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(PHILADELPHIA) -- A new class of cancer drugs - called CDK4/6 inhibitors -- recently approved to treat breast cancer can stunt the cancer's growth and replication. It is also being explored for a number of other cancers. Unfortunately, patients often develop resistance to the therapy, and the cause of that resistance has been difficult to pin down. Researchers at the Sidney Kimmel Cancer Center at Jefferson Health recently discovered the key resistance mechanism in prostate cancer and identified a molecular inhibitor that could help fight the disease when resistance develops.

"We provide evidence that a drug, already in development, could help fight the cancers that develop resistance to CDK4/6 inhibitors," said senior author Karen E. Knudsen, PhD, Director of the Sidney Kimmel Cancer Center at Jefferson Health. "This could potentially offer patients a more effective therapy to try when the CDK4/6 inhibitors fail."

The results were recently published in the journal Clinical Cancer Research.

In order to first explore how tumors become resistant to CDK4/6-inhibitor therapy, Dr. Knudsen and her team, including first author Renée de Leeuw, used a cellular model of prostate cancer that let them hone in on the process of resistance. The researchers found that as prostate cancer cells become resistant to CKD4/6-inhibitors they rewire the protein pathways essential for their survival. The transcriptome of the cancer cells fundamentally shifts. This rewiring causes the cells to begin to depend on a different pathway for their growth, the MAPK-6 or MEK pathway, which normally does not play a big role in prostate cancer.

The researchers also showed, when the prostate cancers develop resistance to the CDK4/6 inhibitors and switch to being dependent on the MAPK-6 pathway, the cancer cells become much more aggressive, spreading and seeding metastases more rapidly in mouse models of the disease.

"However, this new dependence offers us an opportunity," said Dr. Knudsen. "MEK-inhibitors are currently being tested and in clinical trials. While these drugs show limited impact on earlier stages of disease they may become effective therapies as prostate cancer cells -- and potentially other cancers as well -- develop CDK4/6 resistance. By hitting cancer cells with one therapy, namely the CDK4/6 inhibitors, followed by a MEK inhibitor, we block the cancer's avenues of escaping death one by one."

MEK inhibitors have been approved for treating melanoma and are currently being tested for prostate cancer in clinical trials. But there are no currently open trials investigating the combination treatment with a MEK and CDK4 inhibitors together. "These studies will be instrumental in guiding the next generation of clinical trials with CDK 4/6 inhibitors in prostate cancer and gives us a strong rationale to target MEK pathway," said co-author W. Kevin Kelly, DO, Professor of Medical Oncology, Director of the Division of Solid Tumor Oncology, and leader of the Prostate Cancer Program at the Sidney Kimmel Cancer Center, which is recognized by the National Cancer Institute as one of eight Prostate Cancer Centers of Excellence.

A new study led by scientists at VCU Massey Cancer Center has shown that an experimental drug known as AZ32 selectively sensitizes brain tumors to radiation and significantly extends the survival of mouse models with human glioblastoma multiforme (GBM), the most common and deadly form of brain cancer. Published in the journal Molecular Cancer Therapeutics, the study builds on the research of principal investigator Kristoffer Valerie, Ph.D., and has paved the way for a phase 1 clinical trial testing a similar but more effective experimental drug, AZ1390, in combination with radiation therapy for the treatment of brain cancer. An accompanying study on AZ1390 that Valerie co-authored was recently published in Science Advances.

AZ32 is a member of a family of compounds referred to as ATM kinase inhibitors. ATM, or ataxia telangiectasia mutated, is an enzyme that facilitates repair of DNA damage in cells. Radiation therapy is first-line treatment for GBM; however, glioma stem cells are often able to resist DNA damage caused by radiation. By inhibiting ATM, AZ32 was shown to disrupt the process by which brain cancer cells resist radiation while sparing and potentially protecting healthy brain tissue.

"In 2009 and 2013, we were the first to show that an ATM kinase inhibitor could make brain cancer cells and tumors sensitive to radiation," says Valerie, a member of the Developmental Therapeutics research program at Massey, in reference to his prior research published in Molecular Cancer Therapeutics and Clinical Cancer Research. "This time with AZ32, we used an ATM kinase inhibitor that penetrates the blood-brain barrier. The combination of AZ32 and radiation was highly effective against GBM cells with mutant versions of the p53 tumor suppressor gene, which normally acts to promote radiation resistance."

As many as 80 percent of GBM patients have cancers with mutant or dysfunctional p53 signaling. The combination therapy forced GBM cells to undergo mitotic catastrophe, which occurs when external stressors cause a cell to inappropriately enter into mitosis, a phase of the cell cycle where cell division occurs, and ultimately led to cell death.

"Our study is the first to show that an ATM kinase inhibitor that can be taken orally and able to penetrate the blood- brain barrier radiosensitizes GBM in mouse models. It is also the first to explain the p53-based mechanism by which ATM kinase inhibitors selectively sensitize brain cancers to radiation," says Valerie. "We are excited to translate these findings into a clinical trial and hopefully bring more effective therapies to patients who typically do not have good outcomes."

This study laid the groundwork for a phase 1 clinical trial (NCT03423628) led by AstraZeneca that will test AZ1390 in combination with radiation therapy for the treatment of brain tumors. It will assess the safety and tolerability of increasing doses of AZ1390 in combination with different regimens of radiation therapy for recurrent GBM, brain metastases and newly diagnosed GBM. The trial is estimated to enroll 132 patients at seven medical centers in the US and the UK, including VCU Massey Cancer Center.

PHILADELPHIA - The addition of fluorine-18 (18F)-fluciclovine positron emission tomography/computed tomography (PET/CT) to the diagnostic work-up of patients with biochemical recurrence of prostate cancer locates previously undetected lesions and changes treatment management for the majority of patients, according to a clinical trial report presented at the 2018 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

"Recurrent prostate cancer poses an important medical challenge," explains Austin R. Pantel, MD, of the University of Pennsylvania in Philadelphia. "Currently approved anatomical imaging procedures have limitations in identifying the sites of recurrence of prostate cancer after definitive treatment. This can make decision-making difficult when assessing these patients." He notes, "Up to 30 percent of patients with prostate cancer will develop local or distant recurrence within 10 years of radical prostatectomy or radiation therapy. Determining the location and extent of recurrent disease optimizes the selection of appropriate management for these men."

For the LOCATE trial (ID# NCT02680041), 213 men with biochemically recurrent prostate cancer were evaluated with 18F-fluciclovine PET/CT after having negative or equivocal findings on conventional imaging, such as a bone scan, CT or magnetic resonance imaging (MRI). This first prospective multicenter study was conducted at 15 sites in the U.S., including both private practices and academic settings. It focused on the association between scan positivity and the clinical variables of recurrence site, practice setting, prostate-specific antigen (PSA) level, and Gleason score (system of grading prostate cancer). Questionnaires completed by treating physicians documented changes in management after the PET study.

Trial results showed that 59 percent (126/213) of patients had their clinical management changed by findings from 18F-fluciclovine imaging. Of those changes, 78 percent (98/126) were classified as "major" (i.e., a change in treatment modality). Disease was detected in the prostate, as well as other tissue, including pelvic and abdominal lymph nodes and, less commonly, bone. Both positive and negative scans impacted patient management. No difference was seen in the rate of positive scans or in the rate of management changes between private practices and academic settings. In addition, no association was found between Gleason score at diagnosis and positive scans.

Pantel points out, "While investigation of the long-term clinical outcomes of these changes in management is warranted, these results indicate, for the first time in a prospective U.S. study, that decisions based on 18F-fluciclovine PET/CT imaging may facilitate more appropriate management in men with biochemical recurrence of their prostate cancer. The study also demonstrates the broad potential applicability of 18F-fluciclovine PET/CT imaging across a range of clinical settings."

He emphasizes, "Selecting appropriate treatment for men with recurrent prostate cancer is critical. Many options are available, and additional information, such as that provided by 18F-fluciclovine PET/CT, may help tailor personalized treatment plans. Clinical studies, such as the LOCATE trial, are important to investigate the role of the current generation of molecular imaging agents in guiding management for men with recurrent prostate cancer. This study highlights the key role of nuclear medicine in directing effective patient management and care."

LOUISVILLE, Ky. - Spine surgeons and researchers at the University of Louisville, concerned about potential opioid misuse resulting from pain management related to surgery, have discovered positive news in a study of back surgery patients. The study, conducted by researchers in the UofL Department of Neurological Surgery, concludes that patients undergoing surgery for degenerative spondylolisthesis are less likely to be dependent on opioids after than before the surgery.

The national opioid epidemic affects millions of Americans. Overdoses claimed more than 42,000 lives in 2016, according to the Centers for Disease Control and Prevention, up from 33,000 in 2015, and Kentucky has the fifth highest rate of overdose deaths of any state, at 33.5 per 100,000 population. Unfortunately, many people who abuse opioids were introduced to the drugs through a physician's prescription to control pain.

"Spine surgery patients deal with an immense amount of pain both before and after surgery. Opioids are used to manage that pain," said Mayur Sharma, M.D., M.Ch., a resident in the UofL Department of Neurological Surgery who led the study. "Patients have been abusively using opioids for pain resulting in the recently declared national opioid crisis. Our work indicates that surgery for degenerative spondylolisthesis is associated with a reduced risk of opioid dependence."

In the research, published last week in Journal of Neurosurgery: Spine, the authors analyzed records for 10,708 patients who had surgery between 2000 and 2012 for degenerative spondylolisthesis, a condition in which one vertebra slips over another one, compressing the nerves in the spinal column, most often occurring in the lower back. The researchers found that 14.85 percent of the patients were opioid dependent within one year prior to the surgery, and 9.9 percent were opioid dependent 3 to 15 months after the surgery. Most of the patients received decompression and fusion surgery for the condition. The authors concluded that overall, opioid dependence was reduced by nearly 5 percent following surgery for degenerative spondylolisthesis.

In addition to the reduction in dependency, analysis of the records showed that younger age and prior opioid dependence were associated with a higher risk for post-surgery opioid dependence. This information may guide physicians in predicting which patients are at higher risk for opioid dependence following surgery.

"It is important to note that 10 percent of patients who come for surgery for degenerative spondylolisthesis will be opioid dependent after surgery. These patients require special attention. Our paper discusses some of the predictive factors to consider," Sharma said.

"Factors predicting opioid dependence in patients undergoing surgery for degenerative spondylolisthesis: analysis from the MarketScan databases," was coauthored by Sharma, Maxwell Boakye, M.D., chief of spinal neurosurgery, Beatrice Ugiliweneza, Ph.D., M.S.P.H., assistant professor, and Zaid Aljuboori, M.D., of UofL, and colleagues at University of California, Davis and Swedish Medical Center in Seattle.

Patients with Type 2 diabetes who were treated with the newer generation of insulin analog drugs did not have substantially better outcomes than those treated with less costly human insulin, according to a study by Yale School of Medicine researchers and colleagues at Kaiser Permanente.

The study is published in the June 23 issue of Journal of the American Medical Association.

"We compared the newer and older types of insulin in a large and diverse population of Kaiser Permanente type 2 diabetes patients who were newly prescribed insulin," said lead author Kasia J. Lipska, M.D., assistant professor of medicine at Yale School of Medicine. "The study was conducted under real-world conditions with uniquely detailed data about possible confounding factors and long-term outcomes."

"We found that for patients with type 2 diabetes in usual practice, the use of the more expensive insulin analogs did not appear to result in better safety -- at least as defined by hospital or emergency visits for hypoglycemia -- or better blood sugar control compared with NPH insulin," Lipska added. "This suggests that many people with type 2 diabetes should consider starting with NPH insulin, instead of insulin analogs, especially if cost is an issue for them."

For the estimated 29 million Americans with diabetes, treatment of type 2 diabetes typically begins with lifestyle modifications and metformin, a pill that lowers the amount of sugar in the blood. However, up to 25% of diabetes patients eventually require additional insulin injections to control their blood sugar.

"For decades, people initiating insulin treatment were prescribed human insulin," said Andrew J. Karter, senior research scientist with the Kaiser Permanente Division of Research. "Then in the 2000s, a new generation of long-acting insulin analogs emerged that were designed to mimic human insulin."

Like human insulin, long-acting insulin analogs can be prescribed as daily or twice-daily injections to help provide predictable levels of blood sugar throughout the day. In clinical trials, insulin analogs modestly reduced the risk of nocturnal hypoglycemia, or low blood sugar during sleep, compared with human insulin.

"The problem is that insulin analogs are much more expensive than human NPH insulin," said Lipska. A vial of insulin analog now costs about $200 to $300, while a vial of NPH insulin costs just $25. The cost of analog insulin has tripled nationally between 2002 and 2013. Dr. Karter's research has shown that high out-of-pocket cost of medications, especially at the time of initiation, are linked to poorer adherence, which directly affects outcomes for diabetes patients."

To compare insulin analogs with NPH insulin, Lipska, Karter and their colleagues followed the new insulin users with type 2 diabetes for an average of 1.7 years. During this time, they examined emergency department visits or hospitalizations related to severe hypoglycemia, as well as changes in their blood sugar (hemoglobin A1c) control. They found that insulin analogs were not associated with a reduced risk of emergency department visits or hospital admissions for severe hypoglycemia, nor did they control hemoglobin A1c levels better than NPH insulin.

"The cost differential between analog and NPH insulins is huge, up to a 10-fold difference," Karter said. "Some people with type 2 diabetes may find the potential benefits of insulin analogs worth the additional cost. But we found no population-level evidence to suggest that the extra expenditure is warranted for most people with type 2 diabetes, particularly when the high cost could prevent some of them from getting the treatment they need or divert resources away from other, potentially beneficial clinical interventions."

Fatigue is a common but underestimated symptom of endometriosis, according to findings from an international study of over 1100 women, published today (Wednesday) in Human Reproduction [1], one of the world's leading reproductive medicine journals.

The study found that the prevalence of fatigue was more than doubled in women diagnosed with endometriosis compared to those who were unaffected by the condition, and it remained significant after the results were adjusted for other factors that might play a role in fatigue, such as pain, insomnia, occupational stress, depression, BMI and motherhood.

"These findings suggest that endometriosis has an effect on fatigue that is independent of other factors and that cannot be attributed to symptoms of the disease," said Professor Brigitte Leeners, deputy head of the Department of Reproductive Endocrinology at the University Hospital Zurich, Switzerland, who led the research.

"Although chronic fatigue is known to be one of the most debilitating symptoms of endometriosis, it is not widely discussed and few large studies have investigated it. We believe that in order to improve the quality of life for women with this condition, investigating and addressing fatigue should become a routine part of medical care, and doctors should investigate and address this problem when they are discussing with their patients the best ways to manage and treat the disease. It would also help these women if steps were taken to reduce insomnia, pain, depression and occupational stress."

Endometriosis is a condition in which the endometrial cells that form the inside of the womb also grow in other areas of the pelvic region, such as the ovaries and the abdominal cavity. The main symptoms are pain and infertility, although not all women will have these symptoms. It is not known what causes it, but it is a common gynaecological disease with a global prevalence of between 6-10%. It can be treated with drugs, such as anti-inflammatories and hormone therapy, and with surgery.

The researchers recruited 1120 women, 560 with endometriosis matched with 560 without it, from hospitals and private practices in Switzerland, Germany and Austria between 2010 and 2016. The women completed a questionnaire that asked about various factors relating to quality of life and endometriosis, as well as medical and family histories, life style and mental disorders. Fatigue and insomnia were categorised into five different levels ranging from 1 (never) to 5 (very often).

They found that 50.7% of women diagnosed with endometriosis suffered from frequent fatigue compared to 22.4% of women without the condition. Fatigue with endometriosis was also associated with a more than seven-fold increase in insomnia, a four-fold increase in depression, a two-fold increase in pain and a nearly 1.5-fold increase in occupational stress. Age, time since first diagnosis and the stage of the disease were not linked to fatigue.

The researchers say that a possible reason why endometriosis could cause fatigue, independently of the other factors, is that the endometrial lesions may be causing inflammation that activates the immune system. Proteins called cytokines that are involved in cell signalling when the immune system is activated have been shown to play a role in fatigue symptoms. Chronic exposure to high stress can result in adrenal fatigue, and this could be an additional possible explanation.

Limitations of the study include the fact that answers to the questionnaires are subjective and at risk of bias from failure to accurately recall experiences in the past six months, and the fact that the researchers did not have information on the exact medication taken during the relevant period.

Are women who suffered child abuse more likely to develop endometriosis?

In a second study [2], also led by Professor Leeners, the researchers found that a history of childhood sexual abuse, emotional abuse and neglect and "inconsistency experiences" was associated with an increased likelihood of endometriosis in adulthood.

A total of 421 women diagnosed with endometriosis were compared with the same number without it. They were recruited from hospital and medical practices in Germany, Switzerland and Austria. They completed a questionnaire that asked about physical, sexual and emotional abuse, emotional and physical neglect, and "inconsistency experiences", which relate to a lack of perception by parents of a child's concerns, as well as aggressive or unpredictable behaviour that might lead to a child feeling unsafe or fearing the family might disintegrate.

Women with endometriosis were significantly more likely than the women without the condition to report a history of sexual abuse (20% versus 14%), emotional abuse (44% versus 28%), emotional neglect (50% versus 42%) and inconsistency experiences (53% versus 41%). There were no statistically significant differences for physical abuse or neglect.

"This is one of the largest studies to investigate the links between childhood experiences and development of endometriosis," said Professor Leeners. "However, the effect sizes are relatively small and we were surprised that there didn't appear to be a link with physical abuse or neglect. We have no clear explanation for this, and larger studies should investigate further to confirm our findings."

She said that she was prompted to carry out the study because of her previous research into sexual abuse and because an increasing number of diseases were beginning to be linked to the environment in which a child grows up, such as diabetes, obesity, asthma and heart disease.

"At present, doctors do not routinely ask women with endometriosis about their childhood experiences. As previous studies have estimated that approximately 20% of children suffer sexual abuse, between 25% and 50% suffer physical abuse, and between 12% to 48% suffer emotional abuse, our findings suggest that doctors should investigate these experiences when taking a patient's history so that women can receive appropriate treatment as early as possible. This might help to prevent other chronic diseases and mental health problems from developing," she concluded.

Arlington, Va., June 26, 2018 - Severe gaps in staffing and outdated coverage benchmarks point to the critical need for evaluating and updating standards for infection preventionist (IP) staffing levels, according to two new studies that explored infection prevention and control resourcing across a variety of healthcare settings. The studies were published in the American Journal of Infection Control (AJIC), the journal of the Association for Professionals in Infection Control and Epidemiology (APIC).

A comprehensive staffing and coverage assessment conducted at Providence Health & Services, a large nonprofit healthcare system, revealed that actual IP labor needs were 31 to 66 percent higher than the current benchmarks system wide.

The Providence study was conducted for all physical locations within the system that required IP oversight, including 34 critical access, community, and tertiary hospitals; one rehabilitation hospital; 13 in-home care programs; 13 long-term care facilities; and 583 ambulatory locations.

After aggregating system-wide needs, the assessment team concluded the new benchmark should be 1.0 IP full-time equivalent (FTE) per 69 beds, indicating a greater IP need than the previously accepted standard of 0.5-1.0 FTE per 100 beds. The new benchmark considers IP oversight for all physical locations including ambulatory, long-term care, and home care settings.

"The study shows how important it is to conduct thorough needs assessments before determining staffing models for any given organization," said Rebecca Bartles, MPH, CIC, FAPIC, Providence St Joseph Health System, Renton, WA, USA, the study's lead author. "While a one-size-fits-all model can't necessarily account for differences across systems, there would be immense value in large healthcare systems pooling together quantitative needs assessment data for analysis."

The results also revealed that the actual percentage of time IPs spent conducting surveillance activities - which include monitoring health outcomes, analyzing processes of care, and working to improve those processes based on the outcomes - took an average of 51 percent of current working hours. All IPs interviewed agreed that although most of their time was spent on surveillance and reporting, the most valuable use of their time is conducting environmental rounding and engaging in caregiver education activities.

A second study, analyzing infection prevention staffing and resources in US acute care hospitals based on results from the 2015 APIC MegaSurvey, exposed similar gaps. The article, by Monika Pogorzelska-Maziarz, PhD, MPH, CIC, FAPIC, Thomas Jefferson University, Jefferson College of Nursing, Philadelphia, PA, USA, and colleagues, drawing from 1,623 survey respondents, provided a snapshot of IP staffing and resources in acute care hospitals, finding important differences between small and large facilities.

Among the APIC MegaSurvey's findings:

The way in which IPs spent their time differed between those that were employed by larger vs. smaller hospitals. IPs working in smaller hospitals spent a significantly smaller proportion of their time on surveillance and prevention and control of healthcare associated infection (HAI) transmission, and a larger proportion of their time on employee and occupational health, along with education and research. The way in which IPs spent their time in smaller hospitals potentially reflects the additional responsibilities they may have in addition to infection control.

Overall median IP staffing was 1.25 IPs per 100 inpatient census.

Responses echoed results from other published studies, finding that few IPs had data management or secretarial support, particularly in smaller hospitals. Being able to delegate administrative tasks frees the IP to spend more time on infection prevention-related work.

"The relationship between IP staffing and rates of HAIs has been documented," said Dr. Pogorzelska-Maziarz. "This study sheds light on the fact that individual organizations should conduct routine assessments to ensure IP staffing is matching the demands of the facility, and it demonstrates the need for information-sharing among organizations."

Both studies support the view that IP staffing recommendations should be based on the care and services provided by a healthcare institution, rather than on a single ratio, which may not be appropriate for all models.

"As the responsibilities of infection prevention and control departments have grown, and the settings of care requiring IP services have expanded, many IPs find that they lack time to conduct activities that will have the most impact on preventing healthcare-associated infections, such as interacting with frontline teams in patient care areas," said 2018 APIC President Janet Haas, PhD, RN, CIC, FSHEA, FAPIC. "These studies demonstrate the critical need to reevaluate staffing models to ensure that the demand for IP services is being adequately met so that we can effectively protect patients from infections."

TORONTO, June 26, 2018 - Antidepressant use in people with chronic obstructive pulmonary disease (COPD) is associated with a 20 per cent increase in likelihood of death and a 15 per cent increase in likelihood of hospitalization due to related symptoms, finds a new study led by researchers at St. Michael's Hospital.

Published today in the European Respiratory Journal, the research suggests that amongst adults with COPD, new users of serotonergic antidepressants - a specific class of the medication - have higher rates of hospitalization, emergency room visits, and mortality related to respiratory conditions, as well as death overall versus non-users of the medications. While the study does not show cause and effect, it suggests strong association.

"We were not surprised by these findings, as there are biological reasons why antidepressants could lead to respiratory issues," said Dr. Nicholas Vozoris, a scientist in the Li Ka Shing Knowledge Institute of St. Michael's Hospital and the lead author. "These drugs can cause sleepiness, vomiting and can negatively impact immune system cells. This increases the likelihood of infections, breathing issues, and other respiratory adverse events, especially in patients with COPD."

COPD is a progressive lung disease that causes increasing breathlessness. It affects more than 10 per cent of those aged 40 and older worldwide. Because of the nature of the disease, upwards of 70 per cent of those with COPD also struggle with symptoms of low mood and anxiety, said Dr. Vozoris, who is also an assistant professor in the Department of Medicine at the University of Toronto and a respirologist at St. Michael's.

Using health administrative databases from the Institute of Clinical Evaluative Sciences (ICES), Dr. Vozoris and his team studied 28,360 new users of serotonergic antidepressants with COPD aged 66 and older and matched them to an equivalent amount of non-users. The analysis revealed that among older adults with COPD, new users of this class of medication have modest, but significant, increases in rates of breathing-related death and all causes of death. The research showed a strong association, but not a definite cause and effect.

"The study results should not cause alarm among those who use these medications, but rather increase caution among patients and physicians," Dr. Vozoris said. "I hope our study encourages increased awareness when prescribing these medications and monitoring for adverse side effects. Also, because there is this association, we as physicians should give thought to psychotherapy and pulmonary rehabilitation as non-drug related treatment."

Dr. Vozoris plans to continue to study other classes of medications used for treatment of psychological issues in patients with COPD to build a more complete picture of medication risks.

A new airborne remote-imaging method that scans entire orchards can identify olive trees infected by a devastating bacterium before visible symptoms appear, according to new research.

The scanning, which can be deployed using planes or drones, may help control the spread of infection and save southern Europe's iconic tree.

Xylella fastidiosa is a devastating bacterium, transmitted by common sap-feeding insects, which causes disease in over 350 plant species. Olive trees are especially vulnerable, with the bacteria causing branches and twigs to wither, and leaves to appear scorched.

Common in the Americas but only recently discovered in Europe, Xylella is spreading around the Mediterranean, with many orchards already destroyed in Italy's olive-oil-producing Apulia region. As there is no cure, the only way to stop the disease's progress is to cull infected trees, with earlier diagnoses being the key to more effective containment.

Pablo Zarco-Tejada of the European Commission, together with experts from Swansea University and other European institutions, used special cameras, fitted aboard a small plane, to perform both hyperspectral (looking across the entire electromagnetic range) and thermal image analyses of orchards. The authors then tested olive trees on the ground for Xylella infection.

Professor Peter North, from the Department of Geography at Swansea University, one of the authors of the research, said: "Our study found that the effects of the bacterial infection can be remotely detected before any visible symptoms appear, allowing for rapid and accurate mapping of Xylella-infected olive trees across target orchards".

Dr Rocio Hernandez-Clemente, a geographer and member of the research team from Swansea University, added: "The spread of plant diseases is predicted to become an increasing problem with climate change, including for the UK. International cooperation is essential for early detection, to control damage and prevent spread. This study demonstrates the possibility of detection of symptoms at an early stage, and may be adapted to drones and aircraft for widespread use".

Doctors often treat melanoma with drugs that unblind the immune system to cancer. And brain metastases associated with melanoma are often treated with precisely targeted radiation known as radiosurgery. Now a University of Colorado Cancer Center study published in the Journal of Neuro-Oncology shows a potential advantage of combining these two techniques: Of 38 melanoma patients treated with immunotherapy and radiosurgery between 2012 and 2017, median overall survival was not reached, meaning that so many of these patients (who historically have had very poor prognosis) were still alive when data was analyzed that it was impossible to predict how long a patient treated in this way would be expected to live. Importantly, the study also shows a significant difference in cancer control depending on the type of immunotherapy used. In melanoma, brain metastases are a major cause of mortality. Patients treated with anti-CTLA4 immunotherapies saw the development of new brain metastases at median 3.1 months, whereas the median was not reached for patients treated with anti-PD-1 immunotherapies.

"We decided to look at this because it's something we commonly do in the clinic. We use immune checkpoint inhibitors, and at the appearance of brain metastases, we're using radiosurgery. Big studies have shown a dramatic increase in survival for melanoma patients with brain metastases, and our study hints at one possible reason why: There may be an underlying synergy between these therapies," says Tyler Robin, MD, PhD, senior resident in radiation oncology at the CU School of Medicine and the paper's first author.

The exact mechanism of this synergy is still under investigation, but studies have shown that radiation treatments can increase the PD-L1 signal on tumors essentially giving the anti-PD-1 or anti-PD-L1 inhibitors a target to act on.

Of the 38 patients treated in this way, none developed severe side effects, though six patients experienced some adverse reaction. Twenty-five patients received anti-CTLA4 immunotherapy, while 13 received anti-PD-1 immunotherapy, with results for anti-PD-1 therapies being across-the-board more successful (full results here).

"Several years ago, a patient might have expected to live months after that diagnosis, but for many patients this is no longer the case," Robin says. "People are actively investigating the combination of immune checkpoint inhibits and radiation, and our data raise the possibility that PD-1 inhibitors are preferential in this setting. We hope that ongoing and future investigations will shed more light on the potential value of this combination."

PHILADELPHIA - A new molecular imaging method can monitor the success of gene therapy in all areas of the brain, potentially allowing physicians to more effectively tackle brain conditions such as Parkinson's disease, Alzheimer's disease and multiple sclerosis. The research was presented today at the SNMMI 2018 Annual Meeting, June 23-26 in Philadelphia.

Gene therapy for diseases of the central nervous system (CNS) is a growing field; however, progress is limited by the absence of imaging techniques that can successfully monitor delivery of the therapy. Although reporter gene systems have been a key tool in molecular imaging for a number of years, they have not allowed monitoring of all areas of the brain. A new positron emission tomography (PET) reporter gene/probe system makes it possible, for the first time, to noninvasively monitor the level and location of gene expression in all areas of the brain, giving the medical team an early indication of the likelihood of treatment success.

"It is challenging to find a reporter gene and imaging agent that can be used in all areas of the brain with a high signal-to-background ratio," said Thomas Haywood, PhD, from the department of radiology at Stanford University, Stanford, California. "18F-DASA-23 is a novel radiotracer, or reporter probe, developed in the Gambhir lab at Stanford that is capable of crossing the blood-brain barrier and targeting the pyruvate kinase M2 protein in the central nervous system with minimal endogenous expression in the brain," he explained. "This allows us to monitor reporter gene expression and ultimately therapeutic gene expression for gene therapy in all regions of the brain." The radiotracer has recently undergone first-in-human trials at Stanford for the early detection of therapeutic response in glioblastoma.

In the study, after validating the utility of pyruvate kinase M2 (PKM2) as a PET reporter gene, mice were infected with a virus containing the gene, then imaged with the 18F-DASA-23 radiotracer over a period of two months to observe the increase in PKM2 expression over time. Results, confirmed by 18F-DASA-23 uptake studies and mRNA analysis, showed a good correlation between PKM2 and the radiotracer (see figure below). Further analysis showed an increase in PKM2 expression in infected mice when compared to controls. These encouraging data suggest PKM2 has the potential to be further developed into a PET reporter gene system for the imaging of gene therapy in the central nervous system.

"Having a reporter gene/reporter probe system that allows monitoring of all areas of the brain opens the door to more accurate and less invasive imaging of the brain and of gene therapies used to tackle diseases of the brain," Haywood said.

Rates of C. difficile infections have decreased 36% in hospitals across Canada, although the virulent NAP1 strain associated with severe illness and deaths is the most common strain, according to research published in CMAJ (Canadian Medical Association Journal)

Clostridium difficile is the most common infectious cause of diarrhea in hospitalized patients in developed countries, causing severe illness and occasionally death. Seniors and people on antibiotic treatment are most vulnerable to infection. However, the NAP1 strain of C. difficile, which is most virulent and can be resistant to treatment with fluoroquinolone antibiotics, has emerged in healthy people and in the community, spreading after several epidemics in the early 2000s.

A pan-Canadian team of researchers from the Canadian Nosocomial Infection Surveillance Program looked at data from 42-53 acute care hospitals over 7 years (2009-2015) to understand patterns of NAP1 strain and effect of infection on patient outcomes. A total 20 623 cases of hospital-acquired C. difficile occurred, mostly in hospitals with more than 200 beds. Infection rates decreased 35.8% across Canada by 2015, although the number of younger patients with the disease increased.

Improvements in infection-control measures (such as improved testing, more judicious use of antibiotics, frequent handwashing, and better and more frequent cleaning of facilities) begun after outbreaks 10-15 years ago may have contributed to the decrease in infection rates.

The large study found an association between the NAP1 strain and death in patients aged 18 and older, not detected by earlier single-centre or provincial-level studies.

"Our findings suggest that, as the proportion of NAP1 strain isolates decreases in relation to all circulating strains, both the rate of health care-associated C. difficile infection and the number of severe cases can be expected to decrease relative to a peer hospital with a higher proportion of NAP1 circulating isolates," says Dr. Kevin Katz, North York General Hospital, Toronto, Ontario.

The authors recommend continued vigilance to better contain infection.

"Infection prevention and control practices, antimicrobial stewardship and environmental cleaning should continue to be strengthened at the local level, as these areas positively affect institutional rates of health care-associated C. difficile infection, regardless of circulating strain types."

Bottom Line: The risk of autism spectrum disorder (ASD) was increased in children of mothers with the three main types of diabetes that complicate pregnancy, findings that add new information on type 1 diabetes and extend what is already known about type 2 and gestational diabetes.

Why The Research Is Interesting: Maternal preexisting type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) diagnosed by 26 weeks have been associated with increased risk of ASD in children in prior research. Less is known about ASD risk associated with maternal preexisting type 1 diabetes (T1D).

Who and When: 419,425 children born at 28 to 44 weeks from 1995-2012.

What (Study Measures and Outcomes): Maternal T1D, T2D and GDM (exposures); diagnosis in children of ASD, which includes autistic disorders, Asperger syndrome and pervasive developmental disorder not otherwise specified (outcomes)

How (Study Design): This was an observational study. Researchers were not intervening for purposes of the study and cannot control all the natural differences that could explain the study findings.

Authors: Anny H. Xiang, Ph.D., Kaiser Permanente Southern California, Pasadena, California, and coauthors

Results: Risk of ASD was higher in children exposed in utero to maternal preexisting T1D, T2D and gestational diabetes diagnosed by 26 weeks compared with no maternal diabetes exposure.

Study Limitations: Risk factors of the father, along with other intrauterine and postnatal exposures, couldn't be assessed.

Study Conclusions: Results suggest the severity of maternal diabetes and the timing of exposure (early vs late in pregnancy) may be associated with the risk of ASD in children of mothers with diabetes.

To Learn More: The full study is available on the For The Media website.

(doi:10.1001/jama.2018.7614)

Editor's Note: This study is being presented at the American Diabetes Association's 78th Scientific Sessions. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Want to embed a link to this report in your story? Link will be live at the embargo time: http://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2018.7614

PORTLAND, Oregon - Fighting cancer means killing cancer cells. However, oncologists know that it's also important to halt the movement of cancer cells before they spread throughout the body. New research, published today in the journal Nature Communications, shows that it may be possible to freeze cancer cells and kill them where they stand.

Raymond Bergan, M.D., Division Chief of Hematology and Medical Oncology and professor of medicine at OHSU, says that the majority of cancer treatment therapies today are directed toward killing cancer. To date, he says, no one has developed a therapy that can stop cancer cells from moving around the body.

"For the vast majority of cancer--breast, prostate, lung, colon, and others--if it is detected early when it is a little lump in that organ and it has not spread, you will live. And generally, if you find it late, after it has spread throughout your body, you will die," says Bergan, also the associate director of medical oncology in the OHSU Knight Cancer Institute and director of the OHSU Bergan Basic Research Laboratory. "Movement is key: the difference is black and white, night and day. If cancer cells spread throughout your body, they will take your life. We can treat it, but it will take your life."

For that reason, the study of cancer cell movement, or motility, has been the focus of his group's research for several decades.

Stopping cancer cell movement

In 2011, Bergan and team took a novel approach to their research by working with chemists to jointly discover a drug that will inhibit the movement of cancer cells.
The Nature Communications paper outlines the multidisciplinary team's work with KBU2046, a compound that was found to inhibit cell motility in four different human cell models of solid cancer types: breast, prostate, colon and lung cancers.

"We used chemistry to probe biology to give us a perfect drug that would only inhibit the movement of cancer cells and wouldn't do anything else," Bergan says. "That basic change in logic lead us to do everything we did."

A multidisciplinary team

The team of investigators includes Bergan's team at OHSU, a chemist from Northwestern University as well as researchers from Xiamen University in China, the University of Chicago, and the University of Washington.
Ryan Gordon, Ph.D., research assistant professor in the OHSU School of Medicine and co-director of the Bergan lab, says drawing upon the strengths of this cross-functional group was key to the research's success. "As we identified areas we were lacking, we looked at new cutting-edge technologies, and if there was something that didn't meet our needs, we developed new assays to address our needs," he says.

The lab of Karl Scheidt, Ph.D., professor of chemistry and professor of pharmacology; director of the Center for Molecular Innovation and Drug Discovery; and executive director of the NewCures accelerator at Northwestern University, was responsible for the design and creation of new molecules which were then evaluated by Bergan's team for their ability to inhibit cell motility. Using chemical synthesis approaches, Scheidt and team accessed new compounds that minimized motility in tumor cells, with few side effects and very low toxicity.

"We've taken a clue provided by nature and through the power of chemistry created an entirely new way to potentially control the spread of cancer," Scheidt says. "It's been a truly rewarding experience working together as a team toward ultimately helping cancer patients."

Refining the drug

Bergan notes the process for narrowing down the specific drug compound was a process of refinement.
"We started off with a chemical that stopped cells from moving, then we increasingly refined that chemical until it did a perfect job of stopping the cells with no side effects," he says. "All drugs have side effects, so you look for the drug that is the most specific as possible. This drug does that."

Bergan says the key to this drug was engaging the heat shock proteins--the "cleaners" of a cell. "The way the drug works is that it binds to these cleaner proteins to stop cell movement, but it has no other effect on those proteins." He says it is a very unusual, unique mechanism that "took us years to figure out."

"Initially, nobody would fund us," Bergan says. "We were looking into a completely different way of treating cancer."

Next step: testing the drug in humans

Ultimately, Gordon says the goal of this research is to look for a new therapeutic to benefit humans.

"The eventual promise of this research is that we're working toward developing a therapeutic that can help manage early stage disease, preventing patients from getting the more incurable later-stage disease," he says. He's quick to note this work has not been tested in humans, and doing so will require both time and money. The team's best estimate is that will take about two years and five million dollars of funding. They are currently raising money to do IND (investigational new drug) enabling studies, a requirement to conduct a clinical trial of an unapproved drug or an approved product for a new indication or in a new patient population.

In addition, Drs. Bergan and Scheidt have founded a company, Third Coast Therapeutics, aimed to bring this type of therapy to patients.

"Our eventual goal is to be able to say to a woman with breast cancer: here, take this pill and your cancer won't spread throughout your body. The same thing for patients with prostate, lung, and colon cancer," Bergan says. "This drug is highly effective against four cancer types (breast, colon, lung, prostate) in the in vitro model so far. Our goal is to move this forward as a therapy to test in humans."

Bergan says his team feels lucky to have the opportunity to conduct this challenging research at the OHSU Knight Cancer Institute, an institute dedicated to novel approaches to detecting and treating cancer.

"What early detection is trying to do is detect an early, lethal lesion. Cancers are lethal because they move," he says. "This drug is designed to stop that movement."

PHILADELPHIA - Influenza A (flu A) hijacks host proteins for viral RNA splicing and blocking these interactions caused replication of the virus to slow, according to new research published in Nature Communications by Kristin W. Lynch, PhD, chair of the department of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania, and doctoral student Matthew Thompson. Their results also suggest that infection with flu A may reduce splicing of some host genes, which could point to novel strategies for antiviral therapies.

Influenza A virus is a common human pathogen that causes 250,000 to 500,000 deaths per year worldwide. "Although vaccines and some antiviral drugs are available, it is crucial to understand influenza virus-host interactions at a molecular level in order to identify host vulnerabilities targeted by flu viruses, which could lead to developing new therapeutic options," said Lynch, whose lab focuses on the specific mechanisms and patterns of alternative RNA splicing and how it relates to human disease,

The transcription of DNA into messenger RNA - the process of a single gene encoding a single protein - isn't as straightforward as once thought. The phenomenon of alternative RNA splicing - where a single gene can encode multiple proteins - was discovered over 30 years ago in viruses.

The flu A genome is comprised of eight single-strand segments of RNA. Three of these segments use alternative splicing to produce two essential viral proteins each, which are important in helping the virus gain entry into host cells. Working with cultures of human lung cells, the team's proposed mechanism of how flu A virus interacts with human RNA splicing machinery suggests that keeping human splicing proteins from binding to the viral genome would help to stop its replication.

As a result, the researchers found that mutating sequences of the viral genome to prevent host proteins from binding caused viral RNA to splice incorrectly and eventually halt replication--thus slowing the spread of the virus in the body.

A balance between the two viral messenger RNAs must be maintained for the virus to successfully infect host cells and replicate. "Regulating splicing of the two viral proteins is a fundamental step in viral-host interaction and so a potentially new anti-viral remedy," Lynch said.

For now, her team is refining their understanding of the intricacies of viral reproduction in host cells. Their hope is to one day identify a specific molecular target for antiviral medications that can be used in the clinic.