Body

New research indicates that for treating insomnia, stimulus control therapy (which reassociates the bed with sleepiness instead of arousal) and sleep restriction therapy are effective, and it is best to use them individually rather than together.

The Worldviews on Evidence-Based Nursing study, which included 517 individuals with chronic insomnia, also found that a strategy focused only on sleep education and hygiene was minimally effective.

"Additional research is needed to further examine the effects of individual and combined therapies," the authors wrote.

Individuals who are obese often experience heartburn and other symptoms of acid reflux. Previous research indicates that gastric bypass surgery for obesity helps alleviate symptoms in the short term, but a new study finds that these benefits often are not long-lasting.

In the Alimentary Pharmacology & Therapeutics study of 2454 patients (mostly women) who had surgery for obesity and who were also taking medicines for acid reflux, symptoms of acid reflux improved in most patients shortly after surgery, but they returned in almost half of all patients within 2 years. Symptoms were more likely to return in women, older individuals, and those with other serious medical problems.

"Physicians and patients should be aware of the limited effect of gastric bypass on reflux in patients with severe obesity, particularly in those with risk factors for post operative reflux," the authors wrote.

A class of immune cells called innate lymphoid cells (ILCs) mediates the body's initial defense against tuberculosis (TB), according to a report published online today in Nature. Boosting this response may provide a new approach to developing treatments and vaccines against TB, which causes more deaths worldwide than any other single infectious disease. The research was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health. It was conducted by scientists at Washington
University School of Medicine in St. Louis in collaboration with scientists at the Africa Health Research Institute in KwaZulu-Natal, South Africa, and other institutions.

Identified only in the past decade, ILCs can initiate quick, nonspecific responses against pathogens and also mount protective immune responses directed against specific pathogens. In this study, researchers observed that among people who were infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, a subset of ILCs moved from the blood to the lungs, where TB infections frequently take hold.

Investigators also tracked the activity of ILCs in several animal models. In mice with intact immune systems, ILCs homed to infected lung tissue and used messenger molecules to recruit the scavenger cells of the immune system, macrophages, to form protective granulomas, or small areas of inflammation, to suppress the infection. Mice without functioning ILCs, however, had low levels of macrophages in lung tissue and poor immune control over their TB. The human and animal data led investigators to conclude that ILCs play an early, pivotal and previously unappreciated role in TB immunity.

Increasingly, Mtb is resistant to conventional antibiotic treatments. While the Bacille Calmette-Guerin (BCG) vaccine can prevent Mtb infection in infants and young children, no vaccine is approved to prevent TB in older children and adults. Because ILCs seem to protect early in TB disease, investigators suggest that probing the newly described pathway may yield novel approaches to TB treatment and prevention.

CLEVELAND, Ohio (June 5, 2019)--Physical fitness is associated with a number of key health outcomes, including heart disease, cognition, mortality, and an overall feeling of well-being. A new study from Singapore now links physical performance with mental health and emotions, suggesting that weak upper and lower body fitness can cause more serious depression and anxiety in midlife women. Results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Although several studies have previously linked depression in midlife women with self-reported low physical activity, this new study is the first known (even in Western populations) to evaluate objective measures of physical performance in relation to depression and anxiety in premenopausal, perimenopausal, and postmenopausal women.

Depression and anxiety are prevalent symptoms experienced by midlife women. This latest study of more than 1,100 women aged 45 to 69 years found, in fact, that 15% of participants, especially those of younger age, reported depression and/or anxiety. Because depression can cause disability, reduced quality of life, mortality, and heart disease, the researchers felt it was important to identify potentially modifiable risk factors that could reduce morbidity and mortality.

The researchers observed significant associations of objective physical performance measures with depression and anxiety. Specifically, they found that weak upper body strength (handgrip strength) and poor lower body strength (longer duration to complete the repeated chair stand test) were associated with elevated depression and/or anxiety symptoms. Future trials will be needed to determine whether strengthening exercises that improve physical performance might similarly help reduce depression and anxiety in midlife women.

Findings were published in the article "Objective measures of physical performance associated with depression and/or anxiety in midlife Singaporean women."

"Strength training has been shown to lead to a significant reduction in depressive symptoms," says Dr. JoAnn Pinkerton, NAMS executive director. "Both strength training and aerobic exercise appear to improve depression, possibly as a result of increased blood flow to the brain or improved coping with stress from the release of endorphins such as norepinephrine and dopamine."

Obesity is an aggravating factor in relapsing-remitting multiple sclerosis, the most common form of the disease. A recent study by the Unit of Neurology and Neurorehabilitation of the I.R.C.C.S. Neuromed in Pozzilli (Italy) confirms that lipid metabolism can have a role in determining the severity of multiple sclerosis.

Published in the Multiple Sclerosis Journal, the research, involving 140 patients, showed that at the time of diagnosis obese patients have a greater risk of presenting higher EDSS (Expanded Disability Status Scale) score, the tool commonly used to assess the severity of multiple sclerosis. Neuromed researchers have also investigated, from a biochemical point of view, the relationship between multiple sclerosis and excessive body weight, analyzing the levels of inflammation in the central nervous system and the lipids concentrations in the blood (cholesterol and triglycerides).

Multiple sclerosis is an inflammatory process, and the authors of the study have focused their investigation on some molecules involved in inflammation. Analysis of cerebrospinal fluid (collected with lumbar puncture) showed in obese patients higher levels of interleukin-6 (IL-6) and leptin, two molecules well known as promoters of the inflammatory process. In contrast, interleukin-13 (IL-13), with anti-inflammatory action, was reduced. Regarding lipid profile, higher levels of triglycerides and a higher ratio of total to HDL cholesterol have been correlated to higher IL-6 levels.

"This study - says Mario Stampanoni Bassi, Neurologist at Neuromed - confirms that obesity is associated with greater symptomatic severity of relapsing-remitting multiple sclerosis. In particular, the analysis of cerebrospinal fluid has highlighted the role of leptin produced by fat cells. Previous studies have shown that leptin is directly involved in the complex relationship between metabolism and inflammation. Our results therefore suggest that excessive body weight, or altered lipid profile, are associated to increased central inflammation causing a worse clinical expression of the disease ".

"It is important - comments Diego Centonze, Full Professor of Neurology at the Tor Vergata University and Head of the Neurology Unit at Neuromed - to precisely define the relationship between obesity, blood lipids and multiple sclerosis. Body weight and dyslipidemias are implicated in various chronic inflammatory conditions, but they are also factors that strictly depend on lifestyle. Specific strategies, such as diet or increased physical activity, may therefore pave the way to the possibility of improving the condition of patients with multiple sclerosis, contrasting the increase of disability over time ".

Results of a Phase II clinical trial conducted at The University of Texas MD Anderson Cancer Center revealed that combination targeted therapy, consisting of rituximab, lenalidomide and ibrutinib (RLI), had an 84.6 percent overall response rate (ORR) and 38.5 percent complete response rate (CRR) when given prior to any chemotherapy for newly diagnosed patients with a specific type of diffuse large b-cell lymphoma (DLBCL).

The first-of-its-kind study examined a treatment regimen without chemotherapy for patients with non-germinal center (non-GCB) DLBCL, and, while confirmatory trials are needed, the findings suggest that patients who respond to targeted therapy initially may not need chemotherapy, currently the standard of care.

The results of the trial will be shared today in an oral presentation at the 2019 American Society of Clinical Oncology Annual Meeting by principal investigator Jason Westin, M.D., assistant professor of Lymphoma & Myeloma.

"The responses we've seen have been remarkable. More than 80 percent of our patients have responded and around 40 percent have had a complete response, showing no evidence of cancer, prior to receiving any chemotherapy," said Westin. "All patients have gone on to receive standard chemotherapy in combination with these targeted treatments per the protocol, and, so far, we've had a 100 percent response rate."

Large-cell lymphomas, which include DLBCL, are diagnosed in approximately 30,000 individuals each year in the U.S., and non-GCB accounts for an estimated 30-40 percent of those cases. Standard treatment for large-cell lymphomas is chemotherapy, but this subtype doesn't respond as well, reaching an estimated cure rate of just 50-60 percent, explained Westin.

The clinical trial enrolled 60 patients at MD Anderson with non-GCB DLBCL and treated those patients with two cycles of RLI, followed by six cycles of RLI with chemotherapy. Westin's team designed the trial to bring new treatment options to these patients based on promising findings in the lab.

"We called the trial 'Smart Start' because we thought this was a smarter way to start therapy for these patients," said Westin. "Standard treatment for large-cell lymphoma has been largely stagnant for the better part of 40 years, despite many advances in our understanding of the disease and a host of new medications. It's exciting to see an idea that worked in the lab now beginning to yield results and show this is a potentially new way forward to fight this disease."

More than 90 percent of patients on this trial remain in remission after one year, said Westin. Additionally, side effects on the trial have been mild, with most driven by the chemotherapy treatment.

Going forward, Westin and colleagues plan to launch clinical trials to investigate whether patients who respond well to RLI treatment upfront can receive little or no chemotherapy and still attain long-term remission.

HANOVER, N.H. - June 4, 2019 - A research team at Dartmouth College has developed a new strategy for drug discovery and development that can be used to produce targeted therapies against diseases such as cancer and neurodegeneration, according to a study published in Nature Communications.

It is hoped that the process will also be useful in the large-scale production of new pharmaceuticals.

The new technique uses a novel synthesis approach for a class of organic compounds known as tetracyclic terpenoids. Tetracyclic terpenoids are responsible for more than 100 FDA-approved drugs and are considered the most successful class of natural product-inspired pharmaceuticals.

"Until now, there was nothing like this available for drug discovery and development," said Glenn Micalizio, the New Hampshire Professor of Chemistry at Dartmouth. "While additional development is expected to enhance the power of this new technology, I believe that we are at the beginning of establishing a truly enabling and potentially transformative technology for the pharmaceutical industry."

The process combines two new chemical reactions that establish bonds between carbon atoms with a unique metal-centered ring-forming reaction also developed by Micalizio.

The new technique allows for uniting molecular building blocks en route to a terpenoid skeleton in just a few chemical transformations. The result is a uniquely efficient and flexible means of enabling drug discovery in this area of natural product-focused medicinal science.

Combined, these reactions allow for exploration of pharmaceutically-privileged regions of chemical space through the straightforward conversion of inexpensive, commercially-available chemicals into high-value, pharmaceutically-relevant compounds.

The research team's initial work has already led to discovery of what could be the most potent and selective modulator of the estrogen receptor beta, a nuclear hormone receptor that is of great interest in industry as a therapeutic target for a wide variety of illnesses.

"This is an important first step toward establishing a new technology platform to greatly facilitate drug discovery across a diverse landscape of therapeutic indications," said Micalizio.

To demonstrate the value of the technique, the study describes the discovery of a molecule that is selectively toxic to glioblastoma--an aggressive and deadly brain tumor--while showing little effect on non-cancerous human neural stem cells and human astrocytes.

"Glioblastomas are incurable, and existing therapies have horrific side effects," said Arti Gaur, an assistant professor of neurology at Dartmouth's Geisel School of Medicine. "It is extremely exciting and encouraging to see that these novel compounds can selectively kill patient-derived brain tumor cells without harming cells from normal, healthy brain tissue."

The team is currently conducting in vivo testing of the new therapeutic agent and further developing chemical aspects of the emerging technology platform.

The work is part of an effort to explore and demonstrate the power of advances in organic chemistry to enable discovery of therapeutics for a wide range of indications, including neurodegeneration, neuroinflammation, and a wide variety of malignancies.

LOS ANGELES -- Latino adults have higher diabetes rates than non-Latinos, yet research shows they are less likely to correctly follow medication instructions provided by their doctors. Furthermore, diabetes can set off a cascade of medical complications, requiring multiple medications that often create a challenging daily regimen. In a new study coming out of the Keck School of Medicine of USC, student researchers have identified several potential approaches for improving medication adherence among Latinos.

Simple measures such as giving patients pillboxes for their medications, helping patients' family members understand their medication regimen and having patients attend weekly education sessions about managing the disease through lifestyle changes are all ways that patients could improve medication adherence.

The study also points toward specific challenges that underserved Latinos may be facing. Such challenges include having difficulty understanding what their medications are for, keeping track of their medications and feeling that they may take too many medications. Cohorts in this study took an average of 6.5 prescribed medications daily.

"Obtaining patients' perspectives is key to finding solutions that help improve their medication adherence and health outcomes," says Andrea Bañuelos Mota, the study's first and corresponding author. "Not only do our findings suggest several potential approaches to intervention for Latinos with diabetes, but they could also pave the way for the development of future evidence-based guidelines." Bañuelos Mota is currently enrolled in the Keck School's Doctor of Medicine/Master of Public Health (MDMPH) degree program.

Published in the Journal of General Internal Medicine (JGIM) on June 4, the cross-sectional study involved conducting surveys of 120 patients from across four safety net clinics in Los Angeles. Patients were at least 18 years old, self-identified as Latino/Hispanic/Chicano, were diagnosed with diabetes for more than six months, and were taking multiple diabetes medications. Furthermore, the study's dependent variable was patients with "controlled diabetes" (i.e., having a hemoglobin A1c level of less than 7.5%) versus patients with "uncontrolled diabetes" (i.e., having a hemoglobin A1c level equal to or greater than 7.5%).

"This study is exemplary of excellent primary care research and brings awareness to the language and literacy barriers faced by our immigrant communities, which health care providers must address to deliver quality medical care," says Jo Marie Reilly, MD, MPH, professor of clinical family medicine (educational scholar). Reilly leads the Keck School's Primary Care Initiative, a program created to promote careers in primary care and the one through which this study was established.

Conceived and led entirely by a team of five medical students -- including Andrea Bañuelos Mota, Emilio Ernesto Feliz Sala, Jennifer M. Perdomo, Joel Alejandro Solis and Walter M. Solorzano -- the study also marks an achievement for the Keck School initiative. "JGIM is one of the highest ranked general internal medicine journals, so it is particularly impressive that a student group got a paper accepted," says Michael Hochman, MD, MPH, a faculty mentor on the project with Reilly. Hochman is an associate professor of clinical medicine and serves as director of the USC Gehr Family Center for Health Systems Science.

ANN ARBOR, Mich. -- Frosted cupcakes, sprinkled donuts and chocolate chip cookies -- all on the list of foods that pediatrician Megan Pesch suddenly found difficult to avoid.

Not at the bakery or grocery store, but on children's clothing.

The mother of three daughters couldn't help but notice that food graphics had become fashionable -- from sleep sacks and pajamas adorned with pink and purple donut patterns to T-shirts decorated with ice cream cones and cutesy sayings about being "sweet."

Pesch, M.D. a developmental behavioral pediatrician who studies childhood eating behaviors at University of Michigan C.S. Mott Children's Hospital, wondered how prominent the trend was and whether it had implications for children's eating habits.

"I started thinking about how food graphics on clothing may impact kids' identification with food starting as early as when they're babies," Pesch says. "Could food on apparel be another influence on food preference and eating behaviors?"

"Turning our kids into walking billboards of junk food reinforces the appeal of these foods," she says. "Whether intentional or not, we are sending positive societal messages about consuming unhealthy food to children and their parents that may influence unhealthy eating behaviors long term."

Unhealthy foods

In a new analysis published in journal Eating Behaviors, Pesch and colleagues looked at 3,870 clothing items over a month-long period in 2018 from four major children's retailers. One in 11 apparel items included food graphics and two-thirds of those foods were unhealthy while others had healthier options, such as fruit. A third of the items featured food graphics "having fun," such as a pizza slice riding a skateboard.

Gender differences were blatant. While girls' clothing mostly brandished pastries and desserts, boys' clothes were more likely to include fast food and salty categories like pizza, hot and fries.

"That may underlie some of these cultural expectations of girls' characteristics versus boys' behavior, specifically that girls are expected to be 'sweet,'" Pesch says.

Other studies have suggested that children's food preferences and eating behaviors are associated with social influences. Children are more likely to taste or eat a food paired with an image of a character, for example. Indeed, mascots and cartoon characters have often been used in food marketing to increase a brand's appeal to children.

There has been less attention to non-brand specific graphic items such as clothing with food icons, Pesch says.

Food as characters

But many food graphics included in the analysis were portrayed as characters. Examples include a dinosaur with a thought bubble thinking about a hamburger, a sequined ice cream cone carrying a purse and soda and fries high-fiving with the word "besties." Or the shirts that featured unicorns, rainbows and a cupcake with the phrase "Dream Big" and a chocolate chip cookie dancing with a glass of milk.

Sayings such as "More Donuts, More Pizza, More Vacays," "Donut Worry Be Happy" and "Always S'More Fun with You" are other examples.

Clothing is believed to be a powerful medium that may influence children's self-identity and graphics portraying unhealthy food as "fun, silly and positive" doesn't seem to be going away, Pesch notes. Donuts, pizza and other junk food items are also showing up more on other kids' items, such as inflatables, toys and gift wrap.

Persist into adulthood

Research suggests that food preferences and eating behaviors established in childhood often persist into adulthood, authors say. It is unknown what messages children may internalize when wearing food-graphic clothing, and if this influences children's food preferences but it should be explored in future research, they say.

"There is nothing wrong with a donut or cookie once in a while. They are 'sometimes foods' and completely fine in moderation," Pesch says.

"But children's association and relationship with food begins developing at a young age. Obesity is much more easily prevented than it is treated."

"We spend a lot of time studying how children develop eating habits and food preferences and what we can possibly do early on to prevent obesity," she says. "Food graphics on children's products may provide insights into how society shapes children's emotional relationships with food and reinforces obesity-promoting messaging."

An in-home exercise program reduced subsequent falls in high-risk seniors by 36 per cent, according the results of a 12-month clinical trial published today in the Journal of the American Medical Association.

The study, conducted by UBC faculty of medicine researchers in partnership with the clinical team at the Falls Prevention Clinic at Vancouver General Hospital, found a reduction in fall rate and a small improvement in cognitive function in seniors who received strength and balance training through the clinical trial.

"When we think about falls we often think about loss of muscle strength and poor balance," said Dr. Teresa Liu-Ambrose, principal investigator at the Vancouver Coastal Health Research Institute and professor in the department of physical therapy at the University of British Columbia. "However, the ability to remain upright and not fall is also dependent on cognitive abilities--calculating how far to lift your foot to get over a curb, making a decision as to when to cross the road, and paying attention to your physical environment while you are having a conversation."

Falls increase risk of injury and loss of independence for older adults. Exercise is a widely recommended fall prevention strategy, but whether it can reduce subsequent falls in those who have previously fallen is not well established.

The study involved 344 adults aged 70 and older who had been referred to the Falls Prevention Clinic following a fall that had resulted in a visit to a medical facility, such as an emergency room. Participants had a history of falls, with an average of three prior falls per person, and generally had symptoms of frailty and limited mobility.

The study had participants perform a set of balance and resistance training exercises in the comfort of their homes, using simple equipment such as free weights, a minimum of three times per week. Over the course of six months, a physical therapist made five home visits to prescribe exercises and ensure that exercises were done properly. For those who completed the program, the results were notable. Participants were less likely to experience repeat falls, and as a secondary benefit, they improved in some markers of cognitive function.

Falls in older adults are the third-leading cause of chronic disability. According to the Public Health Agency of Canada, 20 to 30 per cent of Canadian seniors suffer falls each year, and falls are the leading cause of hospitalization for adults over age 65.

"It is well known that exercise benefits older people in general, but what was special about this study group was that they are at very high risk for losing their independence--they had both mobility and cognitive impairments and another fall may mean the inability to live in their own homes. Many already had difficulty navigating public spaces independently," said Liu-Ambrose, who holds a Canada Research Chair in Physical Activity, Mobility, and Cognitive Neuroscience.

"Older adults who experience falls that require medical attention falls are medically complex and at high risk for both morbidity and mortality, and we demonstrated that exercise is a practical and cost-effective intervention that can improve older peoples' outcomes after a significant fall," she added.

Liu-Ambrose and her team at the Centre for Hip Health and Mobility are now looking at whether the exercise program resulted in reduced health care utilization and medical cost savings in this high-risk population.

Scientists at VCU Massey Cancer Center have identified key biological pathways that regulate the spread of tumor cells to vital organs. These findings may have a significant influence on the development of new therapies that slow or prevent breast cancer metastasis.

Metastasis refers to the spread of cancer cells to other organs, and the likelihood of curing cancer is significantly reduced once the disease has spread. Nearly all breast cancer deaths are caused by metastasis within vital organs.

The concept of cancer metastasis has long been supported by the "seed and soil" proposal, in which it is theorized that cancer cells (seeds) are dependent upon the tissue of organs (soil) to thrive in sites beyond their point of origin. This hypothesis laid the foundation for why cancer metastases are more common in certain organs over others, such as the lungs, lymph nodes, bones or liver. The idea is that these organs offer a more fertile environment for cancer cell growth. Since this proposal's inception over a century ago, much more emphasis has been placed on studying the seeds rather than the soil. Scientists have focused heavily on the genetic properties of cancer cells that have spread to other organs, but what have remained much less understood are the genomic properties of the organic tissue that harbors successful metastatic growth.

Research led by Chuck Harrell, Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor of pathology at the VCU School of Medicine, set out to better understand the cancer-specific and organ-specific genomic qualities that contribute to successful breast cancer metastasis.

Using mouse models containing cells from breast cancer patients, Harrell developed novel metastasis representations of different types of breast tumors found in humans.

"These are the first models that characterize how cancer cells genetically change when they have spread to different organs, and, in parallel, that demonstrate how the organ genetically responds to the invading cancer cells," Harrell said.

In this study, published in Breast Cancer Research, Harrell created RNA sequencing datasets for metastatic models of ER-positive, triple negative and HER-2 positive breast cancer, with a particular focus on triple negative breast cancer due to the lack of current treatment options available.

"We discovered that during the growth of breast cancer metastases, genomic changes occurred within both the cancer cells and the organ microenvironment," Harrell said. "Our experiments identified key biological pathways that control the growth of breast cancer metastases, and we believe these findings can be used to help develop targeted therapeutics that prevent or slow cancer progression."

Specifically, they identified the SRC signaling pathway as highly activated in breast cancer metastases. This pathway plays a role in cell growth and embryonic development, and it impacts other pathways to promote blood vessel formation, cell survival and proliferation. However, drugs that inhibit the SRC pathway have already been developed and were proven clinically ineffective as a sole method of cancer therapy, often leading to continued tumor growth.

"Multiple pathways within the cancer cells, and potentially within the host organ as well, may need to be targeted to inhibit the growth of metastases," Harrell said. "Our ongoing efforts are aimed at identifying synergistic combinations of drugs that inhibit the SRC pathway and other pathways that promote metastasis."

Building on this research, Harrell and his team conducted a second related study, published in Clinical and Experimental Metastasis, focused on the characterization of how fourteen different patients' breast cancer cells grew when they had spread to the liver.

"We were able to determine that the breast cancer cells grew at varying rates and many were structurally distinct as liver metastases," Harrell said. "Evaluating the diversity of presentation within metastatic disease is essential to developing novel targeted therapies."

Additionally, Harrell observed a correlation between increased spread of tumor cells and a greater influx of innate immune cells, which are the body's automatic first line of defense against disease. This finding warrants further investigation of innate immune cell interaction with breast cancer liver metastases and the liver microenvironment.

Harrell said this research is important because scientists need reliable metastasis models to use in order to determine the drugs that can be an effective alternative for treating surgically inaccessible cancer cells.

Oregon is considering a bill to implement paid family leave, House Bill 2005, following in the footsteps of Washington, which approved a similar policy in 2017.

Oregon Health and Science University-Portland State University School of Public Health researchers concluded that it's not just approving paid family leave that's important for employees -- how that policy is implemented to make it equitable for all employees is just as critical.

OHSU-PSU School of Public Health Assistant Professors Dawn Richardson, Julia Goodman and David Hurtado published "Employee Experiences with a Newly Adopted Paid Parental Leave Policy: Equity Considerations for Policy Implementation" in Health Equity's May edition.

The researchers partnered with Multnomah County to evaluate a new paid leave policy adopted in November of 2015. Their findings offer insight and guidance for organizations implementing or considering implementation of paid family leave as well as steps to ensure equity in employee access to and experience of paid leave.

"If Oregon approves paid family leave, we're hoping our work with Multnomah County can offer support to employers in Oregon to really think about how they carry out the policy," Richardson said. "Assuming it passes, this is a significant shift in employee benefits and there's not a lot of guidance on how to do this, and how to do this well."

The researchers found that the policy was successful in supporting employees in taking paid leave when adding a child to their family through birth, adoption, or fostering. Overwhelmingly, employees were pleased with the benefit and noted how important it was for their families.

But the researchers also found that some employees experienced inequity in the policy's implementation despite it being approved and accessible for all eligible county employees.

One participant, a woman of color, said she saw her experience of inequity replicated despite the new policy.

"Depending on the supervisor, someone gets something very generous and then a person in the next unit over gets not a lot," the participant commented. "This is kind of horrible for all of us to see that, to see this inequity, even though we have these great policies."

Another participant said she had three different supervisors while preparing to take family leave, which led to inequitable decisions.

"I feel like that supervision piece can make it extremely inequitable for people to experience their parental leave," the participant commented. "I had one plan with the first supervisor, which was very understanding, a very generous plan. And then that person left the week I went on leave. And suddenly I had this new person, and they didn't want to honor the plan that I had in place."

The researchers were quick to point out that these experience are not specific to Multnomah County and would very likely be the story in any similar organization. Despite the best intentions of policies like these, an explicit focus on equity is needed.

Richardson and Goodman said supervisory training is one key to achieving workplace equity. Supervisors need to be clear on what the policy entails and how to guide employees navigating paid leave and the blending together of multiple benefits.

"The culture of the workplace matters a lot," Richardson said. "How are families shown they are truly valued?"

Culture and environment influence how employees experience the policy. Factors driving experience include department size and resources, demographic makeup and the supervisor's attitude.

If employees perceive that their use of paid leave is burdensome on the employer, it could have negative implications on the employee's contribution to the workplace.

"The employees who felt most supported also felt passionate about their employer, felt committed, and returned to work in ways that facilitated better productivity," Richardson said.

As Oregon considers approving its own paid family leave policy, she added that much of the negative debate comes down to the burden of cost -- specifically on small businesses.

"The costs are the costs. But who do we as a society believe should pay those costs? And who benefits? Without paid leave, the costs are entirely on the shoulders of workers," she said.

Numerous studies show offering paid family leave benefits both the employee and employer in the long run, but the conversation hasn't transitioned past the upfront cost.

"We need to think about where we want to invest. And part of that investment is not just in adopting the policy, it's in training people," Richardson said. "It's in seeing the policy through."

Employers may struggle with the costs of providing these benefits, she added, but she, Goodman and Hurtado hope work like theirs can show in the long-term the cost is worth it.

HOUSTON - (June 3, 2019) - Help for patients with sickle cell disease may soon come from gene editing to fix the mutation that causes the disease and boost the patient's own protective fetal hemoglobin.

New research shows that using CRISPR-Cas9 and a corrective short DNA template to repair the sickle cell mutation in a patient's hematopoietic stem cells (HSCs) could be efficient and safe.

Bioengineer Gang Bao of Rice University's Brown School of Engineering conducted the research in collaboration with Texas Children's Hospital, Baylor College of Medicine and Stanford University. The revelation is one of several in a new study led by Bao and Vivien Sheehan, an assistant professor at Baylor and a member of the sickle cell program at Texas Children's Hematology Center.

The open-access study appears in the Oxford Academic journal Nucleic Acids Research.

Sickle cell disease, which affects about 100,000 Americans and millions worldwide, is a painful and often fatal inherited condition. A single mutation in hemoglobin subunit beta (aka beta-globin) forces normal, disc-shaped red blood cells to stiffen and take characteristic "sickle" shapes. These cells can damage vessel walls and clot small blood vessels, stopping the delivery of oxygen to tissues.

Today, some people afflicted with the disease are treated with stem cells from a matched, related donor, an option researchers says is available to fewer than 15% of patients. A better strategy would be modifying the patient's own hematopoietic stem and progenitor cells (HSPCs), an option theoretically available to every patient because there would be no risk of rejection.

Ideally, stem cells isolated from the patient's bone marrow would be gene-edited and tested, and chemotherapy would be used to reduce the patient's stem cells to make room for the edited cells. Bao said the corrected cells would then be implanted back into the patient, where they could proliferate and spawn healthy blood cells.

For the new study, and for the first time, Bao and his team tested patient HSPCs in rodents and demonstrated that a fraction of the gene-edited cells from patients could survive and function for about 4 months.

These stem cells were from the peripheral blood of five patients and the bone marrow of two patients with the disease, all obtained by Sheehan. The Sheehan lab characterized the type of hemoglobin made by the edited cells and showed that gene editing can provide enough protective and normal hemoglobin to prevent sickling, even under the severe hypoxia that promotes sickling.

Early tests using wild-type Cas9 protein - the "scissors" that target and cut specific sections of DNA - from Streptococcus pyogenes led to stem cells with high levels of unintended DNA edits. These off-target edits included large chromosomal deletions and inversions that could cause disease.

In a second round of tests, the Rice lab adopted a more recent "high-fidelity" version of Cas9 developed by Integrated DNA Technologies. That led to significantly reduced off-target edits, Bao said.

Not all the stem cells isolated from a patient with the sickle mutation are fixed by gene editing. At best, according to experiments by the Bao lab, it fixed up to 40% of them. In another 50% of cells, DNA was cut and not repaired by the corrective DNA template, but that appeared to boost the stem cells' expression of fetal hemoglobin (HbF), a type made by a different gene that does not carry the sickle mutation and is normally turned off a few months after birth.

Fetal hemoglobin is known to mute the effects of sickle cell disease. Bao suspects that if the expression of fetal hemoglobin in edited cells persists, 90% of the stem cells from patients will either have the sickle mutation fixed, or have sickling prevented by fetal hemoglobin.

"Our hope is that if we take out a fraction of HSPCs from a patient's bone marrow and damage the remaining ones, then edit the HSPCs and deliver them back, the combination of gene-corrected and HbF-expressing cells will be enough to cure the disease," Bao said.

That 10% of stem cells continued to produce sickle cells should not be a big concern, he said. "The good news is that normal red blood cells have a lifespan about nine times that of the sickle cells," Bao said. "That means over time, the majority of the red blood cells would be normal cells. That's the scenario we would like to see."

The researchers don't yet know if cutting beta-globin to boost fetal hemoglobin levels would provide a long-lasting benefit or whether it risks inducing beta thalassemia, a blood disorder that reduces the production of hemoglobin. "There is a risk, and we need to understand it better," Bao said.

It is also unclear how many stem cells must be edited to provide long-term relief to a patient. "We don't know what percentage of the HSCs with gene correction could effectively treat sickle cell disease," he said. "Some people say just a few percent, and some say 5-10%. My guess is around 5% would be sufficient, but the exact percentage could only be established through clinical trials."

The road to human trials may still take some time, Bao said. "Technology-wise, we are ready to do a clinical trial," he said. "But just getting approval for a trial will require a lot of resources. We need to compile the data and do additional experiments to address the safety issues."

CHICAGO - Neoadjuvant, or pre-surgical, treatment with nivolumab plus ipilimumab resulted in an overall major pathologic response (MPR) rate of 33 percent of treated patients with early-stage, resectable non-small cell lung cancers, meaning these patients had less than or equal to 10 percent viable tumor remaining at surgery. With these results, the combination immunotherapy met the pre-specified trial efficacy endpoint of the phase II NEOSTAR trial conducted by researchers at The University of Texas MD Anderson Cancer Center.

The trial arm testing nivolumab alone in the treated population of patients achieved a 17 percent MPR rate, for an overall MPR rate across both trial arms of 25 percent. The results of the trial will be shared today in an oral presentation at the 2019 American Society of Clinical Oncology Annual Meeting by principal investigator Tina Cascone, M.D., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology.

"The NEOSTAR trial results definitely tell us this combination is clinically promising and warrants further investigation, possibly in combination with other therapies" said Cascone. "By learning from these results and from our preclinical and translational findings, we can identify the best combination and make a major step forward in the field to limit tumor recurrence for our early-stage lung cancer patients."

Patients with early-stage or locally advanced lung cancer have the potential to be cured of their disease, but more than half of those patients will have a recurrence if treated with surgery alone, explained Cascone. Therefore, there is an urgent need to identify the most effective neoadjuvant therapy options to reduce the risk of relapse.

Preclinical studies in mice revealed that increased expression of PD-L1, an immune checkpoint protein, in lung adenocarcinoma tumors is critical for the development and survival of metastases, providing the rationale for testing immunotherapy in the neoadjuvant setting.

"Prior to this study, we knew that single agent neoadjuvant immunotherapy has achieved a MPR rate of 22 to 45 percent, but the combination of anti-PD-1 and anti-CTLA-4 immune checkpoint blockade before surgery in resectable NSCLC patients had not yet been tested," said Cascone. "In mouse models of resectable and spontaneously metastatic non-small cell lung cancer, the combination of immunotherapy prior to surgery was superior to adjuvant combined therapy in prolonging survival and reducing the frequency of lung metastases, supporting further investigation of neoadjuvant combined immune checkpoint blockade in the clinical setting"

The researchers designed the trial to test the effectiveness of combination immune checkpoint inhibitors priory to surgery. The trial enrolled 44 patients who were randomized to receive either neoadjuvant nivolumab (anti-PD-1) alone or nivolumab plus ipilimumab (anti-CTLA-4).

The trial's primary endpoint was MPR, hypothesized to be higher for single and/or combination immune checkpoint inhibitors compared to the rate induced by historical neoadjuvant chemotherapy controls. The pre-specified trial efficacy endpoint for a specific treatment to be considered promising was greater than or equal to six MPRs in the intent to treat population.

MPR has been adopted as a surrogate endpoint in neoadjuvant trials for patients with resectable non-small cell lung cancer patients, as it has been shown to positively correlate with improved overall and recurrence-free survival outcomes, explained Cascone.

Seven out of 21 patients treated pre-operatively with the combination therapy achieved an MPR, and four of 23 patients treated with nivolumab alone achieved an MPR.

Although the trial was not powered to make a comparison between the two arms, the combination therapy appeared more effective at reducing viable tumor at surgery. Six patients (38 percent) that received the combination therapy and underwent surgery on trial achieved a complete pathological response, or tumor disappearance at resection, compared to just two patients (10 percent) receiving nivolumab alone. Also, the majority of patients with more than 50 percent viable tumor remaining at surgical resection received single-agent nivolumab therapy.

The treatments were generally well-tolerated, said Cascone, with no unacceptable toxicity or increased perioperative morbidity and/or mortality noted, however, careful perioperative monitoring is advised with these agents.

The trial also collected a variety of biospecimens from patients before, during and after treatment, which enabled researchers to investigate why results vary from patient to patient and understand the dynamic changes induced by therapy in potential biomarkers. They discovered that elevated tumor expression of the immune checkpoint protein PD-L1 prior to therapy was positively correlated with radiographic responses and with pathologic tumor regression at surgery.

Preliminary immunologic characterization of resected tumors from patients treated with immunotherapy indicated that the combination therapy is associated with an increased number of tumor-infiltrating lymphocytes as compared to monotherapy, and that some of these T cells might have tumor reactive activity. Additional results to be presented in a poster session show that combination therapy appeared to be associated with greater diversity and reactivity of T lymphocytes in resected tumors as compared to pretreatment tumor specimens (Abstract # 8532).

"This is important because we don't see patients with early-stage lung cancer as often as patients with metastatic disease in the clinic, and we want to take advantage of this opportunity for our patients. There are limitations to this trial, as it was overall a small cohort, but the positive results suggest we should continue to evaluate neoadjuvant combination immunotherapy as an option for our patients. Our ongoing exploratory analyses will help us to better understand this response and to identify potential biomarkers that could inform future trials," said Cascone

The researchers already have added and are nearing complete enrollment in a third arm of the NEOSTAR trial to evaluate neoadjuvant nivolumab plus platinum-based chemotherapy. Because of successful accrual, additional arms are being considered to evaluate further combination approaches.

A UCLA-led study has found that using a drug called ribociclib in combination with a common hormone therapy may help premenopausal women with the most common type of breast cancer live longer than if they only receive the hormone therapy.

Ribociclib is considered a cyclin-dependent kinase inhibitor that works by blocking the activity of proteins called cyclin-dependent kinase 4/6 enzymes, which promote cell division and cancer growth.

The study involved 672 women under 59 years old when the study began who had advanced hormone-receptor positive/HER2- breast cancer. Seventy percent of the women who took the combination therapy were alive after 42 months, compared to 46% for women who treated with only the hormone therapy.

The results will be featured in a press briefing on June 1 at the American Society of Clinical Oncology annual meeting and will be published in the New England Journal of Medicine on Tuesday, June 4 (embargo lifts on June 1 at 6:30 a.m. during ASCO's press briefing).

Dr. Sara Hurvitz, director of the Breast Cancer Clinical Research Program at the UCLA Jonsson Comprehensive Cancer Center, said the study is the first to show a significant benefit in overall survival for women in this age group with metastatic hormone-receptor positive breast cancer.

"This trial was unique because it looks at younger women who haven't gone through menopause," said Hurvitz, the study's lead author, who is also an associate professor of hematology/oncology at the David Geffen School of Medicine at UCLA. "This is an important group to study since advanced breast cancer is the leading cause of cancer death in women 20 to 59, and the vast majority of breast cancer is hormone-receptor positive."

None of the women in the study had been previously treated for metastatic cancer. Half of the subjects were given hormone therapy and a placebo. The other half received hormone therapy in addition to ribociclib.

Hormone therapy, also called endocrine therapy, is an essential part of treatment for hormone-receptor positive breast cancer, a form of the disease in which a woman's own hormones promote cancer growth. Given as an oral medication, the therapy works by blocking or lowering the levels of estrogen production so cancer cells can't use them to grow and spread -- but it eventually stops working in some women.

Among women who received the combination therapy, the disease did not progress for an average of 23.8 months, compared to 13 months for those who received endocrine therapy and the placebo.

"It's great to see that we're extending the length of someone's life, not just the length of time their disease is controlled," Hurvitz said. "Very few trials show an improvement in overall survival. That's what is so phenomenal about the data."

From 1976 to 2009, the incidence of advanced breast cancer among U.S. women under 40 increased an average of about 2% per year, a larger increase than for any other age group.

In the early 2000s, a team of UCLA Jonsson Cancer Center researchers led by Dr. Dennis Slamon were on the forefront of discovering that cyclin-dependent kinase inhibitors are effective in treating hormone receptor positive breast cancer. Their work ultimately helped lead to the FDA approval of ribociclib and other related drugs to treat metastatic breast cancer.