Body

DALLAS, Sept. 25, 2019 -- On-the-job exposure to high levels of pesticides raised the risk of heart disease and stroke in a generally healthy group of Japanese American men in Hawaii, according to new research published in the Journal of the American Heart Association, the open access journal of the American Heart Association.

"This study emphasizes the importance of using personal protective equipment during exposure to pesticides on the job and the importance of documenting occupational exposure to pesticides in medical records, as well as controlling standard heart disease risk factors," said Beatriz L. Rodriguez, M.D., Ph.D., M.P.H., co-author of the study and professor of geriatric medicine at the University of Hawaii at Manoa.

The findings are the latest to emerge from the Kuakini Honolulu Heart Program, which enrolled over 8,000 Japanese American men on Oahu between 1965 and 1968. Men enrolled in the study were 45 to 68 years of age and self-reported their occupation. The group has since undergone multiple examinations and researchers are also tracking all causes of death and some disease outcomes. Data on rates of heart disease and stroke were available through December 1999, for up to 34 years of follow-up.

Pesticide exposure was estimated using a scale from the Occupational Safety and Health Administration that assesses the intensity and length of occupational exposure for each job. Compared to men who were not exposed to pesticides at work, in the first 10 years of follow-up, the researchers found:

Roughly a 45% higher risk of heart disease or stroke in those with high pesticide exposure, (46% after adjusting for age, and 42% after adjusting for other heart disease risk factors as well as age); and

There was no significant relationship between low to moderate exposure to pesticides and the risk of heart disease or stroke.

Pesticides have a long half-life, so health effects may occur years after exposure. By analyzing different time lags, the researchers found that the maximum effect of exposure on heart disease and stroke risk was during the first 10 years.

"After following the men for 34 years, the link between being exposed to pesticides at work and heart disease and stroke was no longer significant. This was probably because other factors tied to aging became more important, masking the possible relation of pesticides and cardiovascular disease later in life," Rodriguez said.

The study was conducted only in men of Japanese descent, and the results may not apply to women or other races.

"Previous studies have found that men and women may respond differently to pesticide exposure. One class of pesticides may give women heart attacks but not men and other pesticides may give men heart disease but not women. Hormones may also play a role in the impact of pesticide exposure and the development of cardiovascular disease," said Zara Berg, Ph.D., co-author of the study and adjunct science professor at Fort Peck Community College in Poplar, Montana.

Although the study was conducted solely in first or second-generation Japanese American men, similar results were found in Taiwan for high pesticide exposure in middle age.

In so-called whole genome sequencing, surveys are made of the total genome of an individual. It is still relatively rare in healthcare today, but it occurs at an increasing rate, for example in order to make an accurate diagnosis in the case of a rare disease. A genetic mapping of an individual is routinely compared to a so-called reference genome, a description of the human genome that is considered to be "standard." In such a comparison, approximately 5 million deviations are normally found. Most are without any major significance, but some of them can cause disease or disabilities.

Now researchers at Karolinska Institutet have re-analysed the whole genome for one thousand Swedish individuals in the SweGen cohort studied in collaboration with Uppsala University and for each one circled the sections that do not match the reference genome. In the next stage, the researchers have analyzed this particular non-matching genome. This work entailed the identification of 61 000 DNA sequences, which is a volume equivalent to approximately one whole chromosome. These new sequences, which are not included in today's reference genome, affected more than 80 genes, of which a dozen are linked to various diseases.

The researchers then went on to further analyse these new sequences. They were compared to the genome library available for chimpanzees, for the African population as well as for Icelanders. As it turns out, this work paid off - it turned out that these new sequences, identified in one thousand Swedish individuals, are largely found in all of these populations. This means that they are very old and that they are well distributed in the human population.

"The non-identified genetic material that we have not previously been able to match against the reference library during whole genome sequencing, proved to be normal variants of our genome, in many cases ancient," said Jesper Eisfeldt, Civil Engineer specializing in biotechnology and PhD student in the Rare Diseases research group at the Department of Molecular Medicine and Surgery at Karolinska Institutet. "This shows that the human genome is more heterogeneous than previously known and as a result we need to update our reference genome. But it also shows that we are more like the chimpanzee than we previously thought and that more in-depth studies of the chimp's genome are necessary in order to understand human genetic diversity."

BIRMINGHAM, Ala. - The most common form of the kidney disease called glomerulonephritis is IgA nephropathy.

IgA nephropathy is believed to be caused by IgA1-containing immune complexes formed in the blood that ultimately deposit in the glomeruli -- the filtering apparatus of the kidneys. When kidney glomeruli become damaged, the kidneys lose their ability to remove waste from the blood and to retain blood proteins, and the injury can lead to kidney failure.

In IgA nephropathy kidney biopsies, IgA1 is the main immunoglobulin detected in the glomeruli by a clinical test called routine immunofluorescence. But those tests were often failing to detect immunoglobulin IgG, which was believed to be another vital contributor to the disease.

Now a study published in the Journal of the American Society of Nephrology by researchers at the University of Alabama at Birmingham largely validates the hypothesis that a second immunoglobulin, IgG, is a crucial part of the pathogenic immunodeposits in glomeruli of patients with IgA nephropathy. Up to now, routine immunofluorescence microscopy -- which identifies the presence of IgA in all cases of IgA nephropathy -- failed to show IgG in 50 to 80 percent of kidney biopsies. In addition, IgG found in those positive tests had never been tested for antigenic specificity, such as specificity against the IgA1.

UAB researchers hypothesized that the IgA1 was blocking the IgG from being detected in routine immunofluorescence microscopy, say co-corresponding authors Dana Rizk, M.D., and Jan Novak, Ph.D. When a different reagent, a small nanobody that detects the very end of the IgG molecule was used, IgG was detected in all biopsy specimens, including those that did not show IgG by routine immunofluorescence. Moreover, a highly sensitive confocal microscopy showed co-localization of the IgA1 and IgG in glomerular deposits of the biopsy-tissue specimens.

Furthermore, the IgG that UAB researchers extracted from both groups of biopsies specifically bound to the galactose-deficient IgA1, the glycoform of IgA1 that is known to be elevated in IgA nephropathy. The IgG autoantibody specific for galactose-deficient IgA1was not found in control extracts from two other forms of glomerulonephritis that do not involve galactose-deficient IgA1 -- primary membranous nephropathy and lupus nephritis. These tests together confirmed that the IgG autoantibodies specific for galactose-deficient IgA1 are unique for immunodeposits of patients with IgA nephropathy.

"These results reveal, for the first time, that IgA nephropathy kidney biopsies, with or without IgG by routine immunofluorescence, contain IgG autoantibodies specific for galactose-deficient IgA1," Novak said. "These findings support the importance of these autoantibodies in the pathogenesis of IgA nephropathy."

"These IgG autoantibodies specific for galactose-deficient IgA1are present also in blood of patients with IgA nephropathy, and the autoantibody levels predict disease progression. Thus, we can measure these autoantibodies in blood to identify patients who could benefit from a future disease-specific therapy, or monitor patients for responses to the therapy," Novak said. "And better understanding of these autoantibodies can help us to develop new, disease-specific treatments for IgA nephropathy."

Over the years there has been uncertainty over which drugs are best for patients with Type 2 diabetes and one of its common complications, kidney disease. An observational study using medical record information from nearly 50,000 U.S. military veterans sheds new light on this issue.

Among the 30 million U.S. adults with Type 2 diabetes, 20% have impaired kidney function. In patients like this, metformin, the recommended first-line drug therapy for Type 2 diabetes, is associated in the new study with 20 percent decreased risk of major adverse cardiovascular events when compared to a class of common diabetes drugs called sulfonylureas.

The lower risk associated with metformin translates as 5.8 fewer of these events per 1,000 person-years compared to sulfonylureas. The events tracked in the study include heart attack, stroke, transient ischemic attack and cardiovascular death.

The study by researchers at Vanderbilt University Medical Center appears in JAMA, the flagship journal of the American Medical Association.

"Until recently the use of metformin in patients with diabetes and impaired kidney function was cautioned against due to safety concerns. The effectiveness of metformin demonstrated in this study will further support a potential change in prescribing practices for these patients. We believe these results should encourage providers to continue use of metformin in mild-to- moderate kidney disease," said a leader of the study, Christianne Roumie, MD, MPH, associate professor of Medicine and Pediatrics at VUMC.

Among patients receiving care from 2001 through 2016 within the national Veterans Health Administration, 174,882 were newly diagnosed with Type 2 diabetes, started using either metformin or a sulfonylurea, and developed impaired kidney function.

The new study is focused on 24,679 patients who continued on metformin and 24,799 who continued on a sulfonylurea (the study excluded patients who added other diabetes medications on top of these drugs). To account for other factors that might influence cardiovascular risk, Roumie and colleagues evaluated patient characteristics like age, sex, race, other illnesses, body mass index and blood pressure.

Median follow-up was 1.0 years for patients taking metformin, 1.2 years for sulfonylurea users. Metformin users experienced 1,048 adverse events while sulfonylurea users experienced 1,394, or 23.0 and 29.2 per 1,000 person-years, respectively. After adjustment for other risk variables, this amounted to a 20% reduced risk with metformin compared to a sulfonylurea.

A large cohort study of women who have had one or more previous cesarean sections suggests that attempting a vaginal birth in a subsequent pregnancy is associated with higher health risks to both the mother and the infant than electing for another cesarean.

The research, published in the open access journal PLOS Medicine on September 24, addresses a lack of robust information on the outcomes of birth options after previous cesarean section and can be used to counsel women about their choices.

Around the world there have been increases in cesarean section deliveries, leading to a larger proportion of pregnant women with a history of cesarean section. Guidelines recommend that these women be counselled about the benefits and harms of planning a subsequent cesarean or attempting a vaginal birth yet there is little evidence around this.

Kathryn Fitzpatrick of the Nuffield Department of Population Health, University of Oxford, and colleagues used data from 74,043 full term births of single babies in Scotland between 2002 and 2015. For women who have had previous cesarean section, the researchers estimated the short term maternal and perinatal health outcomes associated with attempting a vaginal birth compared to planning another cesarean section. 45,579 women gave birth by planned cesarean and 28,464 attempted vaginal birth, 28.4% of whom went on to have an emergency cesarean section.

Attempting vaginal birth was associated with an increased risk of the mother having serious birth and post-birth related problems compared to electing for another cesarean section. Attempting vaginal birth was more likely to result in uterine rupture (69 vs 17 women, adjusted odds ratio [aOR] 7.3, 95% confidence interval [CI] 3.9-13.9), a blood transfusion (324 vs 226 women, aOR 2.3, 95% CI 1.9-2.8), sepsis (76 vs 78 women, aOR 1.8, 95% CI 1.3-2.7 ), surgical injury (aOR 3.0, 95% CI 1.8-4.8), and more serious infant outcomes such as stillbirth, admission to neonatal unit, resuscitation requiring drugs or intubation, or an Apgar score less than seven at five minutes (2,049 vs 2,570).

It should be noted that the absolute risk of complications were small for either type of delivery. Overall, just 1.8% of those attempting a vaginal birth and 0.8% of those having a planned cesarean experienced serious maternal complications. 8.0% of those attempting a vaginal birth and 6.4% of those having a planned cesarean had one or more of the adverse infant outcomes examined.

Kathryn Fitzpatrick, who led the study, said: "Our findings can be used to counsel and manage women with previous cesarean section and should be considered alongside existing evidence on the increased risk of serious maternal morbidity in subsequent pregnancies associated with elective repeat cesarean section." Further studies are needed to confirm these findings and investigate the longer-term outcomes associated with multiple cesareans or attempting vaginal birth following previous cesarean.

Having a lower body-mass index (BMI), but also having a higher waist-to-height ratio (WHtR), is associated with worse outcomes among Asian patients with heart failure, according to a study published September 24 in the open-access journal PLOS Medicine by Carolyn Lam of the National Heart Centre Singapore, and colleagues. As noted by the authors, the combined use of BMI and abdominal measures could potentially inform heart failure management better, especially among the particularly vulnerable patients with low BMI and high WHtR in Asia.

Among heart failure patients, Asian patients are more likely to be lean (have a low BMI,

Higher BMI was associated with better outcomes but higher WhtR was associated with worse outcomes. In combined analysis, the "lean-fat" subgroup with low BMI and high WHtR (?0.55) made up 13.9% of the heart failure population in Asia, were more likely to be women (35.4%) from low-income countries (47.7%), predominantly in South/Southeast Asia, had the highest prevalence of diabetes (46%), worst quality-of-life scores (63.3 ± 24.2), and highest rate of composite events ([51/232], 22%), compared to other subgroups (p

According to the authors, clear national policies that underscore the prevention of abdominal obesity and the promotion of a healthy BMI through awareness, education and lifestyle modification should be championed. The authors note that because these analyses were based on data from multinational registries, they may be affected by selection bias and unmeasured confounding.

WASHINGTON (Sept. 24, 2019) -- Older breast cancer patients who exercised before being diagnosed may be at a lower risk for cardiovascular disease compared to those who did not, according to a study published today in the inaugural issue of JACC: CardioOncology.

As advances in screening and treatment have led to greater survival rates among breast cancer patients, they are now at a greater risk for age-related diseases. Cardiovascular disease is now the leading cause of death in patients with primary breast cancer over 65 years of age.

Researchers examined 4,015 patients with a confirmed diagnosis of primary breast cancer enrolled in the Women's Health Initiative (WHI), which included postmenopausal women aged 50 to 79 years. Women with cardiovascular disease, a history of any other malignancy prior to enrollment or a body mass index less than or equal to 18.5kg/m2 were excluded.

In the WHI, exercise history at baseline and follow-up were assessed with a questionnaire where patients reported the frequency, duration and intensity of leisure-time physical activity. In this analysis, researchers examined exercise data that were collected at the visit closest to breast cancer diagnosis and that was between five years and one month prior to diagnosis. Metabolic equivalent task (MET) values were assigned for levels of physical activity per week and exercise was categorized in quartiles: less than 2.5 MET-hours/week (994 patients); 2.50 to greater than 8.625 (1,008 patients); 8.625 to less than 18 (1,011 patients); and greater than or equal to 18 (1,002 patients).

During the study, 324 cardiovascular events occurred. The researchers found that exercising prior to a breast cancer diagnosis was associated with a 20 to 37 percent reduction in the risk of first cardiovascular events. The risk of heart attack and heart failure were not impacted, suggesting that exercise may be associated with a greater risk reduction in other cardiovascular events such as angina, coronary revascularization, peripheral artery disease or stroke. Individuals meeting current physical activity recommendations (9 MET-hours/week), prior to diagnosis had a 46 percent lower risk of coronary heart disease death compared to those who exercised less than recommended.

"This study is the first to show the exposure to exercise prior to a cancer diagnosis may potentially protect against or mitigate the established adverse cardiovascular consequences observed in breast cancer patients, adding to the growing evidence base supporting the importance of exercise to prevent cardiovascular events in high-risk populations," said Tochi M. Okwuosa, director of the cardio-oncology program at Rush University Medical Center in Chicago and lead author of the paper.

According to the authors, patients who were more physically active prior to breast cancer diagnosis are likely to have a more favorable cardiovascular profile, including higher cardiorespiratory fitness. These patients may have a higher cardiovascular reserve capacity to tolerate the cardiovascular toxic effects that are sometimes experienced as a side effect of cancer treatment. These patients are also more likely to be more active during cancer treatment, which has, in other studies, found to be associated with a lower risk of cardiovascular events.

"As more and more patients survive their breast cancer, cardiovascular disease is and will continue to become a major risk of morbidity and mortality for survivors," said Lindsay L. Peterson, MD, MSCR, and Jennifer A. Ligibel, MD, in an editorial comment accompanying the paper. "Finding strategies to help patients engage in recommended amounts of physical activity prior to and after breast cancer diagnosis will be critical to improving outcomes in women with early breast cancer, in particular in the rising number of older adults with breast cancer."

"This study is important as it provides much needed evidence to support non-pharmacologic strategies to improve upon cardiovascular outcomes in cancer patients and guidance to the community of health care providers on the importance of physical activity for our patients," said JACC: CardioOncoloy editor-in-chief Bonnie Ky, MD, MSCE, FACC.

LA JOLLA--(September 24, 2019) Colorectal cancer is a common lethal disease, and treatment decisions are increasingly influenced by which genes are mutated within each patient. Some patients with a certain gene mutation benefit from a chemotherapy drug called cetuximab, although the mechanism of how this drug worked was unknown.

Salk scientists have combined computational biology with experimental investigations to discover, for the first time, the mechanism for why these patients respond to cetuximab, which will help doctors identify more effective, targeted treatment plans for people diagnosed with colorectal cancer. The findings were published in Science Signaling on September 24, 2019, and demonstrate the power of blending computational and experimental approaches as well as how foundational scientific research can translate to an immediate impact for patients.

"This study has direct clinical implications because now doctors can start prescribing this effective drug to colorectal cancer patients with this mutation immediately," says Edward Stites, senior author of the paper and an assistant professor in the Integrative Biology Laboratory. "The work also highlights the necessity of mathematical models based on fundamental biochemistry as a tool for understanding the behaviors of biological networks that are relevant to disease."

Approximately 40 percent of patients with colorectal cancer have a mutated KRAS gene in cells in their tumors. Most KRAS mutants cause the patient not to benefit from cetuximab. Patients with the KRAS G13D mutation are exceptions and have appeared to respond to cetuximab, but the mechanism of action has not been apparent so this drug is not commonly used on these patients. Doctors are hesitant to prescribe a drug without a known mechanism due to possible interaction with other medications or unforeseen side effects.

"Our goal was to elucidate a mechanism for why tumors that harbor KRAS G13D mutations are sensitive to cetuximab," says Thomas McFall, first author on the paper and a postdoctoral fellow in the Stites lab. "Understanding this mechanism will aid doctors in receiving insurance support for prescribing cetuximab, which could benefit upwards of 10,000 colorectal cancer patients per year."

To understand why KRAS G13D tumors responded to cetuximab, the researchers first used computational models to simulate complex reactions and tease out biochemical differences between healthy and mutant genes based on the biochemical understanding of each process and previous clinical trial data. This told them where to look in their laboratory tests to identify and quantify the molecular mechanism that explains why KRAS G13D patients respond differently. The researchers replicated their findings across three genetically distinct cell lines to demonstrate the reliability of the results.

In a cell with no KRAS mutations, a known tumor suppressor called neurofibromin keeps healthy KRAS proteins well-behaved. But most KRAS mutations are overly active and cannot be controlled by neurofibromin. When mutated KRAS is present, neurofibromin attempts to control the mutant KRAS at the expense of controlling the healthy KRAS. So why is the KRAS G13D mutation any different? Why does it respond to Cetuximab? The scientists discovered that even though KRAS G13D is overly active, it is doing so without neurofibromin being aware. Thus, neurofibromin can still keep the healthy KRAS under control. Additionally, the researchers demonstrated that cetuximab will only work to suppress tumors as long as there is neurofibromin available to suppress the activity of healthy KRAS.

"This work demonstrates the power of computational systems biology approaches to address problems in personalized medicine," says Stites. "Doctors could sequence the gene to find out if the patient has this KRAS G13D variant, and if they do, then doctors could confidently prescribe cetuximab. That's important, because it will give many cancer patients a new treatment option."

Next, the authors plan to examine the mechanisms of more KRAS gene mutation variants that do not bind to neurofibromin, as patients with these variants may also benefit from taking cetuximab.

PHILADELPHIA - Within six months of the U.S. Food and Drug Administration's (FDA) move to restrict the label of two immunotherapies, usage of those therapies among oncologists dropped by about 50 percent, according to a new study from researchers in the Abramson Cancer Center at the University of Pennsylvania. The findings come as the world of cancer medicine grapples with the rapid pace of approval for new therapies, particularly as it relates to the FDA's accelerated approval (AA) program. Researchers say these findings offer reassurance that oncologists can be nimble enough to quickly incorporate the latest guidelines into their practices when new safety data comes to light. JAMA published the results today.

The FDA's AA program has come under significant scrutiny in recent months. Supporters say it can bring promising drugs into the clinic more quickly, which can benefit millions of patients. Critics say these drugs should not come to market before undergoing randomized phase III clinical trials, which is considered the gold standard in medical and drug development research.

"We felt it was important to evaluate what the data says about this program, and our findings show oncologists are quick to respond to emerging safety data for drugs approved through this process," said the study's senior author Ronac Mamtani, MD, MSCE, an assistant professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The study examined usage rates of two immunotherapies approved for first-line use in advanced bladder cancer patients who are not eligible for standard cisplatin-based chemotherapy: the PD-1 inhibitor pembrolizumab and the PD-L1 inhibitor atezolizumab. The FDA approved both therapies in 2017 based on phase II studies. However, data from ongoing phase III studies showed patients had decreased survival when taking these drugs compared to undergoing first-line platinum-based chemotherapy. This led the FDA to restrict the label indications compared to the original approval. The restrictions went into effect in June 2018.

Using a de-identified data set from the Flatiron Health database, which is derived from the health records from more than 280 oncology clinics across the United States, Penn researchers initiated a study to examine the treatments for 1,965 patients with advanced bladder cancer. Between May 2018 and January 2019, the rate of immunotherapy usage among these patients decreased from 51.9 percent to 30.3 percent per 100 patients. The rate of chemotherapy usage increased from 37 percent to 60.6 percent per 100 patients. Rates of PD-L1 testing also increased from 9.3 percent to 21.2 percent per 100 patients.

"Given the rapid expansion of approvals for immunotherapies, understanding how oncologists react to post-approval safety concerns is crucial, and our study suggests uptake of these changing recommendations can occur very quickly," said the study's lead author Ravi B. Parikh, MD, MPP, an instructor in Medical Ethics and Health Policy at the University of Pennsylvania.

Blythe Adamson, PhD, senior qualitative scientist at Flatiron Health, is the study's co-lead author and Aaron Cohen, MD, MSCE, associate medical director of Flatiron Health, is the study's co-senior author.

While this study provides reassurances about the agility of oncologists, the researchers caution there are other factors that could be contributing to the trends they observed. They say further study is needed to continue to assess the effect of label changes on clinical practice.

"The strategy was to design the drug to be able to hook into the hole of the FTase and GGTase I, otherwise the surface of the proteins are too large and slippery," Dr. Junko Ohkanda of Shinshu University explains her strategy behind her paper chosen by Chemistry - A European Journal as a "Hot Paper".

Pharmaceutical companies around the world have been trying to concoct an effective drug to target K-Ras proteins for the last 20 to 30 years. When K-Ras proteins mutate, they cause the multiply switch to remain perpetually on, becoming an aggressive and untreatable form of cancer. In 90 to 100% of the difficult lung and pancreatic cancers, K-Ras is said to play a role. 30% of all cancers is said to have some form of Ras mutation.

Scientists have had trouble designing a drug to infiltrate K-Ras due to a lack of interactive pockets. A new strategy was devised to attack the FTase, an important enzyme in the lipid modification of K-Ras. Without FTase, the mutated K-Ras would be unable to multiply uncontrollably. Scientists have developed large numbers of FTase inhibitors, but found it difficult to inactivate K-Ras modification.

Even when the FTase was inhibited, K-Ras modifications were not stopped because GGTase I was also reacting with the K-Ras, despite its different reactive cavity. It was not understood why, until its mechanism was elucidated that FTase and GGTase I are both made of two protein parts, one of which is the same, with the exact same DNA.

Near the activated cavity FTase and GGTase I have the same cluster of acidic amino acids, like glutamic acid and aspartic acid, carrying a negative charge. When closely observing the K-Ras C-terminus, it had an interactive positive charge. Other Ras proteins do not have this positively charged area. Only K-Ras has this cluster of positive charges. This is why even if the FTase was inhibited, the K-Ras still reacted with the GGTase I, even though its cavity was different.

This is where Dr. Ohkanda had her moment of inspiration. In theory, the pocket of the enzyme and the cystine key attach and join together. But in this case the surfaces of the proteins, with the plus and the minus also interact. Even if the FTase is inhibited the K-Ras mistakenly interacted with the GGTase I. Dr. Ohkanda and her colleagues thought with one compound they could work two functions.

The strategy was to design a molecule to mimic the part of the K-Ras that acts on the active pocket and also the acidic surface. It goes without saying that the function of the drug must happen inside the cell. Large molecules that are useful in protein-protein interactions are often too large to go inside the cell. This is a problem that riddles many drug developers: delivery methods.

Dr. Ohkanda thought if she could rationally design the thiol on the end of the K-Ras to hook on to the active pocket of the FTase and GGTase I, the extended interactive positive charge portion could interact and penetrate the cell membrane. If the cysteine portion could hook on into the cavity, the connected interactive positive chain can be small and delivered strategically to the acidic surface of the enzymes.. It was difficult to minimize the size of the compound while increasing its stability and keeping its ability for chemical reactions. By using a peptidomimetic of the same length and same key, they were able to successfully penetrate the cell in vitro, disrupting the runaway K-Ras multiplication.

More studies are needed to increase the activity of the compound, test in vivo and to evaluate its toxicity long before the compound can be used as a treatment for cancers. Dr. Ohkanda continues to work with an international team of experts to elucidate the mechanism of action and their interactions to rationally design effective drugs to stop the multiplication of such cells.

The survey, which assessed knowledge of the prostate in 3,010 men over 50 years in the UK, Germany and France, found that just one in 4 men (26%) over the age of 50 are correctly able to identify the prostate's main function.

The study revealed a variety of misconceptions surrounding prostate health and, in particular, enlarged prostates (also known as benign prostate enlargement (BPE) or hyperplasia (BPH)) with just 38 percent of respondents able to correctly identify the disorder. A healthy prostate is about the size of a walnut and its main function is to produce prostatic fluid to carry the sperm. Whilst it does grow slowly as men grow older, only one in 6 (17%) respondents correctly stated that the symptoms relating to an enlarge prostate are not a "normal" sign of ageing.

Commenting on these findings, urologist Professor Hein Van Poppel, Adjunct Secretary General of the EAU, explains "The results are worrying, especially as the survey targeted men in the age group that are most likely to suffer from prostate-related conditions, such as prostate cancer and an enlarged prostate. The incidence of these conditions and their impact on medical practice is only going to become greater due to the ageing population, so we must ensure that men are well informed to enable quick consultation and treatment if required."

The cause of an enlarged prostate is unknown, but it is believed to be linked to hormonal changes as men age. Common indicators of the condition include the sudden urge to urinate, a straining or painful sensation when urinating, feeling that the bladder is not completely empty, and getting up more than once at night to urinate. Nearly 50 percent of men (aged 50-60) don't recognise these symptoms. The symptoms are often mild, but the severity can impair quality of life and research suggests that men with moderate or severe symptoms have an increased risk of serious heart conditions, such as stroke and cardiac death.

Enlarged prostate symptoms rarely discussed with partners or family members. When asked who they would speak to if they experienced any issues related to urinating, most respondents (61%) stated that they would visit their GP for further information. Interestingly, this question posed strong regional differences from France and the UK (67% and 66% respectively) and in Germany (50%). Just one-quarter of men (24%) specified that they would 'Google' their symptoms to find out further information, demonstrating that patients in this age bracket would prefer to speak directly to healthcare professionals.

Only 13 percent of men said they would discuss symptoms with their partner or family to receive more information. Professor Van Poppel comments, "Previous research showed that women actually know more about men's health issues than men do. Therefore, we encourage men to discuss their urological symptoms and conditions with partners or families, as well as visiting specialised healthcare professionals such as urologists."

There are multiple treatment options for an enlarged prostate, which include medical treatment, surgery through the urethra or lower abdomen, laser therapy, water vapour therapy, a change in diet or injections. Half of the survey respondents preferred having the option of different treatments, with38 percent favouring that their doctor recommended one treatment option (12% had no preference).

Younger respondents (aged 50-55) and those from Germany were more likely to favour shared decision-making between different treatment options from their doctor than older respondents (70+) and people from France or the UK.

Van Poppel concludes, "Every patient's condition differs but, together with a specialised urologist, they should be able to make an informed decision on what their optimal treatment is. With so many options now available from medical management, minimally invasive therapies and surgical options; men with complaints should go and seek help since they are very likely to be helped rather easily."

Affecting as many as 30% of cancer survivors, chronic insomnia can be effectively treated with intensive cognitive-behavioral techniques, but such methods are time-consuming, costly, and limited by the availability of trained specialists. In a study published online today by the journal Cancer, investigators at Dana-Farber Cancer Institute report that a single-session sleep education program for survivors can cure insomnia in many participants, and that those who don't benefit from this approach are often helped by a more extensive, but still modest, three-session program.

The findings are based on a trial of this 'stepped care' approach involving 51 cancer survivors with moderate to severe insomnia. After participating in the one-time sleep-education program, 41% of participants saw their insomnia successfully treated. Fourteen of those whose insomnia remained took part in the second step, a three-part program using a cognitive-behavioral approach to insomnia treatment that investigators had previously shown to be effective. Of that group, 71% had their insomnia resolved after completing the program.

"Our results demonstrate that a stepped care model - in which the first treatment is low-intensity and easily accessible to patients - can be effective for improving insomnia in cancer survivors," said Dana-Farber's Eric Zhou, PhD, first author of the study. "This represents a tremendous opportunity to treat a problem that can significantly diminish cancer survivors' health and quality of life when not addressed."

The difficulty sleeping that many survivors experience often originates during treatment for their cancer, as a result of a combination of factors including their anxiety, fatigue, or pain. While these problems may diminish or disappear after treatment, insomnia often lingers, Zhou stated.

The two-step model used in this trial grew out of a recognition that while cognitive-behavioral therapy (CBT) works well in alleviating chronic insomnia in cancer survivors, it can be difficult to access or utilize. Developed about 20 years ago, CBT for insomnia is a form of talk therapy that helps patients understand the maladaptive sleep behaviors and thought patterns that cause their insomnia to persist - and teaches them to adopt healthier behaviors and change their thoughts at night. A shortage of providers trained in CBT for insomnia has limited the number of cancer survivors who can take advantage of this approach. Even when these specialists are available, survivors may balk at the cost or duration of standard treatment, which usually involves six to eight sessions.

The first step in this trial - the one-session sleep-education class - was designed so that it could be easily implemented by a small cancer center, with limited resources or staff. "The content is straightforward, the skills needed to teach it are basic," said Zhou, who developed the class with senior author Christopher Recklitis, PhD, MPH, of Dana-Farber. "It could be led by someone with an interest in mental health and sleep, without extensive training in behavioral sleep medicine. In a few hours, they could acquire enough knowledge about sleep and sleep habits to be able to offer this kind of program."

Much of the material covered in the session is not especially advanced and can be found on "tips for sleeping" handouts commonly available at primary care clinics and cancer centers, but investigators have found that, in the absence of instructions on how to implement these new sleep behaviors or setting appropriate expectations for the timeline and magnitude of sleep improvements, a printed sheet often is inadequate. "There's little guidance on how to make the text a reality," Zhou remarked. "The gap between what's already available to patients on handouts and what we offered is small, but the added guidance we offered resulted in sizable gains to the participants' sleep."

While the second step of the model needs to be led by a clinician trained in CBT for insomnia - and therefore might not be feasible for all cancer centers - the fact that it is offered in a group setting, rather than a one-on-one consultation, would expand its availability.

Upon enrolling the study, participants provided information on their medical history, the severity and duration of their insomnia, and their mood during and after treatment. Investigators found that survivors who had experienced sleep problems for a shorter period of time and felt less of a burden from those problems and less pain, were most likely to benefit from the single, sleep education session. Among patients not helped by that session, those with the greatest desire to improve their sleep were most likely to sign up for the second step of the program. These findings may help clinicians identify patients likely to be helped by a single session and those apt to participate the second step of the program.

"Universal implementation of the first step in our program is a very reasonable goal as a part of a commitment to quality survivorship care at all cancer centers," Recklitis said.

Survey results of a national sample of elderly people with type 2 diabetes suggest that many long-time patients downplay medical and social factors that underpin professional recommendations for fewer medications and less aggressive treatment of high blood sugar.

The survey study, conducted by Johns Hopkins Medicine researchers, concludes that many older adults with diabetes, when deciding to stop diabetes medicines, don't value factors recommended to individualize diabetes treatment. Instead, they voted in the opposite direction than the suggested American Diabetes Association (ADA) guidelines on several factors.

A report on the findings appears in the September 2019 of the Journal of the American Medical Association (JAMA) Internal Medicine.

An estimated 30 million adults in the United States are living with type 2 diabetes, a condition marked by the body's inability to produce enough or properly use insulin to regulate glucose, a main source of energy for cells. While weight loss, good diet, exercise and medications can control high blood sugar levels, treatment guidelines developed by the ADA and other professional groups are designed to be adjusted as people age, life expectancy shortens, and such factors as drug side effects, treatment compliance and quality of life issues play different roles.

"What our study found is that many geriatric patients, 65 years or older, with type 2 diabetes perceive their treatment plans much differently than do their care providers, and may be more likely to choose a more aggressive treatment plan than what guidelines recommend, which poses greater risk for complications, injury or even death," says Nancy Schoenborn, M.D., associate professor of geriatric medicine at the Johns Hopkins University School of Medicine and leader of the research team.

The researchers found that many patients especially did not agree with recommendations to stop a medicine.

"The current American Diabetes Association guidelines for managing type 2 diabetes aren't intuitive to patients, and we need to do a better job helping them understand the benefits and consequences of making changes to treatment regimens that must evolve over time on an individualized basis," Schoenborn says.

One reason that the Johns Hopkins Medicine researchers decided to study the patient-versus-provider perspective on diabetes care and management was to assess whether ADA-recommended guidelines about individualized diabetes care -- which doctors often use as a reference for patient treatment -- were intuitive to patients or if patients had different perceptions about their care. They also wanted to learn how patient preferences about their diabetes care evolved.

For the study, the researchers created and conducted an online survey using Knowledge Panel, the nation's largest probability-based online questionnaire format representing the U.S. adult population. Data were collected for 818 participants between December 2018 and January 2019 of a representative sample of people age 65 and older living with type 2 diabetes for up to 20 years. The average age of participants was 74 years, and 54% were male. Participants identified as white (68%), African American (15%), Hispanic (9%) and other (8%). `

The study subjects were asked to rate seven factors reflected in treatment guidelines including ADA guidelines: length of time with diabetes, development of any diabetes-related complications, other health conditions, life expectancy, risk of side effects from treatment, treatment cost and treatment effort.

Specifically, participants were asked to share their perceived importance of each of the seven pre-defined factors in deciding to add or stop a medication; and in deciding which patients should receive less aggressive or more aggressive diabetes treatment.

The ADA guidelines recommend generally less aggressive diabetes treatment for patients who have had long-standing diabetes. However, the researchers found that 60% of the people surveyed were in opposition to the guidelines and felt instead that the longer one lived with diabetes, the more aggressive treatment should be. The guidelines also recommend less aggressive diabetes treatment for patients who have many other health conditions and those who already have developed complications from diabetes. However, the researchers found that 76% of the people surveyed felt that those who already have complications from diabetes should be treated more aggressively than those without complications, and 67% felt that people with many other health conditions should be treated more aggressive than those with no other health conditions.

According to Schoenborn, the ADA guidelines take into consideration life expectancy and treatment side effects. Thus, more aggressive diabetes treatment is appropriate for patients with longer life expectancies, a recommendation with which 78% of the study participants agreed.

The challenges arise, Schoenborn says, when physicians and patients must come to a consensus about treatment tradeoffs and measures based on disease progression, complications from other health problems, and medication side effects and compliance. Approximately forty-seven percent of participants did not think that any of the seven factors were important enough to stop a medication, and only 8% considered stopping a medication if they were required to spend a lot of effort managing their diabetes.

Schoenborn says the study findings suggest that physicians who care for older people with diabetes could benefit from materials that better explain to patients why they recommend certain treatment options over others.

"It's often hard for patients to understand the rationale behind the treatment options," says Schoenborn. "Physician awareness of the disconnect along with an individualized approach to each patient may result in a better, more acceptable plan."

Next steps for Schoenborn and her team involve looking at the impact of altering or stopping medications for older adults with diabetes, a process known as deprescribing.

"Past research has shown that deprescribing efforts can reduce the risk of medication side effects and drug-drug interactions, and improve quality of life," Schoenborn says.

CLEVELAND, Ohio (September 24, 2019)--Expressing your true feelings is not only good for your mental health, but it could also be important for your physical health. A new study associates self-silencing (inhibiting one's self-expression) with greater carotid plaque buildup which could lead to a stroke and other cardiovascular problems. Study results will be presented during The North American Menopause Society (NAMS) Annual Meeting in Chicago, September 25 to 28, 2019.

Individuals engage in a range of behaviors to maintain close relationships, some of which may be costly to their own health. One such behavior is self-silencing, which is sometimes used to avoid conflict or relationship loss. Although self-silencing has been linked to worse mental and self-reported physical health in women, it has not been previously examined in relation to women's cardiovascular health.

In this new study of 304 perimenopausal and postmenopausal nonsmoking women, researchers tested whether self-silencing was associated with carotid atherosclerosis. They found that greater self-silencing was related to increased odds of plaque independent of socio-demographics, CVD risk factors, and depression. The results were based on women's self-reporting on a range of factors such as how often they expressed anger or put someone else's needs before their own. Ultrasound imaging was used to quantify carotid plaque.

"Given increased public health interest in women's experiences in intimate relationships, our results suggest that women's socio-emotional expression may be relevant to their cardiovascular health," says Karen Jakubowski, PhD, lead author of the study, from the Department of Psychiatry at the University of Pittsburgh.

"Studies like this one are valuable as they highlight the importance of understanding how a woman's emotional disposition can affect her physical health," says Dr. Stephanie Faubion, NAMS medical director. "These results should encourage healthcare providers to take into consideration socio-emotional factors when outlining a preventive care plan for their patients."

CLEVELAND, Ohio (September 24, 2019)--Previous studies suggested an association between hot flashes and cardiovascular (CVD) disease. But little research linked hot flashes to "hard" clinical CVD events like heart attacks and strokes. A new study measuring clinical CVD outcomes presents the strongest evidence of frequent or persistent hot flashes associated with higher CVD event risk. Study results will be presented during The North American Menopause Society (NAMS) Annual Meeting in Chicago, September 25-28, 2019.

Most studies that have previously attempted to link hot flashes with an increased risk of CVD have relied on subclinical measures of CVD, which are proxies for clinical CVD, but not actual events. They have also relied upon recalled measures as hot flashes from years earlier, which can be biased by memory. The Study of Women's Health Across the Nation (SWAN), a longitudinal 20-year study of the menopause transition, is uniquely positioned to confirm this link because it assessed hot flashes regularly throughout the menopause transition and has also collected information on CVD events as women age.

In this latest study based on SWAN data, researchers tested whether the hot flashes early in the transition or persistent hot flashes over the transition impacted incident CVD risk. They found that frequent, as well as persistent, hot flashes over the menopausal transition translated into a higher risk of having a CVD event in the future. They additionally discovered that this association was not explained by standard CVD risk factors. In fact, frequent hot flashes at the beginning of the study were associated with a doubling of risk of clinical CVD events, and persistent hot flashes over the study with an 80% increased risk of clinical CVD events in the subsequent 20 years.

"This is the strongest test of whether hot flashes are associated with actual clinical CVD events, such as heart attacks and strokes, which represent the most clinically relevant outcome," says Dr. Rebecca Thurston, lead author of the study from the University of Pittsburgh. "It's the strongest because we measured hot flashes prospectively multiple times over the course of the menopause transition, which is different than most other studies of CVD events that ask women to recall their hot flashes over months or years. We also had measures of clinical CVD events, rather than other proxy measures. We brought these data together to address this important question in a more rigorous fashion than prior studies."

"With heart disease being the number one killer of women, it's critical that we understand its many different risk factors in order to help create more preventative and treatment strategies for women transitioning through menopause," says Dr. Stephanie Faubion, NAMS medical director.