Researchers at Mount Sinai School of Medicine have shown for the first time in an animal model that vitamin C actively protects against osteoporosis, a disease affecting large numbers of elderly women and men in which bones become brittle and can fracture.
‘This study has profound public health implications, and is well worth exploring for its therapeutic potential in people,’ said lead researcher Mone Zaidi, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease, and of Structural and Chemical Biology, and Director of the Mount Sinai Bone Program.
‘The medical world has known for some time that low amounts of vitamin C can cause scurvy and brittle bones, and that higher vitamin C intake is associated with higher bone mass in humans, ‘said Dr. Zaidi. ‘What this study shows is that large doses of vitamin C, when ingested orally by mice, actively stimulate bone formation to protect the skeleton. It does this by inducing osteoblasts, or premature bone cells, to differentiate into mature, mineralising speciality cells.’
The researchers worked with groups of mice whose ovaries had been removed, a procedure known to reduce bone density, and compared them with control mice that had ‘sham’ operations, which left their ovaries intact. The mice with ovariectomies were divided into two groups, one of which was given large doses of vitamin C over eight weeks. The scientists measured the bone mineral density in the lumbar spine, femur, and tibia bones.
The mice who received an ovariectomy – and no vitamin C – had a much lower bone mineral density (BMD) versus controls, whereas mice who received a ovariectomy and large doses of vitamin C, had roughly the same BMD as the controls, suggesting vitamin C prevented BMD loss in this group.
‘Further research may discover that dietary supplements may help prevent osteoporosis in humans,’ said Dr. Zaidi. ‘If so, the findings could be ultimately useful to developing nations where osteoporosis is prevalent and standard medications are sparse and expensive.’
The Mount Sinai Medical Center
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Chronic kidney disease changes the composition of intestinal bacterial microbes that normally play a crucial role in staving off disease-causing pathogens and maintaining micro-nutrient balance, according to UC Irvine researchers.
This profound alteration of the gut microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in patients with advanced renal disease, they said.
Study leader Dr. N.D. Vaziri of the UCI School of Medicine’s Division of Nephrology & Hypertension noted that consumption of high-fibre foods and better control of uremia — a disease common in kidney failure — by diet and dialysis may improve the composition of gut microbes and the well-being of patients.
The researchers studied microbial DNA extracted from the stool samples of a group of renal failure patients and healthy control individuals. They found marked differences in the abundance of some 190 types of bacteria in the gut microbiome of those with kidney disease — and confirmed the results in a concurrent study of rats with and without chronic kidney disease.
Vaziri explained that nitrogen-rich waste products — particularly urea and uric acid, which are usually excreted by the kidneys — accumulate in the body fluids of patients with renal failure. This leads to the massive release of these waste products in the gastrointestinal tract, supporting the growth and dominance of microbial species that can utilise these compounds.
The impact of this flooding of the gut by nitrogenous waste products in patients with advanced kidney disease, Vaziri added, is compounded by dietary restrictions on fruits and vegetables, which contain the indigestible fibres that favourable gut microbes feed on. This is because fruits and vegetables contain large amounts of potassium, a mineral normally excreted by the kidneys. In cases of renal failure, potassium levels are high, increasing the risk of cardiac arrest.
One solution, Vaziri said, is to provide longer, more frequent dialysis treatments. This would let more potassium be removed by dialysis and allow for more potassium in the diet. Alternatively, packaged fibre foods that do not contain potassium could be used as a dietary supplement.
The work adds to a growing body of evidence pointing to the role of gut bacteria in disease and health. Recent research by other groups has identified changes in the composition of intestinal microbial flora in people with diabetes, colorectal cancer, obesity and inflammatory bowel disease, among other conditions.
University of California, Irvine
A newly discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent pre-clinical study suggests.
The team, led by Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression. PARP inhibition in various models was found to suppress AR activity, which fuels prostate growth.
Researchers believe that the dual functions of PARP-1—as both a regulator of AR as well as critical for DNA damage repair—could be leveraged for therapeutic benefit. PARP inhibitors could slow down advanced-stage prostate cancer and shrink tumours, the team surmises.
‘We hope to capitalise on this previously unknown function in PARP-1 in prostate cancer,’ said Dr. Knudsen. ‘Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumour effects of castration and delayed onset to castration resistance. ‘
‘This is the basis to support a clinical trial investigating PARP-1 inhibitors in patients with advanced disease,’ she added.
Today, PARP-1 is seen as a valuable target because of its involvement in DNA damage repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumour growth by stopping DNA repair in various cancers.
Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumours arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.
Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, PARP inhibitors targeting both functions could sensitise prostate cancer cells to DNA damage, and potentially improve the efficacy of AR-directed therapies in these patients, the researchers suggest in the paper.
Almost 40 percent of men with prostate cancer progress into an advanced stage, termed castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.
Using various in vitro and in vivo model systems, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer. Additionally, inhibiting PARP-1 suppressed proliferation of cultured, primary human tumour specimens in a state-of-the-art system.
Jefferson’s Kimmel Cancer Center
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Scientists at the Montreal Neurological Institute and Hospital – The Neuro, McGill University working with a team at Oxford University have uncovered the genetic defect underlying a group of rare genetic disorders.
Using a new technique that has revolutionised genetic studies, the teams determined that mutations in the RMND1 gene were responsible for severe neurodegenerative disorders, in two infants, ultimately leading to their early death. Although the teams’ investigations dealt with an infant, their discovery also has implications for understanding the causes of later-onset neurological diseases.
The RMND1 gene encodes a protein that is an important component of the machinery in mitochondria which generates the chemical energy that all cells need to function. Mutations in genes affecting mitochondrial function are common causes of neurological and neuromuscular disorders in adults and children. It is estimated that one newborn baby out of 5000 is at risk for developing one of these disorders. Mortality among such cases is very high.
‘Mitochondria are becoming a focus of research because it’s clear they’re involved in neurodegenerative disorders in a fairly big way,’ says Dr. Eric Shoubridge, an internationally recognised specialist on mitochondrial diseases at The Neuro and lead author of the paper published.
‘For instance, we’re finding that dysfunctional mitochondria may be at the heart of adult-onset disorders like Parkinson’s and Alzheimer’s disease.’
Discovery of the mutations in the RMND1 gene involved using whole-exome sequencing at the McGill University and Genome Québec Innovation Centre. This technique allows all of the genes in the body that code for proteins to be sequenced and analysed in a single experiment. At a cost of about $1000, whole-exome sequencing is much more economical than previous techniques in which lists of candidate genes had to be screened in the search for mutations. The technique is poised to change the face of genetic diagnosis, making testing more efficient and available.
‘Parents who have had a child with a mitochondrial disorder and who are hesitating to have another child now have the possibility to know the cause of the disease. With genetic information, they have reproductive options like in vitro fertilisation,’ says Dr. Shoubridge. The discovery of the RMND1 gene’s role sheds light on disorders of mitochondrial energy metabolism, but therapies to alleviate or cure such disorders remain elusive. Dr. Shoubridge is hopeful that the discovery will encourage pharmaceutical interest. ‘Drug companies are starting to be interested in rare diseases and metabolic disorders like this. They’re picking some genes as potential drug candidates.’
EurekAlert
Many diseases, including cancers, leave genetic clues in the body just as criminals leave DNA at the scene of a crime. But tools to detect the DNA-like sickness clues known as miRNAs, tend to be slow and expensive. Now a chemist and a biologist from University of Copenhagen have invented a method that promises to shave days off the lab work done to reveal diseases, using cheap methods and easy to use analytical apparatuses.
Chemistry researcher Tom Vosch and plant molecular biologist Seong Wook Yang invented a DNA sensor, coupling genetic material to a luminous molecule which goes dark only in the presence of a specific target. Details on their invention,
‘
It’s an unusually quick and elegant method for screening
‘We invented a probe that emits light only as long as the sample is clean. That is an unusually elegant and easy way to screen for a particular genetic target’, says Vosch of the Department of Chemistry’s Nano Science Centre.
You could say that the inventors took their cue from crime detection. In murder cases police technicians use DNA to identify the killer. Similarly Individuals with disease are likely to have a unique miRNA profile. Any disease that is attacking a patient leaves this genetic clue all over the victim. And because the profiles of miRNAs vary by type of cancer, finding it proves beyond a reasonable doubt what made the patient sick.
The new detection method exploits a natural quality of genetic material. A single DNA strand is made up of molecules, so called bases, ordered in a unique combination. When two strands join to form their famous double helix, they do so by sticking to complementary copies of themselves. Likewise strands tailored to match particular miRNAs will stick to the real thing with uncanny precision. But detecting this union of the strands was only made possible when Vosch and Yang paired their skills.
Tom Vosch is specialised in studying molecules that light up. Seong Wook Yang is specialised in miRNA. Together they figured out how to attach the light emitting molecules to DNA sensors for miRNA detection. Vosch and Yang discovered, that when these luminous DNA-strands stick with microRNA-strands, their light is snuffed out, giving a very visible indication that the target miRNA is present in the sample. In other words: When the light goes out, the killer is in the house.
Vosch and Yang tested their Silver Nano Cluster DNA probes with eight different types of genetic material and found that they work outright with six of them. But more importantly, they figured out how to fix the ones that didn’t. This indicates that their method will work in the detection of almost all types of miRNAs, also in all likelihood for cancer related miRNAs. The most widespread current miRNA detection method requires some 48 hours of lab work from raw samples. The new method can do the same job of detection within a maximum of 6 hours.
University of Copenhagen
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A new model developed by Wellcome Trust researchers to predict the persistence of stuttering could be used to screen all children at school age, new research suggests. Stuttering – also known as stammering – is thought to affect one in 20 children under the age of five, and onset generally occurs around the age of three. Around one child in 100 is likely to still be stuttering in their teenage years.
Screening for communication problems at key stages, including school entry, was suggested by the government in its Every Child Matters initiative, which was launched ten years ago.
Professor Peter Howell and colleagues from the Division of Psychology and Language Sciences at UCL (University College London) previously developed a model that allowed them to accurately predict which children at the age of eight would continue to stutter in their teenage years. In this new study, Professor Howell used the model to show that it is possible to screen children for stuttering when they enter primary school, around the age of five.
Professor Howell says: ‘For a screening tool to be used effectively, it needs to meet the rigorous standards for accurately identifying children who stutter separately from children who are fluent. We found that this method can do just that.
‘If we can identify children at risk of stuttering, then we can offer appropriate interventions to help them early on. Primary school is a key time in a child’s development and any help in tackling potential communication problems could make a big difference to the child’s life.’
Professor Howell developed the model working with 222 children who stutter and 103 fluent children, and he and his colleagues validated their findings in 272 children who stutter and 25 fluent children, all between ages five and 18. He used the Stuttering Severity Instrument Version 3 (SSI-3, a standardised test involving measurement of speech symptoms, their durations and physical symptoms accompanying stuttering such as tics), which they had previously been shown to be the only reliable tool for predicting persistence of stuttering.
He found that their model performs extremely well with five-year-olds. At this age, over 96 per cent of children who stutter and over 83 per cent of fluent children would be correctly identified. Although this would mean that some children who do not stutter would be incorrectly classified, Professor Howell and colleagues believe that some of these fluent children may suffer from other communication problems.
Wellcome Trust
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Although placebos have played a critical role in medicine and clinical research for more than 70 years, it has been a mystery why these inactive treatments help to alleviate symptoms in some patients – and not others. Now researchers have for the first time identified genetic differences between placebo responders and non-responders, providing an important new clue to what has come to be known as ‘the placebo effect.’
Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), the new findings demonstrate that genetic differences that account for variations in the brain’s dopamine levels help to determine the extent of a person’s placebo response, a discovery that not only has important implications for patient care, but could also prove to be of significant benefit to researchers in designing and conducting clinical trials to help determine a drug’s effectiveness.
‘There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos, ‘ explains the study’s first author Kathryn Hall, PhD, a research fellow in the Division of General Medicine and Primary Care and member of the Program in Placebo Studies and Therapeutic Encounter (PiPS) at BIDMC. ‘With this new research, we may now be able to use a person’s genetic makeup to predict whether or not they will respond to a placebo.’
The placebo effect occurs when patients show improvement from treatments that contain no active ingredients. For investigators conducting clinical trials of new drugs — which require that new treatments be tested against a placebo control to determine their efficacy– placebo responses can pose a particularly difficult challenge, requiring investigators to recruit additional patients in order to acquire statistically significant data, and substantially adding to the overall cost of the trial.
Because dopamine is known to be important to both reward and pain, the investigators began their search for a genetic placebo marker in the dopamine pathway. Their focus soon turned to the catechol-O-methyltransferase (COMT) gene.
‘COMT made for an excellent candidate because it’s been implicated in the cause and treatment of many conditions, including pain and Parkinson’s disease,’ says Hall. ‘It’s also been found in behavioural genetic models of reward responsiveness and confirmation bias, the tendency to confirm new information based on your beliefs.’
Polymorphisms are gene variations, and in the case of the COMT val158met polymorphism, the changes in the COMT gene result in people having either two copies of the methionine (met) allele, two copies of the valine (val) allele, or one copy of each.
‘People with two copies of met, the ‘met/mets,’ have three to four times more dopamine available in their prefrontal cortex [the brain area associated with cognition, personality expression, decision making and social behaviour] than the people with two copies of val,’ explains Hall. The scientists hypothesised that if dopamine was indeed involved in the placebo response, they would see a difference between how met/met, val/val and met/val genotypes responded to placebo treatments, with the met/met individuals showing a higher response.
To test this hypothesis, the researchers took advantage of a unique opportunity, revisiting a 2008 clinical trial led by PiPS Director Ted Kaptchuk, designed to study the placebo effect in patients with irritable bowel syndrome (IBS). ‘In our original work, IBS patients were assigned to one of three treatment arms and we explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered,’ explains Kaptchuk, Associate Professor of Medicine at HMS and the study’s senior author. The treatment conditions included either being ‘waitlisted’ and receiving no treatment, receiving placebo acupuncture in a business-like clinical manner, or receiving placebo acupuncture treatment from a warm supportive health care provider.
Armed with this original data, the scientists genotyped blood samples from patients from the earlier study, using a statistical method known as regression analysis to analyse the effects of a person’s genotype and the type of treatment received. ‘Our regression analysis found that as the copies of met increased, placebo responses increased in a linear fashion, presumably because more dopamine was available,’ Hall explains. The findings showed that among the IBS patients who had been in the waitlist treatment arm there was no difference in treatment responses between met/met, val/val and met/val genotypes as determined by the IBS-Symptom Severity Scale and Adequate Relief. Among those in the group that received a placebo administered in a businesslike manner, the met/met genotypes showed a small improvement over their val/val and met/val counterparts.
But, says Hall, among the individuals who had received placebo treatment from the warm supportive health care providers, there was a striking difference: the ‘met/mets’ demonstrated a six-fold greater improvement in their IBS symptoms relative to the ‘val/vals.’
‘These findings suggest that it is possible that met/met is a genetic marker for the placebo response and val/val is a marker for non-response,’ says Hall. ‘In addition, our findings underscore differences in placebo response based on the patient’s experience of the clinical environment. In the case of the met/met individuals, you can really see the advantage of a positive doctor-patient relationship. Conversely, our findings suggest that the val/val patients are less influenced by placebo treatment and this sheds light on a clinical challenge faced by many health care providers, whose empathic care helps some people, but makes no difference to others.’
Beth Israel Deaconess Medical Center
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The brains of teenage girls with behavioural disorders are different to those of their peers, UK researchers have found. The study of 40 girls revealed differences in the structure of areas linked to empathy and emotions. Previous work has found similar results in boys.
Experts suggest it may be possible to use scans to spot problems early, then offer social or psychological help. An estimated five in every 100 teenagers in the UK are classed as having a conduct disorder.
It is a psychiatric condition which leads people to behave in aggressive and anti-social ways, and which can increase the risk of mental and physical health problems in adulthood. Rates have risen significantly among adolescent girls in recent years, while levels in males have remained about the same.
In this study, funded by the Wellcome Trust and Medical Research Council, UK and Italian researchers conducted brain scans of 22 teenage girls who had conduct disorder and compared them with scans of 20 who did not.
They also checked the scans against others previously taken of teenage boys with conduct disorder. The team found part of the brain called the amygdala was smaller in the brains of male and female teenagers with conduct disorder than in their peers.
The amygdala is involved in picking up whether or not others feel afraid – and plays a role in people feeling fear themselves. Girls with conduct disorder also had less grey matter in an area of the brain called the insula – linked to emotion and understanding your own emotions.
However the same area was larger in boys with conduct disorder than healthy peers, and researchers are not yet sure why that is the case. The brains of those with the worst behaviour were most different from the norm.
Dr Andy Calder, from the MRC cognition and brain sciences unit, who worked on the study, said: ‘The origins of these changes could be due to being born with a particular brain dysfunction or it could be due to exposure to adverse environments such as a distressing experience early in life that could have an impact on the way the brain develops.’
Dr Graeme Fairchild, of the University of Cambridge who also worked on the study, said there were potential uses for the finding.
‘In the US, people are already using brain scans to argue diminished responsibility. I think we’re too early in our understanding to really do that, but it is happening.
‘It would also be possible to use scans where a person is at high risk of offending in the future.
‘More help could be given to the family and, in the same way that someone with language impairment receives extra help, help could be given to teach a person to understand emotions – and the emotions of others – better.’
BBC
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Blood hormone tests can predict a woman’s risk for developing postmenopausal breast cancer for up to 20 years, according to a study led by Xuehong Zhang, MD, Channing Division of Network Medicine, Brigham and Women’s Hospital (BWH) Department of Medicine.
Using data from the Nurses’ Health Study, Zhang , Susan Hankinson, ScD, Channing Division of Network Medicine, BWH Department of Medicine and colleagues analysed 796 patients with postmenopausal breast cancer who had not received hormone therapy.
They conducted blood hormone tests at two time points: between 1989 and 1990 and between 2000 and 2002. Researchers matched each patient with two controls who were not diagnosed with breast cancer.
‘We found that a single hormone level was associated with breast cancer risk for at least 16 to 20 years among postmenopausal women not using postmenopausal hormones,’ said Zhang. ‘We, and others, are now evaluating if the addition of hormone levels to current risk prediction models can substantially improve our ability to identify high-risk women who would benefit from enhanced screening or chemoprevention-if so, the current data suggest that hormone levels would not need to be measured in the clinic more than once every 10, or possibly 20, years.’
Women with hormone levels in the highest 25 percent for estradiol, testosterone and DHEAS had a 50 percent to 107 percent greater chance for developing breast cancer compared with women in the lowest 25 percent. Relative risks for developing breast cancer were similar at one to 10 years vs. 11 to 20 years (also 16 to 20 years) after blood collection.
Researchers also investigated whether these higher levels were more closely linked to hormone-receptor positive breast cancers and if they predicted risk regardless of tumour aggressiveness.
In the first case, they found that elevated levels of estradiol increase a woman’s risk for hormone receptor-positive breast cancer, specifically oestrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumours.
In general, increased hormone levels, except for DHEAS, tracked closely with increased risk for receptor-positive breast cancer. Data on receptor-negative cancers were inconclusive and need additional, large studies.
Significantly, elevated hormone levels were also associated with aggressive breast cancer, which the study defined as recurrent or fatal cancer.
‘The relationship was comparable or possibly stronger for recurrent and fatal breast cancer than it was for overall breast cancer risk although these results were based on relative small numbers of participants,’ said Zhang.
Researchers also confirmed the protective effect of sex hormone-binding globulin (SHBG), which seems to negate the cancer-causing effects of certain hormones. Women in the highest 25 percent of SHBG levels had a 30 percent lower risk for breast cancer compared with women in the lowest 25 percent for SHBG levels.
Zhang noted that the study had low case numbers for several cancer subgroups, including HER2, triple-negative and basal-like breast cancers. More research is necessary to determine the relationship between elevated hormone levels and these important breast cancer groups.
Brigham and Women’s Hospital
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Men whose testosterone drops following radiation therapy for prostate cancer are more likely to experience a change in PSA levels that signals their cancer has returned, according to new research from Fox Chase Cancer Center.
Specifically, men whose testosterone fell following various forms of radiation therapy were more likely to experience an increase in prostate-specific antigen (PSA)—often the first indication the cancer has recurred.
‘The men who had a decrease in testosterone also appear to be the men more likely to see an increase in PSA after treatment,’ says study author Jeffrey Martin, MD, resident physician in the Department of Radiation Oncology at Fox Chase.
In theory, doctors may one day be able to use testosterone levels to guide treatment decisions, says Martin. ‘For men with a decrease in testosterone, doctors might intervene earlier with other medications, or follow their PSA more closely than they would otherwise, to spot recurrences at an earlier time.’
Martin and his colleagues decided to conduct the study because there is limited information regarding testosterone levels after radiation treatment and what it means for prognosis. To investigate whether a decrease in testosterone has any clinical effects, Martin and his colleagues reviewed medical records from nearly 260 men who received radiation therapy for prostate cancer between 2002 and 2008. The men were treated with either brachytherapy, in which doctors insert radioactive seeds in the prostate, or intensity modulated radiation therapy (IMRT), in which an external beam of radiation is directed at the prostate.
The researchers found that testosterone levels tended to decrease following both forms of radiation therapy. And men who experienced a post-radiation drop in testosterone— particularly a significant drop—were more likely to see their PSA levels rise during the follow-up period.
Still, an increase in PSA—known as biochemical failure—was relatively rare, the authors found. ‘Only 4% of patients with low-risk prostate cancer had biochemical failure at five years,’ says Martin.
Even though researchers have seen testosterone decrease following another form of radiation, these latest findings are still somewhat surprising, says Martin, because testosterone is believed to drive prostate cancer. In fact, some patients with advanced forms are prescribed hormone therapy that attempts to knock down testosterone.
‘Seeing that a drop in testosterone is tied to recurrence is kind of a surprising result,’ says Martin. ‘We don’t necessarily know what this means yet. I think the relationship between testosterone levels following radiation therapy and prognosis needs more study, and until then it’s premature to say this is something patients should ask their doctors about.’
This was a small study that needs to be validated in a larger group of men before doctors begin basing their predictions of recurrence on patients’ testosterone levels, he cautions. ‘I think the link between testosterone and PSA needs more study, in a larger set of patients.’
EurekAlert
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Study shows Vitamin C prevents bone loss in animal models
, /in E-News /by 3wmediaResearchers at Mount Sinai School of Medicine have shown for the first time in an animal model that vitamin C actively protects against osteoporosis, a disease affecting large numbers of elderly women and men in which bones become brittle and can fracture.
‘This study has profound public health implications, and is well worth exploring for its therapeutic potential in people,’ said lead researcher Mone Zaidi, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease, and of Structural and Chemical Biology, and Director of the Mount Sinai Bone Program.
‘The medical world has known for some time that low amounts of vitamin C can cause scurvy and brittle bones, and that higher vitamin C intake is associated with higher bone mass in humans, ‘said Dr. Zaidi. ‘What this study shows is that large doses of vitamin C, when ingested orally by mice, actively stimulate bone formation to protect the skeleton. It does this by inducing osteoblasts, or premature bone cells, to differentiate into mature, mineralising speciality cells.’
The researchers worked with groups of mice whose ovaries had been removed, a procedure known to reduce bone density, and compared them with control mice that had ‘sham’ operations, which left their ovaries intact. The mice with ovariectomies were divided into two groups, one of which was given large doses of vitamin C over eight weeks. The scientists measured the bone mineral density in the lumbar spine, femur, and tibia bones.
The mice who received an ovariectomy – and no vitamin C – had a much lower bone mineral density (BMD) versus controls, whereas mice who received a ovariectomy and large doses of vitamin C, had roughly the same BMD as the controls, suggesting vitamin C prevented BMD loss in this group.
‘Further research may discover that dietary supplements may help prevent osteoporosis in humans,’ said Dr. Zaidi. ‘If so, the findings could be ultimately useful to developing nations where osteoporosis is prevalent and standard medications are sparse and expensive.’ The Mount Sinai Medical Center
Chronic kidney disease alters intestinal microbial flora
, /in E-News /by 3wmediaChronic kidney disease changes the composition of intestinal bacterial microbes that normally play a crucial role in staving off disease-causing pathogens and maintaining micro-nutrient balance, according to UC Irvine researchers.
This profound alteration of the gut microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in patients with advanced renal disease, they said.
Study leader Dr. N.D. Vaziri of the UCI School of Medicine’s Division of Nephrology & Hypertension noted that consumption of high-fibre foods and better control of uremia — a disease common in kidney failure — by diet and dialysis may improve the composition of gut microbes and the well-being of patients.
The researchers studied microbial DNA extracted from the stool samples of a group of renal failure patients and healthy control individuals. They found marked differences in the abundance of some 190 types of bacteria in the gut microbiome of those with kidney disease — and confirmed the results in a concurrent study of rats with and without chronic kidney disease.
Vaziri explained that nitrogen-rich waste products — particularly urea and uric acid, which are usually excreted by the kidneys — accumulate in the body fluids of patients with renal failure. This leads to the massive release of these waste products in the gastrointestinal tract, supporting the growth and dominance of microbial species that can utilise these compounds.
The impact of this flooding of the gut by nitrogenous waste products in patients with advanced kidney disease, Vaziri added, is compounded by dietary restrictions on fruits and vegetables, which contain the indigestible fibres that favourable gut microbes feed on. This is because fruits and vegetables contain large amounts of potassium, a mineral normally excreted by the kidneys. In cases of renal failure, potassium levels are high, increasing the risk of cardiac arrest.
One solution, Vaziri said, is to provide longer, more frequent dialysis treatments. This would let more potassium be removed by dialysis and allow for more potassium in the diet. Alternatively, packaged fibre foods that do not contain potassium could be used as a dietary supplement.
The work adds to a growing body of evidence pointing to the role of gut bacteria in disease and health. Recent research by other groups has identified changes in the composition of intestinal microbial flora in people with diabetes, colorectal cancer, obesity and inflammatory bowel disease, among other conditions. University of California, Irvine
Doubling up on advanced prostate cancer with PARP inhibitors
, /in E-News /by 3wmediaA newly discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent pre-clinical study suggests.
The team, led by Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression. PARP inhibition in various models was found to suppress AR activity, which fuels prostate growth.
Researchers believe that the dual functions of PARP-1—as both a regulator of AR as well as critical for DNA damage repair—could be leveraged for therapeutic benefit. PARP inhibitors could slow down advanced-stage prostate cancer and shrink tumours, the team surmises.
‘We hope to capitalise on this previously unknown function in PARP-1 in prostate cancer,’ said Dr. Knudsen. ‘Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumour effects of castration and delayed onset to castration resistance. ‘
‘This is the basis to support a clinical trial investigating PARP-1 inhibitors in patients with advanced disease,’ she added.
Today, PARP-1 is seen as a valuable target because of its involvement in DNA damage repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumour growth by stopping DNA repair in various cancers.
Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumours arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.
Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, PARP inhibitors targeting both functions could sensitise prostate cancer cells to DNA damage, and potentially improve the efficacy of AR-directed therapies in these patients, the researchers suggest in the paper.
Almost 40 percent of men with prostate cancer progress into an advanced stage, termed castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.
Using various in vitro and in vivo model systems, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer. Additionally, inhibiting PARP-1 suppressed proliferation of cultured, primary human tumour specimens in a state-of-the-art system. Jefferson’s Kimmel Cancer Center
Scientists discover gene behind rare disorders
, /in E-News /by 3wmediaScientists at the Montreal Neurological Institute and Hospital – The Neuro, McGill University working with a team at Oxford University have uncovered the genetic defect underlying a group of rare genetic disorders.
Using a new technique that has revolutionised genetic studies, the teams determined that mutations in the RMND1 gene were responsible for severe neurodegenerative disorders, in two infants, ultimately leading to their early death. Although the teams’ investigations dealt with an infant, their discovery also has implications for understanding the causes of later-onset neurological diseases.
The RMND1 gene encodes a protein that is an important component of the machinery in mitochondria which generates the chemical energy that all cells need to function. Mutations in genes affecting mitochondrial function are common causes of neurological and neuromuscular disorders in adults and children. It is estimated that one newborn baby out of 5000 is at risk for developing one of these disorders. Mortality among such cases is very high.
‘Mitochondria are becoming a focus of research because it’s clear they’re involved in neurodegenerative disorders in a fairly big way,’ says Dr. Eric Shoubridge, an internationally recognised specialist on mitochondrial diseases at The Neuro and lead author of the paper published.
‘For instance, we’re finding that dysfunctional mitochondria may be at the heart of adult-onset disorders like Parkinson’s and Alzheimer’s disease.’
Discovery of the mutations in the RMND1 gene involved using whole-exome sequencing at the McGill University and Genome Québec Innovation Centre. This technique allows all of the genes in the body that code for proteins to be sequenced and analysed in a single experiment. At a cost of about $1000, whole-exome sequencing is much more economical than previous techniques in which lists of candidate genes had to be screened in the search for mutations. The technique is poised to change the face of genetic diagnosis, making testing more efficient and available.
‘Parents who have had a child with a mitochondrial disorder and who are hesitating to have another child now have the possibility to know the cause of the disease. With genetic information, they have reproductive options like in vitro fertilisation,’ says Dr. Shoubridge. The discovery of the RMND1 gene’s role sheds light on disorders of mitochondrial energy metabolism, but therapies to alleviate or cure such disorders remain elusive. Dr. Shoubridge is hopeful that the discovery will encourage pharmaceutical interest. ‘Drug companies are starting to be interested in rare diseases and metabolic disorders like this. They’re picking some genes as potential drug candidates.’ EurekAlert
Glowing DNA invention points towards high speed disease detection
, /in E-News /by 3wmediaMany diseases, including cancers, leave genetic clues in the body just as criminals leave DNA at the scene of a crime. But tools to detect the DNA-like sickness clues known as miRNAs, tend to be slow and expensive. Now a chemist and a biologist from University of Copenhagen have invented a method that promises to shave days off the lab work done to reveal diseases, using cheap methods and easy to use analytical apparatuses.
Chemistry researcher Tom Vosch and plant molecular biologist Seong Wook Yang invented a DNA sensor, coupling genetic material to a luminous molecule which goes dark only in the presence of a specific target. Details on their invention,
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It’s an unusually quick and elegant method for screening
‘We invented a probe that emits light only as long as the sample is clean. That is an unusually elegant and easy way to screen for a particular genetic target’, says Vosch of the Department of Chemistry’s Nano Science Centre.
You could say that the inventors took their cue from crime detection. In murder cases police technicians use DNA to identify the killer. Similarly Individuals with disease are likely to have a unique miRNA profile. Any disease that is attacking a patient leaves this genetic clue all over the victim. And because the profiles of miRNAs vary by type of cancer, finding it proves beyond a reasonable doubt what made the patient sick.
The new detection method exploits a natural quality of genetic material. A single DNA strand is made up of molecules, so called bases, ordered in a unique combination. When two strands join to form their famous double helix, they do so by sticking to complementary copies of themselves. Likewise strands tailored to match particular miRNAs will stick to the real thing with uncanny precision. But detecting this union of the strands was only made possible when Vosch and Yang paired their skills.
Tom Vosch is specialised in studying molecules that light up. Seong Wook Yang is specialised in miRNA. Together they figured out how to attach the light emitting molecules to DNA sensors for miRNA detection. Vosch and Yang discovered, that when these luminous DNA-strands stick with microRNA-strands, their light is snuffed out, giving a very visible indication that the target miRNA is present in the sample. In other words: When the light goes out, the killer is in the house.
Vosch and Yang tested their Silver Nano Cluster DNA probes with eight different types of genetic material and found that they work outright with six of them. But more importantly, they figured out how to fix the ones that didn’t. This indicates that their method will work in the detection of almost all types of miRNAs, also in all likelihood for cancer related miRNAs. The most widespread current miRNA detection method requires some 48 hours of lab work from raw samples. The new method can do the same job of detection within a maximum of 6 hours. University of Copenhagen
Stuttering test could be used to screen all schoolchildren, study suggests
, /in E-News /by 3wmediaA new model developed by Wellcome Trust researchers to predict the persistence of stuttering could be used to screen all children at school age, new research suggests. Stuttering – also known as stammering – is thought to affect one in 20 children under the age of five, and onset generally occurs around the age of three. Around one child in 100 is likely to still be stuttering in their teenage years.
Screening for communication problems at key stages, including school entry, was suggested by the government in its Every Child Matters initiative, which was launched ten years ago.
Professor Peter Howell and colleagues from the Division of Psychology and Language Sciences at UCL (University College London) previously developed a model that allowed them to accurately predict which children at the age of eight would continue to stutter in their teenage years. In this new study, Professor Howell used the model to show that it is possible to screen children for stuttering when they enter primary school, around the age of five.
Professor Howell says: ‘For a screening tool to be used effectively, it needs to meet the rigorous standards for accurately identifying children who stutter separately from children who are fluent. We found that this method can do just that.
‘If we can identify children at risk of stuttering, then we can offer appropriate interventions to help them early on. Primary school is a key time in a child’s development and any help in tackling potential communication problems could make a big difference to the child’s life.’
Professor Howell developed the model working with 222 children who stutter and 103 fluent children, and he and his colleagues validated their findings in 272 children who stutter and 25 fluent children, all between ages five and 18. He used the Stuttering Severity Instrument Version 3 (SSI-3, a standardised test involving measurement of speech symptoms, their durations and physical symptoms accompanying stuttering such as tics), which they had previously been shown to be the only reliable tool for predicting persistence of stuttering.
He found that their model performs extremely well with five-year-olds. At this age, over 96 per cent of children who stutter and over 83 per cent of fluent children would be correctly identified. Although this would mean that some children who do not stutter would be incorrectly classified, Professor Howell and colleagues believe that some of these fluent children may suffer from other communication problems. Wellcome Trust
Researchers identify genetic marker for placebo response in IBS patients
, /in E-News /by 3wmediaAlthough placebos have played a critical role in medicine and clinical research for more than 70 years, it has been a mystery why these inactive treatments help to alleviate symptoms in some patients – and not others. Now researchers have for the first time identified genetic differences between placebo responders and non-responders, providing an important new clue to what has come to be known as ‘the placebo effect.’
Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), the new findings demonstrate that genetic differences that account for variations in the brain’s dopamine levels help to determine the extent of a person’s placebo response, a discovery that not only has important implications for patient care, but could also prove to be of significant benefit to researchers in designing and conducting clinical trials to help determine a drug’s effectiveness.
‘There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos, ‘ explains the study’s first author Kathryn Hall, PhD, a research fellow in the Division of General Medicine and Primary Care and member of the Program in Placebo Studies and Therapeutic Encounter (PiPS) at BIDMC. ‘With this new research, we may now be able to use a person’s genetic makeup to predict whether or not they will respond to a placebo.’
The placebo effect occurs when patients show improvement from treatments that contain no active ingredients. For investigators conducting clinical trials of new drugs — which require that new treatments be tested against a placebo control to determine their efficacy– placebo responses can pose a particularly difficult challenge, requiring investigators to recruit additional patients in order to acquire statistically significant data, and substantially adding to the overall cost of the trial.
Because dopamine is known to be important to both reward and pain, the investigators began their search for a genetic placebo marker in the dopamine pathway. Their focus soon turned to the catechol-O-methyltransferase (COMT) gene.
‘COMT made for an excellent candidate because it’s been implicated in the cause and treatment of many conditions, including pain and Parkinson’s disease,’ says Hall. ‘It’s also been found in behavioural genetic models of reward responsiveness and confirmation bias, the tendency to confirm new information based on your beliefs.’
Polymorphisms are gene variations, and in the case of the COMT val158met polymorphism, the changes in the COMT gene result in people having either two copies of the methionine (met) allele, two copies of the valine (val) allele, or one copy of each.
‘People with two copies of met, the ‘met/mets,’ have three to four times more dopamine available in their prefrontal cortex [the brain area associated with cognition, personality expression, decision making and social behaviour] than the people with two copies of val,’ explains Hall. The scientists hypothesised that if dopamine was indeed involved in the placebo response, they would see a difference between how met/met, val/val and met/val genotypes responded to placebo treatments, with the met/met individuals showing a higher response.
To test this hypothesis, the researchers took advantage of a unique opportunity, revisiting a 2008 clinical trial led by PiPS Director Ted Kaptchuk, designed to study the placebo effect in patients with irritable bowel syndrome (IBS). ‘In our original work, IBS patients were assigned to one of three treatment arms and we explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered,’ explains Kaptchuk, Associate Professor of Medicine at HMS and the study’s senior author. The treatment conditions included either being ‘waitlisted’ and receiving no treatment, receiving placebo acupuncture in a business-like clinical manner, or receiving placebo acupuncture treatment from a warm supportive health care provider.
Armed with this original data, the scientists genotyped blood samples from patients from the earlier study, using a statistical method known as regression analysis to analyse the effects of a person’s genotype and the type of treatment received. ‘Our regression analysis found that as the copies of met increased, placebo responses increased in a linear fashion, presumably because more dopamine was available,’ Hall explains. The findings showed that among the IBS patients who had been in the waitlist treatment arm there was no difference in treatment responses between met/met, val/val and met/val genotypes as determined by the IBS-Symptom Severity Scale and Adequate Relief. Among those in the group that received a placebo administered in a businesslike manner, the met/met genotypes showed a small improvement over their val/val and met/val counterparts.
But, says Hall, among the individuals who had received placebo treatment from the warm supportive health care providers, there was a striking difference: the ‘met/mets’ demonstrated a six-fold greater improvement in their IBS symptoms relative to the ‘val/vals.’
‘These findings suggest that it is possible that met/met is a genetic marker for the placebo response and val/val is a marker for non-response,’ says Hall. ‘In addition, our findings underscore differences in placebo response based on the patient’s experience of the clinical environment. In the case of the met/met individuals, you can really see the advantage of a positive doctor-patient relationship. Conversely, our findings suggest that the val/val patients are less influenced by placebo treatment and this sheds light on a clinical challenge faced by many health care providers, whose empathic care helps some people, but makes no difference to others.’ Beth Israel Deaconess Medical Center
Brain change link to anti-social behaviour in girlsBrain scans showed significant differences
, /in E-News /by 3wmediaThe brains of teenage girls with behavioural disorders are different to those of their peers, UK researchers have found. The study of 40 girls revealed differences in the structure of areas linked to empathy and emotions. Previous work has found similar results in boys.
Experts suggest it may be possible to use scans to spot problems early, then offer social or psychological help. An estimated five in every 100 teenagers in the UK are classed as having a conduct disorder.
It is a psychiatric condition which leads people to behave in aggressive and anti-social ways, and which can increase the risk of mental and physical health problems in adulthood. Rates have risen significantly among adolescent girls in recent years, while levels in males have remained about the same.
In this study, funded by the Wellcome Trust and Medical Research Council, UK and Italian researchers conducted brain scans of 22 teenage girls who had conduct disorder and compared them with scans of 20 who did not.
They also checked the scans against others previously taken of teenage boys with conduct disorder. The team found part of the brain called the amygdala was smaller in the brains of male and female teenagers with conduct disorder than in their peers.
The amygdala is involved in picking up whether or not others feel afraid – and plays a role in people feeling fear themselves. Girls with conduct disorder also had less grey matter in an area of the brain called the insula – linked to emotion and understanding your own emotions.
However the same area was larger in boys with conduct disorder than healthy peers, and researchers are not yet sure why that is the case. The brains of those with the worst behaviour were most different from the norm.
Dr Andy Calder, from the MRC cognition and brain sciences unit, who worked on the study, said: ‘The origins of these changes could be due to being born with a particular brain dysfunction or it could be due to exposure to adverse environments such as a distressing experience early in life that could have an impact on the way the brain develops.’
Dr Graeme Fairchild, of the University of Cambridge who also worked on the study, said there were potential uses for the finding.
‘In the US, people are already using brain scans to argue diminished responsibility. I think we’re too early in our understanding to really do that, but it is happening.
‘It would also be possible to use scans where a person is at high risk of offending in the future.
‘More help could be given to the family and, in the same way that someone with language impairment receives extra help, help could be given to teach a person to understand emotions – and the emotions of others – better.’ BBC
Blood hormone levels can predict long-term breast cancer risk
, /in E-News /by 3wmediaBlood hormone tests can predict a woman’s risk for developing postmenopausal breast cancer for up to 20 years, according to a study led by Xuehong Zhang, MD, Channing Division of Network Medicine, Brigham and Women’s Hospital (BWH) Department of Medicine.
Using data from the Nurses’ Health Study, Zhang , Susan Hankinson, ScD, Channing Division of Network Medicine, BWH Department of Medicine and colleagues analysed 796 patients with postmenopausal breast cancer who had not received hormone therapy.
They conducted blood hormone tests at two time points: between 1989 and 1990 and between 2000 and 2002. Researchers matched each patient with two controls who were not diagnosed with breast cancer.
‘We found that a single hormone level was associated with breast cancer risk for at least 16 to 20 years among postmenopausal women not using postmenopausal hormones,’ said Zhang. ‘We, and others, are now evaluating if the addition of hormone levels to current risk prediction models can substantially improve our ability to identify high-risk women who would benefit from enhanced screening or chemoprevention-if so, the current data suggest that hormone levels would not need to be measured in the clinic more than once every 10, or possibly 20, years.’
Women with hormone levels in the highest 25 percent for estradiol, testosterone and DHEAS had a 50 percent to 107 percent greater chance for developing breast cancer compared with women in the lowest 25 percent. Relative risks for developing breast cancer were similar at one to 10 years vs. 11 to 20 years (also 16 to 20 years) after blood collection.
Researchers also investigated whether these higher levels were more closely linked to hormone-receptor positive breast cancers and if they predicted risk regardless of tumour aggressiveness.
In the first case, they found that elevated levels of estradiol increase a woman’s risk for hormone receptor-positive breast cancer, specifically oestrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumours.
In general, increased hormone levels, except for DHEAS, tracked closely with increased risk for receptor-positive breast cancer. Data on receptor-negative cancers were inconclusive and need additional, large studies.
Significantly, elevated hormone levels were also associated with aggressive breast cancer, which the study defined as recurrent or fatal cancer.
‘The relationship was comparable or possibly stronger for recurrent and fatal breast cancer than it was for overall breast cancer risk although these results were based on relative small numbers of participants,’ said Zhang.
Researchers also confirmed the protective effect of sex hormone-binding globulin (SHBG), which seems to negate the cancer-causing effects of certain hormones. Women in the highest 25 percent of SHBG levels had a 30 percent lower risk for breast cancer compared with women in the lowest 25 percent for SHBG levels.
Zhang noted that the study had low case numbers for several cancer subgroups, including HER2, triple-negative and basal-like breast cancers. More research is necessary to determine the relationship between elevated hormone levels and these important breast cancer groups. Brigham and Women’s Hospital
Drop in testosterone tied to prostate cancer recurrence
, /in E-News /by 3wmediaMen whose testosterone drops following radiation therapy for prostate cancer are more likely to experience a change in PSA levels that signals their cancer has returned, according to new research from Fox Chase Cancer Center.
Specifically, men whose testosterone fell following various forms of radiation therapy were more likely to experience an increase in prostate-specific antigen (PSA)—often the first indication the cancer has recurred.
‘The men who had a decrease in testosterone also appear to be the men more likely to see an increase in PSA after treatment,’ says study author Jeffrey Martin, MD, resident physician in the Department of Radiation Oncology at Fox Chase.
In theory, doctors may one day be able to use testosterone levels to guide treatment decisions, says Martin. ‘For men with a decrease in testosterone, doctors might intervene earlier with other medications, or follow their PSA more closely than they would otherwise, to spot recurrences at an earlier time.’
Martin and his colleagues decided to conduct the study because there is limited information regarding testosterone levels after radiation treatment and what it means for prognosis. To investigate whether a decrease in testosterone has any clinical effects, Martin and his colleagues reviewed medical records from nearly 260 men who received radiation therapy for prostate cancer between 2002 and 2008. The men were treated with either brachytherapy, in which doctors insert radioactive seeds in the prostate, or intensity modulated radiation therapy (IMRT), in which an external beam of radiation is directed at the prostate.
The researchers found that testosterone levels tended to decrease following both forms of radiation therapy. And men who experienced a post-radiation drop in testosterone— particularly a significant drop—were more likely to see their PSA levels rise during the follow-up period.
Still, an increase in PSA—known as biochemical failure—was relatively rare, the authors found. ‘Only 4% of patients with low-risk prostate cancer had biochemical failure at five years,’ says Martin.
Even though researchers have seen testosterone decrease following another form of radiation, these latest findings are still somewhat surprising, says Martin, because testosterone is believed to drive prostate cancer. In fact, some patients with advanced forms are prescribed hormone therapy that attempts to knock down testosterone.
‘Seeing that a drop in testosterone is tied to recurrence is kind of a surprising result,’ says Martin. ‘We don’t necessarily know what this means yet. I think the relationship between testosterone levels following radiation therapy and prognosis needs more study, and until then it’s premature to say this is something patients should ask their doctors about.’
This was a small study that needs to be validated in a larger group of men before doctors begin basing their predictions of recurrence on patients’ testosterone levels, he cautions. ‘I think the link between testosterone and PSA needs more study, in a larger set of patients.’ EurekAlert