer, the David H. Koch Professor at MIT and a member of the Koch Institute, the Institute for Medical Engineering and Science, and the Department of Chemical Engineering; and Michael Cima, the David H. Koch Professor of Engineering at MIT and a member of the Koch Institute and the Department of Materials Science and Engineering.

Putting the lab in the patient

Most of the commonly used cancer drugs work by damaging DNA or otherwise interfering with cell function. Recently, scientists have also developed more targeted drugs designed to kill tumor cells that carry a specific genetic mutation. However, it is usually difficult to predict whether a particular drug will be effective in an individual patient.

In some cases, doctors extract tumor cells, grow them in a lab dish, and treat them with different drugs to see which ones are most effective. However, this process removes the cells from their natural environment, which can play an important role in how a tumor responds to drug treatment, Jonas says.

“The approach that we thought would be good to try is to essentially put the lab into the patient,” he says. “It’s safe and you can do all of your sensitivity testing in the native microenvironment.”

The device, made from a stiff, crystalline polymer, can be implanted in a patient’s tumor using a biopsy needle. After implantation, drugs seep 200 to 300 microns into the tumor, but do not overlap with each other. Any type of drug can go into the reservoir, and the researchers can formulate the drugs so that the doses that reach the cancer cells are similar to what they would receive if the drug were given by typical delivery methods such as intravenous injection.

After one day of drug exposure, the implant is removed, along with a small sample of the tumor tissue surrounding it, and the researchers analyze the drug effects by slicing up the tissue sample and staining it with antibodies that can detect markers of cell death or proliferation.

Ranking cancer drugs

To test the device, the researchers implanted it in mice that had been grafted with human prostate, breast, and melanoma tumors. These tumors are known to have varying sensitivity to different cancer drugs, and the MIT team’s results corresponded to those previously seen differences.

The researchers then tested the device with a type of breast cancer known as triple negative, which lacks the three most common breast cancer markers: estrogen receptor, progesterone receptor, and Her2. This form of cancer is particularly aggressive, and none of the drugs used against it are targeted to a specific genetic marker.

Using the device, the researchers found that triple negative tumors responded differently to five of the drugs commonly used to treat them. The most effective was paclitaxel, followed by doxorubicin, cisplatin, gemcitabine, and lapatinib. They found the same results when delivering these drugs by intravenous injection, suggesting that the device is an accurate predictor of drug sensitivity.

In this study, the researchers compared single drugs to each other, but the device could also be used to test different drug combinations by putting two or three drugs into the same reservoir, Jonas says.

“This device could help us identify the best chemotherapy agents and combinations for every tumor prior to starting systemic administration of chemotherapy, as opposed to making choices based on population-based statistics. This has been a longstanding pursuit of the oncology community and an important step toward our goal of developing precision-based cancer therapy,” says Jose Baselga, chief medical officer at Memorial Sloan Kettering Cancer Center and an author of the paper.

The researchers are now working on ways to make the device easier to read while it is still inside the patient, allowing them to get results faster. They are also planning to launch a clinical trial in breast cancer patients next year.

“This is a stunning advance in the approach to treating complex cancers,” says Henry Brem, a professor of neurosurgery and oncology at Johns Hopkins School of Medicine who was not involved in the research. “This work is transformative in that it now opens the doors to truly personalized medicine with the right drug or drug combination being utilized for each tumor.”

Another possible application for this device is to guide the development and testing of new cancer drugs. Researchers could create several different variants of a promising compound and test them all at once in a small trial of human patients, allowing them to choose the best one to carry on to a larger clinical trial.

Unique UIC Center Will Study Alcohol's Effect on Genes

Newswise — Funded by a five-year, $7 million federal grant, the University of Illinois at Chicago College of Medicine will create a new center, the first of its kind, to study the effect of long-term alcohol exposure on genes.

The National Institute on Alcohol Abuse and Alcoholism, one of the National Institutes of Health, awarded the funding to establish a Center for Alcohol Research in Epigenetics (CARE). Subhash Pandey, UIC professor of psychiatry, will direct the center.

"Epigenetics" refers to chemical changes to DNA, RNA, or specific proteins, that change the activity of genes without changing the genes themselves. Epigenetic changes can occur in response to environmental or even social factors, such as alcohol and stress -- and these changes have been linked to changes in behavior and disease.

Epigenetics plays a role in the development and persistence of neurological changes associated with alcoholism, says Pandey, who is director of neuroscience alcoholism research at UIC and research career scientist at the Jesse Brown VA Medical Center.

The CARE researchers will investigate how alcohol-related epigenetic changes influence gene expression and "synaptic remodeling" -- the networking of nerve cells to each other. They will also look closely at how these changes correlate with behavior, such as anxiety and depression, and whether epigenetics may play a role in the withdrawal symptoms that make abstinence difficult.

“This award will allow the College of Medicine to build on Professor Pandey’s exemplary research on chronic alcohol use and alcoholism in addition to bolstering our leadership in understanding the causes of alcoholism as well as finding new ways to treat this devastating disease,” said Dr. Dimitri Azar, dean of the University of Illinois College of Medicine.

In a recent study using an animal model, Pandey and colleagues at UIC found that epigenetic changes resulting from exposure to alcohol during adolescence were associated with abnormal brain development and anxiety and alcohol preference in adulthood. In earlier work, the researchers were able to show that reshaping of the DNA scaffolding that supports and controls the expression of genes in the brain may play a major role in alcohol withdrawal symptoms, particularly anxiety.

Several brain regions play a crucial role in regulating both the positive and negative emotional states associated with alcohol addiction. Pandey said the center will look at the circuitry involved in reward and pleasure, depression, cognition, and anxiety.

CARE researchers will study disease using preclinical animal models and post-mortem examination of human brain. Investigators will also do neuroimaging of patients diagnosed with alcohol abuse and dependence and search for "biomarkers" of alcoholism -- measurable indicators in blood that correlate with alcohol addiction.

There are two causes of dependence on alcohol, said Pandey -- people may drink to get pleasure, or to self-medicate to relieve depression or anxiety. But alcohol addiction may itself cause depression and anxiety, feeding into a cycle.

“Ultimately, we hope these studies may lead to the identification of molecular cellular targets and gene networks which can be used to develop new pharmacotherapies to treat or prevent alcoholism,” Pandey said.

UIC's CARE is the only NIH-funded alcohol research center in Illinois, said Dr. Anand Kumar, Lizzie Gilman Professor and head of psychiatry, and is "well positioned to perform state-of-the-art basic translational and clinical research in alcoholism.”

In addition to its research projects, CARE will provide resources for training and community outreach. Based in the UIC psychiatry department, it includes collaborators from biophysics and physiology, anesthesiology, the Jesse Brown VA Medical Center, and the University of Illinois Urbana-Champaign campus.

Other members of the CARE research team are Alessandro Guidotti, Mark Brodie, Amy Lasek, Rajiv Sharma, Dennis Grayson, Harish Krishnan, David Gavin, Douglas Feinstein, Chunyu Liu, Dulal Bhaumik, Mark Rasenick and Marc Atkins of UIC; and Alvaro Hernandez and Victor Jongeneel from the Roy J. Carver Biotechnology Center at UIUC.

Unique UIC Center Will Study Alcohol's Effect on Genes

Newswise — Funded by a five-year, $7 million federal grant, the University of Illinois at Chicago College of Medicine will create a new center, the first of its kind, to study the effect of long-term alcohol exposure on genes.

The National Institute on Alcohol Abuse and Alcoholism, one of the National Institutes of Health, awarded the funding to establish a Center for Alcohol Research in Epigenetics (CARE). Subhash Pandey, UIC professor of psychiatry, will direct the center.

"Epigenetics" refers to chemical changes to DNA, RNA, or specific proteins, that change the activity of genes without changing the genes themselves. Epigenetic changes can occur in response to environmental or even social factors, such as alcohol and stress -- and these changes have been linked to changes in behavior and disease.

Epigenetics plays a role in the development and persistence of neurological changes associated with alcoholism, says Pandey, who is director of neuroscience alcoholism research at UIC and research career scientist at the Jesse Brown VA Medical Center.

The CARE researchers will investigate how alcohol-related epigenetic changes influence gene expression and "synaptic remodeling" -- the networking of nerve cells to each other. They will also look closely at how these changes correlate with behavior, such as anxiety and depression, and whether epigenetics may play a role in the withdrawal symptoms that make abstinence difficult.

“This award will allow the College of Medicine to build on Professor Pandey’s exemplary research on chronic alcohol use and alcoholism in addition to bolstering our leadership in understanding the causes of alcoholism as well as finding new ways to treat this devastating disease,” said Dr. Dimitri Azar, dean of the University of Illinois College of Medicine.

In a recent study using an animal model, Pandey and colleagues at UIC found that epigenetic changes resulting from exposure to alcohol during adolescence were associated with abnormal brain development and anxiety and alcohol preference in adulthood. In earlier work, the researchers were able to show that reshaping of the DNA scaffolding that supports and controls the expression of genes in the brain may play a major role in alcohol withdrawal symptoms, particularly anxiety.

Several brain regions play a crucial role in regulating both the positive and negative emotional states associated with alcohol addiction. Pandey said the center will look at the circuitry involved in reward and pleasure, depression, cognition, and anxiety.

CARE researchers will study disease using preclinical animal models and post-mortem examination of human brain. Investigators will also do neuroimaging of patients diagnosed with alcohol abuse and dependence and search for "biomarkers" of alcoholism -- measurable indicators in blood that correlate with alcohol addiction.

There are two causes of dependence on alcohol, said Pandey -- people may drink to get pleasure, or to self-medicate to relieve depression or anxiety. But alcohol addiction may itself cause depression and anxiety, feeding into a cycle.

“Ultimately, we hope these studies may lead to the identification of molecular cellular targets and gene networks which can be used to develop new pharmacotherapies to treat or prevent alcoholism,” Pandey said.

UIC's CARE is the only NIH-funded alcohol research center in Illinois, said Dr. Anand Kumar, Lizzie Gilman Professor and head of psychiatry, and is "well positioned to perform state-of-the-art basic translational and clinical research in alcoholism.”

In addition to its research projects, CARE will provide resources for training and community outreach. Based in the UIC psychiatry department, it includes collaborators from biophysics and physiology, anesthesiology, the Jesse Brown VA Medical Center, and the University of Illinois Urbana-Champaign campus.

Other members of the CARE research team are Alessandro Guidotti, Mark Brodie, Amy Lasek, Rajiv Sharma, Dennis Grayson, Harish Krishnan, David Gavin, Douglas Feinstein, Chunyu Liu, Dulal Bhaumik, Mark Rasenick and Marc Atkins of UIC; and Alvaro Hernandez and Victor Jongeneel from the Roy J. Carver Biotechnology Center at UIUC.

Key Tissue Engineering Step Taken in Forming New Blood Vessels

Researchers moved a step closer toward coaxing the body into producing its own replacement blood vessels after discovering that suppressing parts of the innate immune system may raise the chances of a tissue engineered vascular graft's success.


In a study (“The innate immune system contributes to tissue-engineered vascular graft performance”) appearing in The FASEB Journal, scientists showed that by controlling the reaction that natural killer cells, platelets, and the acute inflammatory response have to the graft, they could also reduce the abnormal narrowing of the grafts (stenosis), which is the cause of most failures. This discovery sets the stage for a second, more successful, generation of tissue engineered grafts designed to help regenerate components of the cardiovascular system, according to Cameron Best, a researcher involved in the work from the tissue engineering and surgical research department at the research institute at Nationwide Children's Hospital in Columbus, OH.

“Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs [tissue engineered vascular grafts],” wrote the investigators.

"Our aim is to extend these findings toward the development of a safe and effective tissue engineered vascular grafts for the management of congenital heart disease," said Mr. Best. "We hope that our translational approach is applicable to other areas of regenerative medicine and a model for investigators in the field."

Mr. Best and colleagues made this discovery by observing that immunodeficient mice mount a blunted acute inflammatory response to implanted TEVGs grafts and that stenosis, or narrowing of the blood vessel, did not occur. Researchers then treated wild type mice with either a natural killer cell depleting antibody or anti-platelet drugs and found that the rate of stenosis in each of these models was about half of that observed in the normal, untreated, mouse. This suggests that the combined effects of acute inflammation, natural killer cells and platelets are critical to TEVG performance.

"When most people think of regenerative medicine, they think of growing new hearts or kidneys," said Gerald Weissmann, M.D., editor-in-chief of The FASEB Journal. "What most people don't realize is that just being able to engineer new blood vessels would go a long way toward saving lives and alleviating suffering. This research is significant because it identifies what goes wrong with today's engineered blood vessels, and reveals a solution on what to do to fix this problem."

Key Tissue Engineering Step Taken in Forming New Blood Vessels

Researchers moved a step closer toward coaxing the body into producing its own replacement blood vessels after discovering that suppressing parts of the innate immune system may raise the chances of a tissue engineered vascular graft's success.


In a study (“The innate immune system contributes to tissue-engineered vascular graft performance”) appearing in The FASEB Journal, scientists showed that by controlling the reaction that natural killer cells, platelets, and the acute inflammatory response have to the graft, they could also reduce the abnormal narrowing of the grafts (stenosis), which is the cause of most failures. This discovery sets the stage for a second, more successful, generation of tissue engineered grafts designed to help regenerate components of the cardiovascular system, according to Cameron Best, a researcher involved in the work from the tissue engineering and surgical research department at the research institute at Nationwide Children's Hospital in Columbus, OH.

“Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs [tissue engineered vascular grafts],” wrote the investigators.

"Our aim is to extend these findings toward the development of a safe and effective tissue engineered vascular grafts for the management of congenital heart disease," said Mr. Best. "We hope that our translational approach is applicable to other areas of regenerative medicine and a model for investigators in the field."

Mr. Best and colleagues made this discovery by observing that immunodeficient mice mount a blunted acute inflammatory response to implanted TEVGs grafts and that stenosis, or narrowing of the blood vessel, did not occur. Researchers then treated wild type mice with either a natural killer cell depleting antibody or anti-platelet drugs and found that the rate of stenosis in each of these models was about half of that observed in the normal, untreated, mouse. This suggests that the combined effects of acute inflammation, natural killer cells and platelets are critical to TEVG performance.

"When most people think of regenerative medicine, they think of growing new hearts or kidneys," said Gerald Weissmann, M.D., editor-in-chief of The FASEB Journal. "What most people don't realize is that just being able to engineer new blood vessels would go a long way toward saving lives and alleviating suffering. This research is significant because it identifies what goes wrong with today's engineered blood vessels, and reveals a solution on what to do to fix this problem."

New Study Data Could Lead to Reversal of Aging Process

Scientists believe they have discovered the key driver in the human aging process, which could lead to preventing age-related disease or even reversing the aging process itself. [evgenyatamanenko/iStock]

There are many among us who believe that time is a predator, patiently waiting for our bodies to age and yield toward its inevitable fate. However, there are few within the sciences that look at the ageing process through a different lens—viewing it as a disease, one that can be treated, slowed, and possibly even reversed.

Scientists from the Salk Institute and the Chinese Academy of Science have published new data that they believe identifies a key driver in the aging process. The researchers found that the genetic mutations associated with Werner syndrome, a disorder that leads to premature aging and death is triggered by the deterioration of DNA bundles known as heterochromatin. A greater understanding of this process could lead to the treatment and prevention of age-related disorders such as Alzheimer’s,diabetes, and even cancer.

"Our findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin, and that this disruption of normal DNA packaging is a key driver of aging," explained Juan Carlos Izpisua Belmonte, Ph.D., professor in the gene expression laboratory at the Salk Institute and senior author on the paper. "This has implications beyond Werner syndrome, as it identifies a central mechanism of aging—heterochromatin disorganization—which has been shown to be reversible."

The findings from this study were published recently in Science through an article entitled "A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging."

Werner syndrome (WS), also known as adult progeria, is a genetic disorder that causes rapid aging and recapitulates certain aspects of the human physiological aging process. The disease is caused by a mutation within the Werner syndrome, RecQ helicase like gene (WRN). This enzyme typically helps maintain genomic stability and integrity, however in WS, the mutant protein disrupts DNA replication, repair, and gene expression.

Dr. Izpisua Belmonte and his colleagues sought to determine how mutated WRN could wreak so much havoc on cellular process. To that end, the researchers generated an in vitro model of WS employing human embryonic stem cells that contained a genetic deletion of the WRN gene.

The investigators observed that the altered stem cells recapitulated the WS phenotype and began to age more rapidly. At the molecular level they found that the deletion of WRN led to disruptions within the structure of heterochromatin, a scenario that could lead to global gene expression changes through epigenetic regulation.

"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation," stated Dr. Izpisua Belmonte. "More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations—like remodeling an old house or car—to prevent, or even reverse, age-related declines and diseases."

While their results are exciting and could have a major impact for age-related disease research, Dr. Izpisua Belmonte expressed caution in over interpreting the results, as more extensive studies will be required to fully understand the relationship between heterochromatin disorganization and aging

New Study Data Could Lead to Reversal of Aging Process

Scientists believe they have discovered the key driver in the human aging process, which could lead to preventing age-related disease or even reversing the aging process itself. [evgenyatamanenko/iStock]

There are many among us who believe that time is a predator, patiently waiting for our bodies to age and yield toward its inevitable fate. However, there are few within the sciences that look at the ageing process through a different lens—viewing it as a disease, one that can be treated, slowed, and possibly even reversed.

Scientists from the Salk Institute and the Chinese Academy of Science have published new data that they believe identifies a key driver in the aging process. The researchers found that the genetic mutations associated with Werner syndrome, a disorder that leads to premature aging and death is triggered by the deterioration of DNA bundles known as heterochromatin. A greater understanding of this process could lead to the treatment and prevention of age-related disorders such as Alzheimer’s,diabetes, and even cancer.

"Our findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin, and that this disruption of normal DNA packaging is a key driver of aging," explained Juan Carlos Izpisua Belmonte, Ph.D., professor in the gene expression laboratory at the Salk Institute and senior author on the paper. "This has implications beyond Werner syndrome, as it identifies a central mechanism of aging—heterochromatin disorganization—which has been shown to be reversible."

The findings from this study were published recently in Science through an article entitled "A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging."

Werner syndrome (WS), also known as adult progeria, is a genetic disorder that causes rapid aging and recapitulates certain aspects of the human physiological aging process. The disease is caused by a mutation within the Werner syndrome, RecQ helicase like gene (WRN). This enzyme typically helps maintain genomic stability and integrity, however in WS, the mutant protein disrupts DNA replication, repair, and gene expression.

Dr. Izpisua Belmonte and his colleagues sought to determine how mutated WRN could wreak so much havoc on cellular process. To that end, the researchers generated an in vitro model of WS employing human embryonic stem cells that contained a genetic deletion of the WRN gene.

The investigators observed that the altered stem cells recapitulated the WS phenotype and began to age more rapidly. At the molecular level they found that the deletion of WRN led to disruptions within the structure of heterochromatin, a scenario that could lead to global gene expression changes through epigenetic regulation.

"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation," stated Dr. Izpisua Belmonte. "More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations—like remodeling an old house or car—to prevent, or even reverse, age-related declines and diseases."

While their results are exciting and could have a major impact for age-related disease research, Dr. Izpisua Belmonte expressed caution in over interpreting the results, as more extensive studies will be required to fully understand the relationship between heterochromatin disorganization and aging

The PhoneBrasil Group is set to unveil its new Smartphone concept, The Glass

The PhoneBrasil Group is set to unveil its new Smartphone concept, The Glass

The PhoneBrasil Group is set to unveil its new Smartphone concept, The Glass

The PhoneBrasil Group is set to unveil its new Smartphone concept, The Glass

Humanitarian Organization Utilizes Jacada Visual IVR to Enhance Nepal Disaster Relief Donations

Humanitarian Organization Utilizes Jacada Visual IVR to Enhance Nepal Disaster Relief Donations

Humanitarian Organization Utilizes Jacada Visual IVR to Enhance Nepal Disaster Relief Donations

Humanitarian Organization Utilizes Jacada Visual IVR to Enhance Nepal Disaster Relief Donations

The Cigna Foundation to be Honored by Arogya World

The Cigna Foundation to be Honored by Arogya World

The Cigna Foundation to be Honored by Arogya World

The Cigna Foundation to be Honored by Arogya World

FedEx Pledges $1 Million in Aid to Support Relief of Nepal Earthquake Disaster

FedEx Pledges $1 Million in Aid to Support Relief of Nepal Earthquake Disaster

FedEx Pledges $1 Million in Aid to Support Relief of Nepal Earthquake Disaster

FedEx Pledges $1 Million in Aid to Support Relief of Nepal Earthquake Disaster

Grace Myu: Malaysia Beauty, Fashion, Lifestyle Blogger: VS Sassoon iPink Instant Studio Professional Hair ...

Grace Myu: Malaysia Beauty, Fashion, Lifestyle Blogger: VS Sassoon iPink Instant Studio Professional Hair ...: When I was younger, my mom was always spotted with hair rollers on (imagine that vintage looking image of stay-at-home-moms) and she ma...

Grace Myu: Malaysia Beauty, Fashion, Lifestyle Blogger: VS Sassoon iPink Instant Studio Professional Hair ...

Grace Myu: Malaysia Beauty, Fashion, Lifestyle Blogger: VS Sassoon iPink Instant Studio Professional Hair ...: When I was younger, my mom was always spotted with hair rollers on (imagine that vintage looking image of stay-at-home-moms) and she ma...

Review provides further insight into link between hormone therapy and breast cancer

A review of data from two Women's Health Initiative clinical trials reveals the varying effects of menopausal hormone therapy on the incidence of breast cancer over time. The results are published in the journal JAMA Oncology.


The review revealed that use of estrogen plus progestin was associated with a steady increase in breast cancer incidence, while estrogen alone was found to reduce breast cancer risk.

Hormone replacement therapy was once considered the standard treatment for women suffering menopausal symptoms. It involves the use of medications that contain female hormones - commonlyestrogen or a combination of estrogen and progestin (a form of progesterone) - to replace those lost followingmenopause.

But in 2002 came the results of a clinical trial as part of the Women's Health Initiative (WHI), which found a link between use of combined hormone therapy and increased risk of breast cancer - a finding that was supported by another WHI trial a year later.

According to Dr. Rowan T. Chlebowski, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, CA, and colleagues, the results of these trials led to a significant reduction in the use of hormone therapy.

However, the authors point out that while combined hormone therapy was associated with increased breast cancer risk in these trials, the use of estrogen alone was not. In fact, estrogen use was associated with reduced breast cancer incidence and deaths.

"Such results raised questions regarding the short- and long-term postintervention effects of these two regimens on breast cancer," say the authors.

As such, Dr. Chlebowski and colleagues conducted a longer-term review of the two WHI trials with the aim of going a better understanding of how the use of hormone therapy influences the risk of breast cancer.
Hormone therapy with estrogen alone reduced breast cancer risk

One trial involved 16,608 women with an intact uterus who were randomized to receive combined hormone therapy - estrogen plus progestin - or a placebo for an average of 5.6 years.

The other trial involved 10,739 women who had undergone a hysterectomy who were randomly assigned to receive estrogen alone or a placebo for an average of 7.2 years.

The review revealed that use of estrogen plus progestin throughout the entire intervention period was associated with a steady increase in breast cancer incidence.

However, around 2.75 years after combined hormone therapy began - deemed the early postintervention period - the researchers identified a sharp reduction in breast cancer incidence among women whose therapy had been discontinued.

"This likely represents a therapeutic influence of change in hormone environment on preclinical breast cancers similar to that seen with adjuvant aromatase inhibitor or tamoxifen use in early-stage breast cancer," the authors note.

An increased risk of breast cancer remained for years after treatment ceased, however.

In the estrogen-only trial, the researchers identified an overall significant reduction in breast cancer incidence throughout the entire intervention period. This risk was lowest in the early postintervention period, the team found, though they note it increased over time.

"Nonetheless," say the authors, "use of estrogen alone reduced breast cancer risk throughout the cumulative follow-up."

The researchers say the early reduction in breast cancer risk with estrogen therapy alone may reflect a treatment effect on preclinical breast cancers. "Estrogen receptor-positive cancers respond to sudden lowering of estrogen exposure with tumor reduction," they note.

Commenting on their findings, the team says:


"With longer follow-up of the two WHI hormone therapy trials, a complex pattern of changing year-to-year influences on breast cancer was observed.

The ongoing influences on breast cancer after stopping hormone therapy in the WHI trials require recalibration of breast cancer risk and benefit calculation for both regimens, with greater adverse influence for estrogen and progestin use and somewhat greater benefit for use of estrogen alone."
Review offers 'compelling new evidence' of progesterone's role in breast cancer

In an editorial linked to the study, Rama Khoka, PhD, of the Princess Margaret Cancer Center in Toronto, Canada, and colleagues say this latest review of the WHI trials reveals "compelling new evidence" for the significant role progesterone plays in breast cancer, noting that it has "traditionally taken a backseat to estrogen."

"Although the WHI trials relate to the menopausal setting, lessons learned from them continue to provide additional value in appreciating a potential role of progesterone even in premenopausal breast cancer," they add.

"Furthermore, investigation into the cellular and mechanistic underpinnings of progesterone's impact on the normal breast and breast cancer may provide new opportunities for knowledge translation and therapeutic intervention in breast cancer."

Coffee 'could halve breast cancer recurrence' in tamoxifen-treated patients

A new study led by researchers from Lund University in Sweden claims women diagnosed with breast cancer who are taking the drug tamoxifen could halve their risk of recurrence by drinking coffee.

The findings - published in the journal Clinical Cancer Research - build on those from a previous study conducted by Lund University researchers in 2013, in which the team found a link between coffeeconsumption and reduced breast cancer recurrence in 300 women who used tamoxifen.

In that study, however, the researchers were unable to explain why coffee appeared to protect against the return of breast cancer in these women.

"Now, unlike in the previous study, we have combined information about the patients' lifestyle and clinical data from 1,090 breast cancer patients with studies on breast cancer cells," say researchers Ann Rosendahl and Helena Jernström, both of Lund University and Skåne University Hospital, also in Sweden.

After skin cancer, breast cancer is the most common cancer among women in the US, affecting around 1 in 8 women in their lifetime.

Hormone therapy is a standard treatment for patients with estrogen receptor-positive (ER+) breast cancer, most commonly administered after a patient undergoes surgery for the disease. Tamoxifen is one drug used for hormone therapy. It works by preventing estrogen from binding to breast cancer cells, which stops them growing and dividing.

Of the 1,090 women with breast cancer included in the study, around 500 were treated with tamoxifen. The women's coffee consumption was assessed and allocated to one of three categories: low consumption (less than one cup a day), moderate consumption (two to four cups and day) and high consumption (five or more cups a day).

The researchers found that among the women who were treated with tamoxifen, those who had moderate or high coffee consumption had half the likelihood of breast cancer recurrence than those who had low coffee consumption or did not drink the beverage at all.

What is more, the team found that tamoxifen-treated women who consumed at least two cups of coffee a day had smaller tumors and a lower proportion of hormone-dependent tumors than women who consumed less coffee.
Caffeine, caffeic acid 'reduces cell division and increases cell death'

Next, the researchers analyzed the effects of two substances present in coffee - caffeine and caffeic acid - on breast cancer cells.

The team found that both of these compounds - particularly caffeine - reduced cell division and increased cell death among both ER+ and estrogen receptor-negative (ER-) breast cancer cells. When tamoxifen was applied, the effect was even stronger.

"This shows that these substances have an effect on the breast cancer cells and turn off signaling pathways that the cancer cells require to grow," say Rosendahl and Jernström.

The researchers add:


"The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER+ and ER- breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth."

The team stresses, however, that breast cancer patients should not swap their medication for coffee. "But if you like coffee and are also taking tamoxifen," add Rosendahl and Jernström, "there is no reason to stop drinking it. Just two cups a day is sufficient to make a difference."

Last month, Medical News Today reported on a study claiming just one cup of coffee a day could significantly reduce the risk of liver cancer, while another study found consuming five cups a day could reduce the risk of heart attack.

Coffee 'could halve breast cancer recurrence' in tamoxifen-treated patients

A new study led by researchers from Lund University in Sweden claims women diagnosed with breast cancer who are taking the drug tamoxifen could halve their risk of recurrence by drinking coffee.

The findings - published in the journal Clinical Cancer Research - build on those from a previous study conducted by Lund University researchers in 2013, in which the team found a link between coffeeconsumption and reduced breast cancer recurrence in 300 women who used tamoxifen.

In that study, however, the researchers were unable to explain why coffee appeared to protect against the return of breast cancer in these women.

"Now, unlike in the previous study, we have combined information about the patients' lifestyle and clinical data from 1,090 breast cancer patients with studies on breast cancer cells," say researchers Ann Rosendahl and Helena Jernström, both of Lund University and Skåne University Hospital, also in Sweden.

After skin cancer, breast cancer is the most common cancer among women in the US, affecting around 1 in 8 women in their lifetime.

Hormone therapy is a standard treatment for patients with estrogen receptor-positive (ER+) breast cancer, most commonly administered after a patient undergoes surgery for the disease. Tamoxifen is one drug used for hormone therapy. It works by preventing estrogen from binding to breast cancer cells, which stops them growing and dividing.

Of the 1,090 women with breast cancer included in the study, around 500 were treated with tamoxifen. The women's coffee consumption was assessed and allocated to one of three categories: low consumption (less than one cup a day), moderate consumption (two to four cups and day) and high consumption (five or more cups a day).

The researchers found that among the women who were treated with tamoxifen, those who had moderate or high coffee consumption had half the likelihood of breast cancer recurrence than those who had low coffee consumption or did not drink the beverage at all.

What is more, the team found that tamoxifen-treated women who consumed at least two cups of coffee a day had smaller tumors and a lower proportion of hormone-dependent tumors than women who consumed less coffee.
Caffeine, caffeic acid 'reduces cell division and increases cell death'

Next, the researchers analyzed the effects of two substances present in coffee - caffeine and caffeic acid - on breast cancer cells.

The team found that both of these compounds - particularly caffeine - reduced cell division and increased cell death among both ER+ and estrogen receptor-negative (ER-) breast cancer cells. When tamoxifen was applied, the effect was even stronger.

"This shows that these substances have an effect on the breast cancer cells and turn off signaling pathways that the cancer cells require to grow," say Rosendahl and Jernström.

The researchers add:


"The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER+ and ER- breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth."

The team stresses, however, that breast cancer patients should not swap their medication for coffee. "But if you like coffee and are also taking tamoxifen," add Rosendahl and Jernström, "there is no reason to stop drinking it. Just two cups a day is sufficient to make a difference."

Last month, Medical News Today reported on a study claiming just one cup of coffee a day could significantly reduce the risk of liver cancer, while another study found consuming five cups a day could reduce the risk of heart attack.

World First Remote Heart Surgery Using Robotic Arm

A pioneering world first robotics system operation is to be conducted at Glenfield Hospital Leicester thanks to expertise at the University of Leicester and University Hospitals of Leicester.

Dr André Ng, Senior Lecturer in Cardiovascular Sciences at the University of Leicester and Consultant Cardiologist and Electrophysiologist, Glenfield Hospital, University Hospitals of Leicester, is the first person in the world to carry out the operation remotely on patients using this system.

He will use the Catheter Robotics Remote Catheter Manipulation System for the first time in a heart rhythm treatment procedure.

The system is novel because it allows a doctor to carry out a common heart treatment procedure remotely using a robotic arm.

These procedures involve inserting thin wires, called catheters, into blood vessels at the top of the groin and advanced into the heart chambers. Electrodes on the catheters record and stimulate different regions of the heart to help the doctor identify the cause of the heart rhythm problem which usually involves an abnormality in the electrical wiring system of the heart. Once this area is identified, one of the catheters will be placed at the location to ablate or "burn" the tissue to cure the problem. Catheter ablation has been developed and used over the past 2 decades effectively in many patients suffering palpitations due to heart rhythm disturbances.

Dr Ng said: "The new Robotic procedure is an important step forward because, while some procedures are straightforward, others can take several hours. Because X-rays are used to allow the doctor to monitor what is going on inside the patient, it means that doctors standing close to the patient wear radiation shields such as lead aprons which are burdensome. Protracted procedures can lead to clinician fatigue and high cumulative radiation exposure.

"The benefit of the Robotics system to the patient is that movement of the catheter could be done with great precision. It is anticipated that further developments of the system may allow complex procedures to be made more streamlined. On the other hand, benefits to the doctor are that heavy lead aprons would not be necessary as he / she will be controlling the movements of the catheter using the Remote Controller at a distance from the patient outside the radiation area and that he / she can be sitting closer to the monitors displaying electrical signals and x-ray images as opposed to standing at some distance across the room from them which is current practice."

Dr Ng and his team's international standing and leading position in the management of heart rhythm disorders are reflected in the invitation to be the first to apply this new Robotics System in clinical procedures which also affirms the world-class research and pioneering work at the University of Leicester.

The Remote Catheter Manipulation System (RCMS, Catheter Robotics Inc., New Jersey) is a new system and Dr André Ng, who has extensive experience in EPS procedures, has been selected to apply the system in human studies for the first time in the world. Two other remote navigation systems are commercially available but one uses a huge magnetic field to control a magnetic tip catheter whilst the other uses a large deflectable sheath to move the catheter. The RCMS has the benefit of using standard EPS catheters which can be dismounted and remounted onto the system with ease. The technology has obtained CE mark through rigorous bench safety testing and pre-clinical studies and has now arrived at a stage where it can be applied to clinical procedures.

Dr Ng is an expert in the management of heart rhythm disturbances especially in catheter ablation and the use of mapping systems in such procedures. The Department of Cardiology at Glenfield Hospital is one of the largest Electrophysiology Centres in the UK performing over 600 EPS procedures every year. Dr Ng has a distinguished research profile in investigations into cardiac electrophysiology and arrhythmia mechanisms, leading both non-clinical and clinical teams of talented researchers. At the cutting edge of scientific research and development, the innovative work in his group has been acknowledged with many accolades including Young Investigator and Da Vinci Awards. He is also Director of pan-European training programmes on advanced three-dimensional mapping systems and arrhythmia ablation

World First Remote Heart Surgery Using Robotic Arm

A pioneering world first robotics system operation is to be conducted at Glenfield Hospital Leicester thanks to expertise at the University of Leicester and University Hospitals of Leicester.

Dr André Ng, Senior Lecturer in Cardiovascular Sciences at the University of Leicester and Consultant Cardiologist and Electrophysiologist, Glenfield Hospital, University Hospitals of Leicester, is the first person in the world to carry out the operation remotely on patients using this system.

He will use the Catheter Robotics Remote Catheter Manipulation System for the first time in a heart rhythm treatment procedure.

The system is novel because it allows a doctor to carry out a common heart treatment procedure remotely using a robotic arm.

These procedures involve inserting thin wires, called catheters, into blood vessels at the top of the groin and advanced into the heart chambers. Electrodes on the catheters record and stimulate different regions of the heart to help the doctor identify the cause of the heart rhythm problem which usually involves an abnormality in the electrical wiring system of the heart. Once this area is identified, one of the catheters will be placed at the location to ablate or "burn" the tissue to cure the problem. Catheter ablation has been developed and used over the past 2 decades effectively in many patients suffering palpitations due to heart rhythm disturbances.

Dr Ng said: "The new Robotic procedure is an important step forward because, while some procedures are straightforward, others can take several hours. Because X-rays are used to allow the doctor to monitor what is going on inside the patient, it means that doctors standing close to the patient wear radiation shields such as lead aprons which are burdensome. Protracted procedures can lead to clinician fatigue and high cumulative radiation exposure.

"The benefit of the Robotics system to the patient is that movement of the catheter could be done with great precision. It is anticipated that further developments of the system may allow complex procedures to be made more streamlined. On the other hand, benefits to the doctor are that heavy lead aprons would not be necessary as he / she will be controlling the movements of the catheter using the Remote Controller at a distance from the patient outside the radiation area and that he / she can be sitting closer to the monitors displaying electrical signals and x-ray images as opposed to standing at some distance across the room from them which is current practice."

Dr Ng and his team's international standing and leading position in the management of heart rhythm disorders are reflected in the invitation to be the first to apply this new Robotics System in clinical procedures which also affirms the world-class research and pioneering work at the University of Leicester.

The Remote Catheter Manipulation System (RCMS, Catheter Robotics Inc., New Jersey) is a new system and Dr André Ng, who has extensive experience in EPS procedures, has been selected to apply the system in human studies for the first time in the world. Two other remote navigation systems are commercially available but one uses a huge magnetic field to control a magnetic tip catheter whilst the other uses a large deflectable sheath to move the catheter. The RCMS has the benefit of using standard EPS catheters which can be dismounted and remounted onto the system with ease. The technology has obtained CE mark through rigorous bench safety testing and pre-clinical studies and has now arrived at a stage where it can be applied to clinical procedures.

Dr Ng is an expert in the management of heart rhythm disturbances especially in catheter ablation and the use of mapping systems in such procedures. The Department of Cardiology at Glenfield Hospital is one of the largest Electrophysiology Centres in the UK performing over 600 EPS procedures every year. Dr Ng has a distinguished research profile in investigations into cardiac electrophysiology and arrhythmia mechanisms, leading both non-clinical and clinical teams of talented researchers. At the cutting edge of scientific research and development, the innovative work in his group has been acknowledged with many accolades including Young Investigator and Da Vinci Awards. He is also Director of pan-European training programmes on advanced three-dimensional mapping systems and arrhythmia ablation

Robots taking over to help medical research

It has been a long and stealthy takeover, but robots now dominate many leading bioscience laboratories, doing in just hours what once took days or weeks. Now the convergence of automation with nanotechnologies, biomedics and advanced algorithms promises to take robotization of medical research much further.

In May of this year, Ross King, professor of machine intelligence at the UK's University of Manchester, traveled east to talk to students at the University of Nottingham campus in Ningbo, China. His paper "Robot scientists: Automating biology and chemistry" was a vindication of theories he and colleagues first proposed almost a decade ago.

In a 2004 letter to the journal Nature, they asked whether it might be possible to automate the actual "discovery" process of observation, deduction and conclusion. This would use a physically implemented robotic system that applied techniques from artificial intelligence (AI) to carry out cycles of scientific experimentation.
Meet Adam and Eve, robot scientists

In China, as he had earlier at Brunel University in London, Prof. King named the two "robot scientists" Adam and Eve, constructed at the University of Aberystwyth in Wales. These robots form hypotheses, select efficient experiments to discriminate between them, execute the experiments using laboratory automation equipment, and then analyze the results.

Both Adam and Eve have made actual discoveries.

Adam was developed to investigate the functional genomics of yeast (Saccharomyces cerevisiae) and the robot succeeded in autonomously identifying the genes that encode locally "orphan" enzymes in yeast.

Prof. Ross King at the controls for Adam the robot, Aberystwyth University

In biblical fashion, Adam was followed by Eve using similar techniques to create a machine tasked toward automation and integration of drug discovery: screening, hit conformation, and quantitative structure-activity relationship (QSAR) development. Eve uses novel synthetic biology screens that combine the advantages of computational, target-based, and cell-based assays.

Prof. Ross King says:


"Our focus has been on neglected tropical disease, and using Eve, we have discovered lead compounds for malaria, Chagas, African sleeping sickness and other conditions."


Humble origins

Analytical robots like Adam, Eve or the more advanced products now being developed at centers of excellence - such as at the Fraunhofer Institute for Factory Operation and Automation (IFF) in Magdeburg, Germany - are a far cry from the robotic systems that first entered the lab some three decades ago.

The history of a leading company in the field - Hamilton Robotics - demonstrates the progression:
From precision syringes in the 1940s
Through the first semi-automated diluter in 1970
To the first fully automated workstation for sample preparation in 1980.

Such workstations, which mechanically handle samples under full computer control, meet the core dictionary definition of a robot as "a machine capable of carrying out a complex series of actions automatically." Their actual mechanical or physical "work" component also satisfies Karel Čapek's original "forced labor" definition in his 1920 playR.U.R.. This is the play that introduced the word "robot" to the world.
Robots at work

Liquid handling is one of the four core applications for robotics in the laboratory. The others are:

Microplate handling: using robots to move plates around a workcell, between stacks and other devices (liquid handlers, readers, incubators, and so on). Advanced microplate robots integrate with third-party instruments to create work cells that automate applications and protocols to almost any level of complexity.

Automated biological research systems: robots provide automated handling and reading for various aspects of biological and biochemical research, ranging from flow cytometers to specific molecular biology applications such as PCR preparation and purification, colony picking or cell culture development.

Drug discovery screening: the most recent mainstream robotics application allows researchers to run a wide range of cell-based, receptor-based and enzyme-based assays typically used in high throughput screening (HTS).
Do robots offer an advantage?

The laboratory advantages of using robotics seem obvious, starting with the ergonomic benefits of automating tasks that would be tedious, repetitive, injurious or even hazardous for a human.

A robot makes no distinction between the backbreaking low rack a few centimeters off the floor and the one up high, for which a human would need to stand on a chair. Robots can also safely handle toxins, biohazards or operate in sealed or climate-controlled areas that we would find unbearable.

Laboratories originally embraced robotics because it seemed to offer an escape from the "quantity or quality" dilemma - the constant need to trade off speed for accuracy.

By contrast, it seemed robots could perform infinitely repeated operations to a supreme degree of precision that never varied and was infinitely controllable.

However, in practice, and particularly with high throughput screening, some limitations began to emerge. These included:
Long design and implementation time
Protracted transfer from manual to automated methods
Unstable robotic operation, and
Limited error recovery abilities.

Furthermore, the need to reduce steps in robotic processes tended to encourage the use of less accurate homogenous assays over the heterogenous ones that most companies would prefer.
Scaling up

Early 21st century adoption of Allegro and other technologies based on assembly-line techniques overcame many of these problems by passing microplates down a line to consecutive processing modules, each performing just one step of the assay. Speed could be multiplied into the process by making each step bigger, with the 96-well microplate giving way to 384 and now 1,536-well plates.

The new capability of robots to screen such enormous plates unsupervised paved the way for the quantitative high-throughput screening (qHTS) paradigm that can test each library compound at multiple concentrations.

Maximum efficiency and miniaturization gave qHTS the theoretical capacity to carry out cell-based and biochemical assays across libraries of more than 100,000 compounds, testing between 700,000 and 2 million sample wells within a few hours.

However, few companies actually need to screen that many compounds in-house each day, with the associated costs of consumables such as assay reagents, cell cultures, microplates, and pipet tips, as well as the cost of data handling and analysis time.

When you add in the investment overheads for associated infrastructure, robotics can seem like a rich kid's toy.
Robots for hire

During the first decade of the 21st century, growing numbers of contract companies doing high-throughput screening (HTS) offered assay development and screening, data analysis, and other library support.

The use of such contract robotics labs became a lot more popular after they stopped demanding royalty payments on any discovery. Such labs trade on the ability to offer ultra-fast turnaround times, running 24/7 on high-capacity HTS robotic workstations.

Some pharma and biotech companies began to outsource primary screening, keeping the higher-value, more proprietary secondary screening in-house, to enable higher hit rates for their teams. However, even these approaches are becoming redundant with new technology.
Rifle versus shotgun approach

Essentially, high-throughput screening is the shotgun approach to research - using robotics to throw many thousands of chemical compounds against a target pathogen to see if its cell growth accelerates, stops, or is eliminated. The capacity is awesome, but the costs are high and the unit-to-success ratio is low.

A more sophisticated robotics-enabled paradigm is high-content screening (HCS) - a "rifle" approach that applies molecular specificity based on fluorescence and takes advantage of more sophisticated reagent classes.

High-content screening has the ability to multiplex, along with image analysis coupled to data management, data mining, and data visualization. All these help researchers focus on biological and genomic information and make far more targeted decisions on which assays to run.

Latest technology takes this targeting still further. Hudson Robotics recently announced what it terms high-efficiency screening (HES) for small molecules and antibodies.

High-efficiency screening uses a proprietary algorithm to compile a shortlist of library samples that will be screened. This is then passed on to a robotic workstation where the molecules are cherry-picked and screened in the appropriate assay.

Any molecules found to be active are used to enhance the model and the process is repeated until the user has both a list of active molecules, as well as the final model that can be used to search additional compound collections and guide synthesis of optimized analogs.

In preliminary testing against known compound databases, Hudson says its high-efficiency screening consistently identified the majority of known inhibitors of ten different biological targets after screening under 10% of a library containing some 80,000 diverse molecules.
Future robot trends

Three decades in from the first laboratory use of robotics, it seems clear that the technology is still in its infancy. Robots may seem pervasive in today's biomedical research, but they have a long way to evolve.

For one thing, robots cannot easily coexist with humans, needing to work in safely enclosed areas. The Fraunhofer Institute has been studying this aspect and developed LISA, a prototype mobile lab assistant with touch sensitive "skin" and heat sensors to stop her bumping into humans and vice versa.

Meet LISA. She's the one on the left...

But even LISA is likely to look as clunky as the Wright Flyer once biomedics, 3D printing and nanotechnologies really come into play. A glimpse of the possibilities is offered by the robotic inchworm pioneered by Columbia University.

Biobots like these, or the DNA spiders developed at New York University and the University of Michigan are little more than fascinating, if rather scary, toys at the moment. But they point to a future where robotics moves beyond the research lab into the operating room - or even down into the molecular realm.

Robots taking over to help medical research

It has been a long and stealthy takeover, but robots now dominate many leading bioscience laboratories, doing in just hours what once took days or weeks. Now the convergence of automation with nanotechnologies, biomedics and advanced algorithms promises to take robotization of medical research much further.

In May of this year, Ross King, professor of machine intelligence at the UK's University of Manchester, traveled east to talk to students at the University of Nottingham campus in Ningbo, China. His paper "Robot scientists: Automating biology and chemistry" was a vindication of theories he and colleagues first proposed almost a decade ago.

In a 2004 letter to the journal Nature, they asked whether it might be possible to automate the actual "discovery" process of observation, deduction and conclusion. This would use a physically implemented robotic system that applied techniques from artificial intelligence (AI) to carry out cycles of scientific experimentation.
Meet Adam and Eve, robot scientists

In China, as he had earlier at Brunel University in London, Prof. King named the two "robot scientists" Adam and Eve, constructed at the University of Aberystwyth in Wales. These robots form hypotheses, select efficient experiments to discriminate between them, execute the experiments using laboratory automation equipment, and then analyze the results.

Both Adam and Eve have made actual discoveries.

Adam was developed to investigate the functional genomics of yeast (Saccharomyces cerevisiae) and the robot succeeded in autonomously identifying the genes that encode locally "orphan" enzymes in yeast.

Prof. Ross King at the controls for Adam the robot, Aberystwyth University

In biblical fashion, Adam was followed by Eve using similar techniques to create a machine tasked toward automation and integration of drug discovery: screening, hit conformation, and quantitative structure-activity relationship (QSAR) development. Eve uses novel synthetic biology screens that combine the advantages of computational, target-based, and cell-based assays.

Prof. Ross King says:


"Our focus has been on neglected tropical disease, and using Eve, we have discovered lead compounds for malaria, Chagas, African sleeping sickness and other conditions."


Humble origins

Analytical robots like Adam, Eve or the more advanced products now being developed at centers of excellence - such as at the Fraunhofer Institute for Factory Operation and Automation (IFF) in Magdeburg, Germany - are a far cry from the robotic systems that first entered the lab some three decades ago.

The history of a leading company in the field - Hamilton Robotics - demonstrates the progression:
From precision syringes in the 1940s
Through the first semi-automated diluter in 1970
To the first fully automated workstation for sample preparation in 1980.

Such workstations, which mechanically handle samples under full computer control, meet the core dictionary definition of a robot as "a machine capable of carrying out a complex series of actions automatically." Their actual mechanical or physical "work" component also satisfies Karel Čapek's original "forced labor" definition in his 1920 playR.U.R.. This is the play that introduced the word "robot" to the world.
Robots at work

Liquid handling is one of the four core applications for robotics in the laboratory. The others are:

Microplate handling: using robots to move plates around a workcell, between stacks and other devices (liquid handlers, readers, incubators, and so on). Advanced microplate robots integrate with third-party instruments to create work cells that automate applications and protocols to almost any level of complexity.

Automated biological research systems: robots provide automated handling and reading for various aspects of biological and biochemical research, ranging from flow cytometers to specific molecular biology applications such as PCR preparation and purification, colony picking or cell culture development.

Drug discovery screening: the most recent mainstream robotics application allows researchers to run a wide range of cell-based, receptor-based and enzyme-based assays typically used in high throughput screening (HTS).
Do robots offer an advantage?

The laboratory advantages of using robotics seem obvious, starting with the ergonomic benefits of automating tasks that would be tedious, repetitive, injurious or even hazardous for a human.

A robot makes no distinction between the backbreaking low rack a few centimeters off the floor and the one up high, for which a human would need to stand on a chair. Robots can also safely handle toxins, biohazards or operate in sealed or climate-controlled areas that we would find unbearable.

Laboratories originally embraced robotics because it seemed to offer an escape from the "quantity or quality" dilemma - the constant need to trade off speed for accuracy.

By contrast, it seemed robots could perform infinitely repeated operations to a supreme degree of precision that never varied and was infinitely controllable.

However, in practice, and particularly with high throughput screening, some limitations began to emerge. These included:
Long design and implementation time
Protracted transfer from manual to automated methods
Unstable robotic operation, and
Limited error recovery abilities.

Furthermore, the need to reduce steps in robotic processes tended to encourage the use of less accurate homogenous assays over the heterogenous ones that most companies would prefer.
Scaling up

Early 21st century adoption of Allegro and other technologies based on assembly-line techniques overcame many of these problems by passing microplates down a line to consecutive processing modules, each performing just one step of the assay. Speed could be multiplied into the process by making each step bigger, with the 96-well microplate giving way to 384 and now 1,536-well plates.

The new capability of robots to screen such enormous plates unsupervised paved the way for the quantitative high-throughput screening (qHTS) paradigm that can test each library compound at multiple concentrations.

Maximum efficiency and miniaturization gave qHTS the theoretical capacity to carry out cell-based and biochemical assays across libraries of more than 100,000 compounds, testing between 700,000 and 2 million sample wells within a few hours.

However, few companies actually need to screen that many compounds in-house each day, with the associated costs of consumables such as assay reagents, cell cultures, microplates, and pipet tips, as well as the cost of data handling and analysis time.

When you add in the investment overheads for associated infrastructure, robotics can seem like a rich kid's toy.
Robots for hire

During the first decade of the 21st century, growing numbers of contract companies doing high-throughput screening (HTS) offered assay development and screening, data analysis, and other library support.

The use of such contract robotics labs became a lot more popular after they stopped demanding royalty payments on any discovery. Such labs trade on the ability to offer ultra-fast turnaround times, running 24/7 on high-capacity HTS robotic workstations.

Some pharma and biotech companies began to outsource primary screening, keeping the higher-value, more proprietary secondary screening in-house, to enable higher hit rates for their teams. However, even these approaches are becoming redundant with new technology.
Rifle versus shotgun approach

Essentially, high-throughput screening is the shotgun approach to research - using robotics to throw many thousands of chemical compounds against a target pathogen to see if its cell growth accelerates, stops, or is eliminated. The capacity is awesome, but the costs are high and the unit-to-success ratio is low.

A more sophisticated robotics-enabled paradigm is high-content screening (HCS) - a "rifle" approach that applies molecular specificity based on fluorescence and takes advantage of more sophisticated reagent classes.

High-content screening has the ability to multiplex, along with image analysis coupled to data management, data mining, and data visualization. All these help researchers focus on biological and genomic information and make far more targeted decisions on which assays to run.

Latest technology takes this targeting still further. Hudson Robotics recently announced what it terms high-efficiency screening (HES) for small molecules and antibodies.

High-efficiency screening uses a proprietary algorithm to compile a shortlist of library samples that will be screened. This is then passed on to a robotic workstation where the molecules are cherry-picked and screened in the appropriate assay.

Any molecules found to be active are used to enhance the model and the process is repeated until the user has both a list of active molecules, as well as the final model that can be used to search additional compound collections and guide synthesis of optimized analogs.

In preliminary testing against known compound databases, Hudson says its high-efficiency screening consistently identified the majority of known inhibitors of ten different biological targets after screening under 10% of a library containing some 80,000 diverse molecules.
Future robot trends

Three decades in from the first laboratory use of robotics, it seems clear that the technology is still in its infancy. Robots may seem pervasive in today's biomedical research, but they have a long way to evolve.

For one thing, robots cannot easily coexist with humans, needing to work in safely enclosed areas. The Fraunhofer Institute has been studying this aspect and developed LISA, a prototype mobile lab assistant with touch sensitive "skin" and heat sensors to stop her bumping into humans and vice versa.

Meet LISA. She's the one on the left...

But even LISA is likely to look as clunky as the Wright Flyer once biomedics, 3D printing and nanotechnologies really come into play. A glimpse of the possibilities is offered by the robotic inchworm pioneered by Columbia University.

Biobots like these, or the DNA spiders developed at New York University and the University of Michigan are little more than fascinating, if rather scary, toys at the moment. But they point to a future where robotics moves beyond the research lab into the operating room - or even down into the molecular realm.

What are the adult health consequences of childhood bullying?

Still considered a rite of passage by some, research is now attempting to understand why victims of childhood bullying are at risk of poorer outcomes in adulthood, not only for psychological health, but also physical health, cognitive functioning and quality of life.

Though there is no universal definition of childhood bullying, the term is often used to describe when a child repeatedly and deliberately says or does things that causes distress to another child, or when a child attempts to force another child to do something against their will by using threats, violence or intimidation.

The US Department of Health & Human Services (DHHS) quote studies that show the most common types of bullying are verbal and social:

Research shows that persistent bullying can cause depression and anxiety and contribute to suicidal behavior.
Name calling - 44.2% of cases
Teasing - 43.3%
Spreading rumors or lies - 36.3%
Pushing or shoving - 32.4%
Hitting, slapping or kicking - 29.2%
Leaving out - 28.5%
Threatening - 27.4%
Stealing belongings - 27.3%
Sexual comments or gestures - 23.7%
Email or blogging - 9.9%

The health impact of bullying on children is complex. Research shows that persistent bullying can cause depression and anxiety and contribute to feelings of suicidal behavior.

The DHHS, however, says that media reports often "oversimplify" the relationship between suicide and bullying. Most young people who are bullied do not become suicidal, they state, and most young people who die by suicide have multiple risk factors, beyond bullying alone.

As well as the psychological impact of bullying, though, studies have shown that children who are bullied may also be prone to physical illness, not only during the period in which the bullying took place, but in later life.

For instance, recently Medical News Today reported on a study that found children who are bullied between the ages of 8 and 10 are more likely to experience sleepwalking, night terrors or nightmares at the age of 12.
Victims of bullying have 'poorer health, lower income, lower quality of life' as adults

But other research shows that the long-term health effects of bullying on the victim are potentially much more far-reaching and serious.


Fast facts about bullying
Over 77% of American students have been bullied verbally, mentally and physically
About 85% of incidents receive no kind of intervention, so it is common for bullying to be ignored
In surveys quoted by the DHHS, approximately 30% of young people admit to bullying others.

A 2014 study from researchers at King's College London in the UK found that the negative social, physical and mental health effects of childhood bullying are still evident up to 40 years later.

The study examined data from the British National Child Development Study, which includes information from all children born in England, Scotland and Wales during 1 week in 1958. In total, 7,771 children from that study - whose parents provided information on their child's exposure to bullying when they were aged 7 and 11 - were followed until the age of 50.

Similar to modern rates in both the UK and US, 28% of children in the study had been bullied occasionally, and 15% had been bullied frequently.

The researchers found that, at age 50, participants who had been bullied when they were children were more likely to be in poorer physical and psychological health and have worse cognitive functioning than people who had not been bullied.

Victims of bullying were also found to be more likely to be unemployed, earn less and have lower educational levels than people who had not been bullied. They were also less likely to be in a relationship or have good social support.

People who had been bullied were more likely to report lower quality of life and life satisfaction than their peers who had not been bullied.

Even when factors such as childhood IQ, emotional and behavioral problems, parents' socioeconomic status and low parental involvement were taken into account, the association remained between bullying and negative social, physical and mental health outcomes.

"Our study shows that the effects of bullying are still visible nearly 4 decades later," said lead author Dr. Ryu Takizawa, from the Institute of Psychiatry at King's College London. "The impact of bullying is persistent and pervasive, with health, social and economic consequences lasting well into adulthood."

"We need to move away from any perception that bullying is just an inevitable part of growing up," added co-author Prof. Louise Arseneault. She says that while programs to stop bullying are important, teachers, parents and policymakers need to focus efforts on early intervention to prevent problems caused by bullying persisting into adolescence and adulthood.
How does bullying in childhood affect physical health in adulthood?

Prof. Arseneault has also written in depth on another 2014 study into the long-term health effects of bullying, conducted by a team from Duke University Medical Center in Durham, NC.

Some experts think that bullying results in a kind of "toxic stress" that affects children's physiological responses, possibly explaining why some victims of bullying go on to develop health problems.

That study investigated the hypothesis that bullying victimization is a form of "toxic stress." Proponents of this theory suggest that this toxic stress affects children's physiological responses, which may explain why many - otherwise healthy - victims of bullying go on to develop health problems.

One mechanism that may drive this psychological and physical relationship is the inflammatory response, which occurs when the body is fighting an infection, reacting to an injury or responding to a chronic health problem.

The Duke team assessed the extent of this response in victims of bullying by measuring levels of a protein called C-reactive protein (CRP). High levels of CRP occur during the inflammatory response.

Previously, studies have shown that people who were abused by an adult in their childhood display elevated levels of CRP. Prof. Arseneault says this suggests that the body is reacting to toxic stress in the same way as when it is attempting to fight an infection.

The Duke team analyzed data from the Great Smoky Mountains Study which measured CRP levels in 1,420 children aged 9-16 who had been victims of bullying, as well as bullies and "bully-victims" - children who are victims of bullying and who also bully others.

The researchers found that children who had been involved in bullying multiple times - whether as victims, bullies or bully-victims - had higher levels of CRP than those who were not exposed to bullying.

The team then looked at the participants' CRP measurements as they entered adulthood. The findings were similar - people who had been repeatedly bullied during childhood displayed the highest levels of CRP.

However, in a finding that surprised the researchers, participants who bullied others were found to now have the lowest levels of CRP out of all groups studied - including those who had not been exposed to bullying.

For both the childhood and early-adulthood CRP measurements, the researchers took into account factors such as maltreatment, family dysfunction, anxiety disorders, prior CRP levels and variables associated with CRP, but the associations remained.

Prof. Arseneault comments that previous research along these lines has demonstrated that bullying can influence physiological responses to stress, including altered levels of cortisol, the hormone that is released in the body when under stress. One study involving pairs of identical twins - where one twin had been bullied and the other had not - found that the bullied twins demonstrated a "blunted" level of cortisol response.

Medical News Today spoke to lead author of the study, William E. Copeland, assistant professor at the Center for Developmental Epidemiology at Duke, who confirmed that the elevated CRP levels suggest one mechanism responsible for translating the act of bullying into potentially long-term physical health problems:


"Bullying and the continued threat of being bullying can have physiological consequences. There is evidence that over time this experience can dysregulate biological stress response systems. In our work, victims have higher levels of the inflammatory marker C-reactive protein up to a decade after their bullying experience. Over time, the wear and tear of these physiological changes can limit the individual's ability to respond to new challenges and put them at increased risk for physical illnesses."
Victims, bullies and bully-victims - how do their outcomes compare?

In 2013, Prof. Copeland also co-authored another analysis of data from the Great Smoky Mountains Study, looking into the long-term health consequences of bullying that - as wth the King's College London study - found that victims of bullying have a higher risk of poor health, lower socioeconomic status and problems with forming social relationships as adults.

"Bully-victims" were found to be six times more likely to have a serious illness, smoke regularly or develop a psychiatric disorder in adulthood than those who had not been involved in bullying.

This study also looked at the victims, bullies and bully-victim groups. However, in this study, the bully-victims were found to be the most vulnerable group. Subjects in this group were found to be six times more likely to have a serious illness, smoke regularly or develop a psychiatric disorder in adulthood than those who had not been involved in bullying.

"Not all victims are created equally," Dr. Copeland says of the study's findings. "Victims that attempt to fight back and hurt others tend to be impulsive, easily provoked, have low self-esteem and are often unpopular with their peers. Bully-victims are also more likely to come from dysfunctional families and to have been maltreated by family members."

"As such," he continues, "these children have been exposed to high levels of adversity and lack the skills, temperament and social support to cope effectively. This puts them at profound risk for long-term problems."

The 1,420 participants were interviewed at ages 9, 11 or 13, and then followed up at ages 19, 21 or 24-26 years. Nearly a quarter of the children (23.6%) reported having been bullied, with 7.9% saying they had been bullies, and 6.1% reporting that they had been bully-victims.

While both victims and bully-victims were found to be at risk of poorer health, finances and social relationships as adults, participants who reported being bullies had no association with poorer outcomes in adulthood.

However, Dr. Copeland told us that:


"It is important to be clear here that bullies do not get off scot-free. Pure bullies do have worse outcomes in adulthood but those poor outcomes tend to be due to their preexisting behavior problems and family adversities rather than being a bully per se. For victims, in contrast, the experience of being a victim itself is associated with worse outcomes."

Dr. Copeland considers that the most effective prevention programs involve parent meetings, firm disciplinary methods and strong supervision.

"Once a child has been bullied, it is critical for parents and teachers to be supportive and to ensure that the bullying does not continue," he emphasizes. "Too often, bullying is not taken seriously and is treated like a normal rite of passage."

Though evidence is mounting for physical health problems in adulthood that are associated with childhood bullying, experts say it is the psychological consequences that remain the most concerning, and which are preventable.

Victims of bullying are at increased risk for a range of anxiety disorders, says Dr. Copeland, while bully-victims are at risk for depression and suicide.

"This is tragic because we have effective, tested treatments for all of those problems," he says. "The problem is that very few people with such mental health problems get the help they need."