Body

Some antidepressants could potentially be used to treat a wide range of diseases caused by bacteria living within cells, according to work by researchers in the Virginia Commonwealth University School of Medicine and collaborators at other institutions.

Research published in the April print edition of the journal Life Science Alliance, shows that antidepressant drugs called FIASMAs, including desipramine, amitriptyline, and nortriptyline, halt the growth or kill four different intracellular bacterial pathogens in tissue cell culture and animal models.

"Antibiotic options for diseases caused by intracellular bacteria are limited because many of these drugs cannot penetrate our cell membranes. In essence, the bacteria are protected," said Jason Carlyon, Ph.D., leader of the study and professor in the VCU Department of Microbiology and Immunology.

Tetracycline antibiotics are most commonly prescribed to treat intracellular bacterial infections because they can cross cell membranes to reach the microbes. However, tetracyclines can cause allergic reactions in some patients and physicians advise against their use by pregnant women and children due to undesirable side effects. Additionally, antibiotic resistance in some intracellular bacteria has been reported.

"It would be highly beneficial to have a class of drugs to treat such diseases in patients for whom tetracyclines are contraindicated," Carlyon said. "These drugs could provide an alternative to antibiotics or even be used in conjunction with them as an augmentation approach to treat infections that typically require prolonged courses of antibiotic therapy, such as those caused by Chlamydia pneumoniae and Coxiella burnetti."

The team of researchers from VCU, Indiana University Medical Center, University of Nebraska Medical Center, University of Arkansas for Medical Sciences, and the University of South Florida, including Carlyon and lead author Chelsea Cockburn, an M.D.-Ph.D. candidate, are the first to investigate the mechanisms by which FIASMAs target multiple intracellular bacteria in detail.

The scientists tested FIASMA susceptibility for four bacterial species that cause human granulocytic anaplasmosis, a tick-borne disease that attacks white blood cells called neutrophils and can be fatal to immune compromised individuals; Q fever, a debilitating pneumonic disease; and two chlamydia infections.

FIASMAs ultimately disrupt how cholesterol, a key nutrient utilized by many intracellular pathogens, traffics inside cells to alter bacterial access to the lipid. The researchers first proved FIASMA treatment efficacy by halting anaplasmosis in both tissue culture and mice. Next, they extended their observations to demonstrate that FIASMA treatment killed the Q fever agent, Coxiella burnetii, and partially inhibited chlamydial infections in cell culture.

"Since FIASMAs influence cholesterol trafficking in the cell and cholesterol plays a role in so many facets of our biology, they have been used to treat a wide variety of conditions and diseases," Carlyon said.

He added that the effect of FIASMAs on intracellular cholesterol ultimately bypasses the need to directly target the bacteria.

"What is so exciting about this study is that the class of drugs we evaluated targets an enzyme in our cells regulating cholesterol, not the bacteria," Carlyon said. "I do not envision the pathogens being able to develop resistance to this treatment because it is targeting a host pathway that they very much need to grow and survive inside of the body."

Other investigators involved in the research included Rebecca Martin, Ph.D., and Daniel Conrad, Ph.D., (VCU), Charles Chalfant, Ph.D., (University of South Florida), Daniel Voth, Ph.D., (University of Arkansas for Medical Sciences), Elizabeth Rucks, Ph.D., (University of Nebraska Medical Center) and Stacey Gilk, Ph.D., (Indiana University School of Medicine).

Research was supported by grants from the NIH-National Institute of Allergy and Infectious Diseases, including 1R01 AI139072, 2R01 AI072683, 5R01 AI018697, 1R01 AI139176, 1R21 AI127931, and 1R21 AI121786, and from the NIH-National Institute of General Medicine Sciences (1P20 GM103625).

New research presented at this year's Euroanaesthesia congress (the annual meeting of the European Society of Anaesthesiology) in Vienna, Austria (1-3 June) shows that commonly used anaesthetic drugs still work, even after exposure to the extreme environmental conditions of the Antarctic. The study was conducted by Professor Major Ricardo Navarro-Suay of Hospital Central de la Defensa "Gómez Ulla", Madrid, Spain (who serves in the Spanish Armed Forces) and colleagues.

Anaesthetists can find themselves working in a wide range of situations and challenging conditions where the supply of medicines can be interrupted or drug efficacy could be altered by environmental factors. This can introduce uncertainties into planning how anaesthetics will be used during a procedure, which in turn can impact patient safety.

The authors studied the effects of exposing four commonly used anaesthetic drugs (fentanyl citrate, etomidate, rocuronium bromide and suxamethonium chloride) to Antarctic weather conditions to determine whether these compounds could be safely and reliably used in such environments.

To evaluate the impact of environmental factors on anaesthetic drugs, the four selected drugs were subjected to the extreme polar climate of Deception Island in Antarctica, with vials of each drug left outside in clear plastic bags (see poster) but nothing to protect them from the bitterly cold conditions.

Measurements were taken of the maximum and minimum values of; daily temperature, wind speed, atmospheric pressure, relative humidity, amount of sunlight, rain, and solar radiation. Drug vials were then examined at 24, 48, and 72 hours for damage to the container itself, any changes or deterioration of the medicine inside, and a detailed chemical analysis was performed to measure any loss of potency of the compounds using high resolution liquid chromatography.

The team found that despite being exposed to Antarctic conditions for up to 72 hours, the drugs were well within the allowed margins of security (99-110%). To explain further how a result of 110% could be achieved, Major Navarro-Suay says: "Sometimes a drug can be changed or improved with weather conditions, like light or cold. The drug administration security interval is from 95 to 110% so these results show we could employ these drugs safely to patients under the extreme conditions like the polar weather found in Antarctica."

He concludes: "This chemical analysis shows that using the common anaesthetic drugs fentanyl, etomidate, rocuronium bromide and suxamethonium chloride appears safe even in this extreme environment in Antarctica."

CHICAGO -- Preliminary results from a University of North Carolina Lineberger Comprehensive Cancer Center study found that just 15 percent of a group of men in North Carolina with early-stage prostate cancer who choose active surveillance instead of treatment followed the recommended monitoring guidelines.

The findings, presented Sunday, June 2, at the American Society of Clinical Oncology Annual Meeting 2019 in Chicago, were drawn from an analysis of 346 men newly diagnosed between 2011 and 2013 with low or intermediate-risk prostate cancer in North Carolina. Researchers analyzed how often men received biopsies and other tests according to the guidelines from the National Comprehensive Cancer Network.

"Active surveillance has rigorous guidelines -- people need regular PSA tests, they need prostate exams, they need prostate biopsies so you can watch the cancer very closely, and you don't lose the opportunity to treat the cancer when it starts to grow," said UNC Lineberger's Ronald C. Chen, MD, MPH, associate professor in the UNC School of Medicine Department of Radiation Oncology. "One of the main findings of this study is that in this population-based cohort, not in a clinical trial or purely academic setting, only 15 percent of patients in active surveillance received recommended monitoring."

Data have shown that active surveillance is safe, but UNC Lineberger researchers note that those data have been drawn from clinical trials or studies in large academic institutions. To evaluate monitoring in a broad population, they studied a group of patients from North Carolina to determine if they adhered to NCCN active surveillance guidelines, which recommended prostate-specific antigen (PSA) tests at least every six months, digital rectal exams annually, and a repeat biopsy within 18 months of diagnosis.

In the first six months, 67 percent of patients had received a PSA test, and 70 percent received a digital rectal exam. Just 35 percent received a biopsy within the first 18 months. Across all types of tests by 24 months, only 15 percent of patients received monitoring compliant with the guidelines.

"Based off of the NCCN guidelines, which is what we believe most of the community practices would be following in terms of active surveillance guidelines, we're finding very few patients who elected to undergo active surveillance actually received the recommended monitoring," said the study's first author Sabrina Peterson, a student at the UNC School of Medicine.

Researchers also reported they did not find any variables, such as income, race or age, linked with whether or not patients would adhere to the monitoring guidelines. The findings led researchers to call for more research into outcomes for active surveillance outside of controlled studies.

"This raises the question of whether we need to investigate whether active surveillance is a safe option when patients do not receive routine monitoring," Chen said. "Our goal is not to reduce the number of patients choosing active surveillance; rather, the results of this study should increase awareness and efforts to ensure that active surveillance patients are monitored rigorously."

Researchers also analyzed trends linked to patients who stopped active surveillance and started treatment. In addition to finding that disease progression motivated patients to switch to treatment, they found that a patient's level of anxiety was linked to whether or not they stopped active surveillance and switched to treatment.

"When we looked at some of the reasons why people would have treatment instead of active surveillance, anxiety seems to be one of the reasons why people have treatment and stop active surveillance," Chen said.

In addition to Chen, other authors included Sabrina Peterson, Ramsankar Basak, Dominic Himchan Moon, Claire Liang, Deborah S. Usinger, Sarah Walden, and Aaron J. Katz.

The study was supported by the Patient-Centered Outcomes Research Institute and the Agency for Healthcare Research and Quality.

University of Colorado Cancer Center led clinical trial data show that a predictive tool called COXEN may show which bladder cancer patients will respond to pre-surgical chemotherapy, a step towards allowing doctors to offer such chemotherapy to patients likely to respond, while moving more efficiently to other treatment options with patients unlikely to benefit. Results will be presented Monday, June 3 at 8:00am as oral abstract at the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting (ASCO abstract #4506).

"The idea is that for any individual tumor, its gene expression could tell us whether the cancer will respond to a certain kind of chemotherapy," says Thomas Flaig, MD, Associate Dean for Clinical Research at University of Colorado School of Medicine, Chief Clinical Research Officer of UCHealth, and national principal investigator of the COXEN phase II clinical trial. "This is an important clinical application of a concept developed by investigators based in Colorado, which may have implications in predicting the response to chemotherapies across many cancer types."

COXEN, which stands for co-expression gene analysis, was pioneered by former CU Cancer Center Director, Dan Theodorescu, MD, PhD, now director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. Thoedorescu's lab used 60 human-derived cancer cell lines curated by the National Cancer Institute to develop a gene expression approach to predicting the sensitivity of these cells to various chemotherapies. The COXEN principle was operationalized for use in the current clinical trial by Dan Gustafson, PhD, CU Cancer Center investigator and research director at Colorado State University Flint Animal Cancer Center.

"Gustafson is very good at math and translating it into the clinical setting," Flaig says. "He was critical to getting this trial up and running."

The trial enrolled 237 patients with locally advanced bladder cancer, who, as per standard of care, would receive pre-surgical (neo-adjuvant) chemotherapy meant to shrink the cancer and eradicate any microscopic deposits outside of the bladder to increase patients' overall survival. The challenge for patients and doctors has been that there are two approved chemotherapy regimens for this indication - Gemcitabine-Cisplatin (GC) and Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (MVAC).

"It's really been a coin-flip between the two," says Flaig.

Then, once patients start GC or MVAC, most but not all will respond, and there has been no way to predict which patients will benefit. Patients who do respond to GC or MVAC have a higher chance of curative surgery; patients who do not respond to GC or MVAC have wasted precious time during which their cancer can, in fact, grow prior to surgery, making a successful surgery much less likely.

"If they do respond, you've increased your cure rate. If patients don't respond, you've delayed surgery. The problem is that clinicians are making empiric decisions because there are no data to guide specific treatment decisions," Flaig says.

The goal of the current clinical trial was to provide these data. First, participants were randomized to receive either GC or MVAC. Then Flaig and colleagues gathered gene expression signatures for each tumor and asked a simple question using the COXEN approach: Can we predict whether the patient will respond to his or her chemotherapy? Specifically, the doctors including pathologist Scott Lucia, MD, evaluated whether the chemotherapy resulted in "down-staging" of the tumor at the point of surgery, and then whether surgery resulted in removal of all detectable cancer (called "pathologic T0" or a complete pathologic response).

While COXEN was unable to predict whether a patient responded to the MVAC chemotherapy regimen, when MVAC and GC results were pooled, COXEN showed a statistically significant ability to predict which patients responded using the GC biomarker.

"This was not meant to be a definitive trial, but rather a phase II trial that could give us a signal whether COXEN is able to identify responders in a multi-center, prospective trial. I think the GC COXEN biomarker did pretty well, and we look forward to continuing our work in this area," Flaig says.

In addition to generating COXEN signatures, tumors from the trial will be evaluated for DNA, microRNA, SNPs, and circulating tumor cells, potentially allowing for the validation of additional biomarkers to increase the power to predict chemotherapy response.

"When this trial started six or seven years ago, bladder cancer was in a different position - we hadn't had an FDA-approved drug in 30 years. Over the course of this trial, there have been six approved drugs, but none of those drugs are applicable to the neoadjuvant setting. However, with the successful completion of this and other recent bladder cancer trials, there's budding optimism that we can design trials like this to help patients with this common disease," Flaig says.

Flaig also points out that regardless of study results, there still remains compelling data to recommend treatment with cisplatin-based chemotherapy - either GC or MVAC - prior to surgery in the treatment of bladder cancer.

"The bladder cancer research community pulled together to get this trial done," Flaig says. "I'm honored to be part of this group asking and answering questions of essential clinical relevance to our patients."

Crizotinib was the first drug licensed to treat ALK-positive non-small cell lung cancer (ALK+ NSCLC). Since then, a range of next-generation ALK-inhibitors including ceritinib, alectinib, and brigatinib have earned FDA approval as second-line therapies after treatment with crizotinib. However, each of these next-generation ALK-inhibitors can also be used in the first-line setting, and an important question becomes which, if any, remain useful when given after another next-generation drug? A study by the Academic Thoracic Oncology Medical Investigators' Consortium (ATOMIC) presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 shows 40 percent response rate in 20 patients treated with brigatnib after first-line treatment with another next-gen ALK inhibitor (ASCO abstract 9027). A French retrospective study of 104 patients also presented at ASCO similarly demonstrated a 50 percent response rate in patients treated with brigatinib after two previous lines of ALK inhibitor therapy.

"Brigatinib is already approved for use post-crizotinib and has already shown positive data versus crizotinib in the first-line setting. Meanwhile, the world has moved around us and now we need to know the activity of this drug after a next generation ALK inhibitor," says study first author, Tom Stinchcombe, MD, of Duke Cancer Center. Study colleagues include senior author, and co-principal investigator D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at University of Colorado Cancer Center and Robert C. Doebele, MD, PhD, director of the CU Cancer Center Thoracic Oncology Research Initiative, who is performing key biomarker analyses in the ATOMIC trial.

"A single, small study had previously suggested brigatinib was not likely to be effective in this setting, presumably because not everyone responds the same way to these agents," says Doebele. "So it is very encouraging to see our own data and that of the French group paint a more encouraging picture, worthy of continued exploration."

In addition to measuring overall response rate, the study will perform detailed molecular analyses to help determine the characteristics of patients sensitive to this drug. The study was also able to capture whether patients had progressed in the body or in the brain during treatment with the first-line next-gen ALK inhibitor, allowing investigators to better understand whether brigatinib may be more useful with patients progressing in one or the other site.

"With lung cancer, people progress in different ways - sometimes in the brain, other times in the body. If a drug has greater or lesser activity in the brain than in the body, the efficacy you quote a patient may need to be different depending on their site of progression. Only by pulling these two things apart can you actually guide someone accurately as to their chance of responding to a drug," says Camidge, who recently helped to define the Response Assessment in Neuro-Oncology guidelines, which argue for measuring a drug's effectiveness separately in the body and the brain during cancer clinical trials.

The current trial also demonstrates the ability of the ATOMIC group to successfully utilize a new clinical trial collaboration framework that occupies a middle-ground between industry-sponsored and cooperative group clinical trials.

"The middle ground used to be single center investigator-initiated trials, which allowed doctors and researchers to test their clinical research ideas fairly quickly and cheaply. But, particularly in lung cancer, with the disease fragmenting into many small disease subtypes defined by their genetic make-up, you can't do many investigator-initiated trials at just one site anymore - you'd never get enough patients. Instead, you need multiple investigators collaborating across multiple sites, supported by their own clinical research organization and that's what we've got with ATOMIC," said Camidge, who directs the consortium.

Crizotinib and entrectinib are both active against ROS1+ non-small cell lung cancer. But which is best? The answer seems easy: Just compare the drugs' clinical trial results. However, not all trials are created equal, and these differences in trial designs can lead to irrelevant comparisons - like comparing athletes' running times without noting that one ran a kilometer while the other ran a mile. Now results from an innovative, "virtual" clinical trial presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 attempt to place crizotinib and entrectinib on an equal playing field. In this analysis, patients taking entrectinib were able to stay on treatment longer and had about almost 6 months longer progression-free survival than patients treated with crizotinib.

"ROS1 alterations are pretty rare. When asked why not just do a randomized clinical trial of entrectinib vs. crizotinib, we responded that we would not have those results for many years - and it would likely be an underpowered study, meaning we might not even get an adequate answer! We didn't think that made sense. While we were doing that, patients with lung cancer, and especially lung cancer patients whose disease had spread to the brain, wouldn't be getting adequate therapy," says Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, and the study's first author.

Instead, Doebele and colleagues (including from entrectinib manufacturer, Roche), decided to take a different approach. Combing through tens of thousands of de-identified electronic patient records from Flatiron Health, the authors found 69 patients treated with crizotinib who matched the enrollment requirements for 53 patients on trials of entrectinib. Finally, they were able to compare apples with apples - a single population treated with one or the other drug.

"The purpose of this trial was to go to this real-world data aggregator, Flatiron Health, to recreate the data of a crizotinib trial so that patients were more like those on entrectinib trials. Although it is challenging to do this from extracted chart data, we tried really hard to select patients who looked similar to those in the entrectinib clinical trial, for example by making sure that a comparable number of patients in the crizotinib arm had brain metastases," Doebele says.

One measure of a drug's effectiveness is how long a patient stays on the drug (because when a drug stops working, patients move on to other treatments). The median time to treatment discontinuation (TTD) of patients in this real-world crizotinib cohort was 8.8 months; the TTD of patients using entrectinib was 14.6 months. Compared with patients on entrectinib, patients on crizotinib had an additional 44 percent chance that their cancer would resume its growth.

"It was an attempt to perform a virtual clinical trial," Doebele says. "There may be a lot of limitations of this type of approach, but we think it's a novel way to use all of this big data that people are generating to learn important things about cancer treatment and speed the use of new drugs to patients who need them."

A University of Colorado Cancer Center study presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 shows that while 73 percent of surveyed oncology providers believe that medical marijuana provides benefits for cancer patients, only 46 percent are comfortable recommending it. Major concerns included uncertain dosing, limited knowledge of available products and where to get them, and possible interactions with other medications.

"I think in some cases we're missing out on providing a useful tool. Providers think it has benefit, but aren't comfortable recommending it," says Ashley E. Glode, PharmD, assistant professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, and the study's first author.

Survey respondents included 48 specialized oncologists, 47 physicians, 53 registered nurses, 17 pharmacists, and 7 "other" oncology providers. Seventy-nine percent reported that educational programs both during training and as continuing medical education courses could increase their comfort level with medical marijuana prescribing. Interestingly, 68 percent of providers reported receiving information about medical marijuana from their patients - the next most common sources of information were news media (accessed by 55 percent of providers), and other providers (53 percent).

"We asked and most providers didn't train in a state where medical marijuana was legal. We need to adapt our healthcare education to include this, and also offer trainings on medical marijuana to current providers," Glode says.

Providers also reported legal and regulatory concerns, especially providers working in academic medical centers who expressed uncertainty whether recommending medical marijuana could jeopardize federal funding (marijuana remains a U.S. Drug Enforcement Agency Schedule 1 drug). Providers felt as if additional clinical data describing the effectiveness of medical marijuana and endorsed guidelines describing the conditions and situations in which it should be used would increase their comfort in prescribing.

"Still, the biggest issue that providers saw is the lack of certainty in dosing," Glode says. "The issue is it's not regulated - a dispensary might say a product has this much THC and this much CBD, but no one is testing that for sure. Limited data suggest that patients should start low and slow, no more than 10mg of THC in a dose, but we don't know that's what patients are really getting. Then from a consumption perspective, inhalation and smoking is the least preferred due to possible damage to the lung. So many doctors recommend edibles, oils, and tinctures, but we still don't have good data comparing dosage across these forms."

Glode and study colleagues including Stephen Leong, MD, hope to expand the survey to gather a more nationally representative sample.

"Knowledge is an issue," Glode says. "If we could do a better job educating our healthcare providers, it might be used more often and potentially more safely."

Locally advanced pancreatic cancer (LAPC) - a tumor that, while still confined to the pancreas, involves major abdominal blood vessels - is one of the worst forms of an already deadly tumor, as it cannot be removed surgically. Now a Massachusetts General Hospital (MGH) Cancer Center clinical trial of a treatment protocol combining intensive chemotherapy and radiation therapy with the blood pressure drug losartan has produced unprecedented results - allowing complete removal of the tumor in 61 percent of participants and significantly improving survival rates.

"Around 40 percent of pancreatic cancer patients have either locally advanced or borderline resectable disease, with historically poor rates of successful surgery," says Janet Murphy, MD, MPH, of the Hematology/Oncology division of the MGH Department of Medicine, co-lead and corresponding author of the report in JAMA Oncology. "To be able to successfully remove the primary tumor in 61 percent of patients sets a new benchmark and offers much hope. To our knowledge, this is the first LAPC clinical trial that defined surgical success as its primary outcome."

The most novel element of the trial - use of the antihypertension drug losartan - builds on findings of co-author Rakesh K. Jain, PhD - director of the Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology - and his colleagues. Those studies found that losartan, which targets the angiotensin signaling pathway, improved the delivery of chemotherapy drugs in animal models of breast, pancreatic and ovarian cancer. It does so by relieving pressures in the tumor microenvironment that physically block drug delivery and reduce the supply of oxygen, which is required for the tumor-killing effects of radiation therapy. Those studies also found that cancer patients who happened to be taking losartan or similar drugs for hypertension tended to live longer than others receiving the same sorts of cancer therapies.

From August 2013 through July 2017 the study enrolled 49 MGH Cancer Center patients with previously untreated LAPC. All participants received chemotherapy with a combination of fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFIRINOX) over a four-month period, during which they also took daily doses of losartan. After CT scan evaluation to determine whether or not blood vessels were still involved in the tumors, patients who no longer had vascular involvement received a short course of proton-beam radiation therapy, while those whose tumors still included major blood vessels had a longer course of conventional radiation therapy. Both groups received capecitabine chemotherapy during this period.

After completing the chemoradiotherapy stage, 34 of the 49 participants were able to have their tumors removed, with 30 of those procedures successfully eliminating all evidence of cancer around the tumor. A pathologic complete response - which signifies no tumor found anywhere - was achieved for three patients. Analysis of circulating biomarkers throughout the course of the study found significant drops in the expression of TGF-β, a key element in the angiotensin-signaling pathway, indicating that losartan was having its desired effect. Both the time until recurrence and the overall survival time were significantly longer than what has previously been seen in LAPC patients.

Murphy says, "A key part of the success of our approach was our surgeons' willingness to attempt an operation even in patients who had the appearance of cancer at or near their blood vessels. We learned in a previous study - confirmed here - that CT scan results and resectability are no longer clearly correlated after chemotherapy and radiation. While we did not see total blood vessel clearance in 61 percent of patients, 61 percent achieved a complete removal of their cancer."

Co-lead author Jennifer Wo, MD, of the MGH Department of Radiation Oncology adds, "Locally advanced pancreatic cancer has been generally considered an incurable disease, so these results mark a dramatic improvement with respect both to rates of conversion to surgical resectability and to long-term disease outcomes. Based on these results we have launched a new, multi-institutional clinical trial that will also include the immunotherapy drug nivolumab, since losartan treatment has also been shown to activate several immune system pathways." Wo is an assistant professor of Radiation Oncology, Murphy is an instructor in Medicine, and Jain is the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School.

PHILADELPHIA -- Public health efforts must emphasize condom use and vaccination together to reduce human papillomavirus (HPV) cases among young sexually active gay men, according to researchers at Drexel University's Dornsife School of Public Health published today in the journal Vaccine. The work builds on other studies demonstrating success of these methods by modeling how many HPV cases can be prevented by increasing the number of people vaccinated. This study contrasted vaccination scale-up with other STI prevention strategies, such as condoms and selecting sexual partners based on HIV status, in the reduction of HPV.

The team simulated a population of 5,329 young men who have sex with men (YMSM) aged 18-26, reflecting the population in Philadelphia, for up to 10 years after they received the FDA-approved HPV vaccine. The researchers recorded anal and oral transmission of the nine types of HPV most likely to cause cancer and genital warts that the vaccine helps prevent. Vaccination was scaled-up at varying levels in the simulation population, reflecting the goal of public health efforts to increase immunization rates.

This scale up of vaccination led to consistent declines in anal and oral HPV. Anal HPV declined by 9 percent, 27 percent, 46 percent and 58 percent at vaccination levels of 25 percent, 50 percent, 80 percent and 100 percent, respectively. Similarly, oral HPV declined by 11 percent, 33 percent, 57 percent, and 71 percent across the same levels of increased vaccine use.

Comparing the prevention strategies, condoms blocked the greatest number of anal transmissions when vaccination was at or below present-day levels. For oral transmission, vaccination was more effective than condom use at all levels of vaccination.

"Education surrounding HPV risk still has a long way to go to protect public health," said lead author Neal Goldstein, PhD, an assistant research professor in the Dornsife School of Public Health and epidemiologist at Christiana Care Health System. "Young gay men tend to be less likely to share intimate details about their sexual health with a medical professional, so public health efforts must put a greater emphasis on what we know works in this particularly at-risk population."

The vaccine is typically a series of two shots, taken six to 12 months apart; although those receiving the shot after age 15 and those with HIV need three shots. The CDC currently recommends that all boys and girls receive their first HPV vaccine shot by ages 11 or 12, up to age 21 for men and 26 for women. HPV can cause warts on hands and feet and lead to anal or cervical cancer.

Currently, YMSM are at higher risk of HPV, yet only about 15 percent of YMSM have received the HPV vaccine, compared to roughly half of United States adolescents as a whole. This is well short of the U.S. Healthy People 2020 - a set of 10 year national health objectives -- goal of 80 percent of eligible adolescents vaccinated. There are roughly 79 million Americans infected with HPV, including more than 43 percent of adults.

"Although public health efforts have focused many efforts on genital HPV, we found the vaccine to be especially impactful in preventing oral infection, which is also just as important," said Goldstein. "It's a simple message -- vaccination before becoming sexually active is key, along with regular condom use -- which protects against many other sexually transmitted infections."

A team led by Professor Norbert Hübner's MDC research group has observed the human heart cells' "protein factories" in action, examining the entire tissue for the very first time. In an article published in Cell, the group reveals their surprising discoveries and the possibilities they contain for the future treatment of heart disease.

The human heart holds many secrets. And not just in a figurative, emotional sense; also from a rational, scientific point of view, we know surprisingly little about the function of the muscular organ that supplies every cell of our bodies with oxygen - and why it sometimes doesn't do what it's supposed to.

A study published in the scientific journal Cell has now shed a little more light on this most vital organ. An international team of 56 researchers led by the MDC examined the proteins produced by the ribosomes - our bodies' cellular protein factories - in the heart cells of both healthy people and those suffering from heart disease. The results were surprising, and included the discovery of a large number of mini-proteins that were previously entirely unknown.

The work involved scientists from Berlin, including several groups from the MDC and Charité, as well as researchers from Bad Oeynhausen, Göttingen, Hamburg, Münster, Australia, the United Kingdom, Japan, the Netherlands, Singapore, and the United States.

DNA contains far more blueprints than previously thought

The DNA stored in the nucleus of every cell contains a blueprint for all proteins produced in the body. The production of protein is a two-step process: transcription and translation. In the first step, copies of DNA fragments are produced in the form of messenger RNAs (mRNAs), which then leave the cell nucleus. In the second step, ribosomes use individual amino acids swimming around in the cell to create the corresponding proteins. While there has been quite a lot of scientific research into transcription, comparatively little is known about the translation process.

"With the help of a relatively new technique known as ribosome profiling, or Ribo-Seq, we have now been able to determine for the first time not only in isolated cells, but also in intact human heart tissue, which mRNA sites the ribosomes migrate to," explains Dr. Sebastiaan van Heesch, a member of Professor Norbert Hübner's Genetics and Genomics of Cardiovascular Diseases group at the MDC and lead author of the study. "Using special algorithms, we were then able to calculate which proteins are produced in the heart during translation."

Using this technique, the researchers discovered a whole series of tiny, previously unknown proteins. Another surprising discovery made by van Heesch and the team was that many of the microproteins were encoded by RNAs that were not believed to have encoding properties - i.e., not thought to contain instructions for building proteins.

Most mini-proteins are used for energy production

Using special microscopic techniques, the scientists were then able to observe that, once produced, more than half of these microproteins migrate to the mitochondria - the energy powerhouses of our cells. "This means that they are obviously used in the heart's energy production processes," says Norbert Hübner. "Since many heart diseases are caused by a faulty energy metabolism, we were particularly interested in this result."

In order to detect possible differences between the translatome (totality of proteins formed) of diseased and healthy hearts, the scientists examined tissue samples from 65 patients with dilated cardiomyopathy (DCM) - a condition in which the heart muscle becomes enlarged. The samples were taken from the patients by biopsy during scheduled heart operations. The tissue of 15 healthy hearts was used for comparison.

DCM, which requires many patients to undergo a heart transplant at some point in their lives, is caused by a mutation in the titin gene - the largest and most important protein of the human heart. "As a result of this genetic mutation, a stop signal is generated in the mRNA that tells the ribosomes to finish their work before the titin has been completed," explains van Heesch. However, not all people who carry this mutation in their DNA will actually develop DCM.

New approaches to heart disease on the horizon

Van Heesch and his colleagues are now investigating the reasons behind their discoveries. "We have observed that ribosomes can sometimes simply ignore this stop signal and continue undeterred with titin production," says the researcher. The goal now, he explains, is to find out the circumstances under which this occurs. Van Heesch explains that it may be due to the position of the genetic mutation on the mRNA, but that it could also be the result of factors that, once identified, may be treatable.

Together with his colleagues, van Heesch also hopes to more closely investigate the role of the newly discovered microproteins. "These proteins seem to be evolutionarily quite young," he says. "We could not find them in mouse hearts, for example." The substances thus offer further evidence, he claims, of just how special the human heart is. Furthermore, the scientist hopes that he will one day be able to use these proteins either for the diagnosis of heart disease or as a target structure for future therapies that will be more effective than ever before in treating a disruption in the heart's energy metabolism.

Women who experience symptoms of depression are at risk of developing multiple chronic diseases, research led by The University of Queensland has found.

UQ School of Public Health PhD scholar Xiaolin Xu said women who experienced symptoms of depression, even without a clinical diagnosis, were at risk of developing multiple chronic diseases.

"These days, many people suffer from multiple chronic diseases such as diabetes, heart disease, stroke and cancer," Mr Xu said.

"We looked at how women progress in the development of these chronic diseases before and after the onset of depressive symptoms."

The Australian Longitudinal Study on Women's Health followed healthy, middle-aged women with no previous diagnosis of depression or chronic illness over 20 years.

The study found 43.2 per cent of women experienced elevated symptoms of depression and just under half the cohort reported they were diagnosed or taking treatment for depression.

Women from the depressed group were 1.8 times more likely to have multiple chronic health conditions before they first experienced depressive symptoms.

"Experiencing depressive symptoms appeared to amplify the risk of chronic illness," Mr Xu said.

"After women started experiencing these symptoms, they were 2.4 times more likely to suffer from multiple chronic conditions compared to women without depressive symptoms."

The research suggests depression and chronic diseases share a similar genetic or biological pathway.

"Inflammation in the body has been linked to the development of both depression and chronic physical diseases," he said.

"Chronic diseases, like diabetes and hypertension, are also commonly associated with depression."

These findings help strengthen healthcare professionals understanding of mental and physical health.

"Healthcare professionals need to know that clinical and sub-clinical depression (elevated depressive symptoms) can be linked to other chronic physical conditions," he said.

"When treating patients for these symptoms, healthcare professionals must realise these people are at risk of developing further chronic illness."

Women with both conditions were more likely to come from low-income households, be overweight and inactive, smoke tobacco and drink alcohol.

"Maintaining a healthy weight, exercising regularly, eating a balanced diet, and reducing harmful behaviours could help prevent and slow the progression of multiple chronic diseases."

BUFFALO, N.Y. -- Long-term exposure to ambient ozone appears to accelerate arterial conditions that progress into cardiovascular disease and stroke, according to a new University at Buffalo study.

It's the first epidemiological study to provide evidence that ozone might advance subclinical arterial disease -- injuries that occur to the artery walls prior to a heart attack or stroke -- and provides insight into the relationship between ozone exposure and cardiovascular disease risk.

"This may indicate that the association between long-term exposure to ozone and cardiovascular mortality that has been observed in some studies is due to arterial injury and acceleration of atherosclerosis," said study lead author Meng Wang, assistant professor of epidemiology and environmental health in the UB School of Public Health and Health Professions.

The paper was published in May in the journal Environmental Health Perspectives.

The longitudinal study followed nearly 7,000 people aged 45 to 84 from six U.S. regions: Winston-Salem, North Carolina; New York City; Baltimore; St. Paul, Minnesota; Chicago; and Los Angeles. Participants were enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) and have been followed for over a decade.

Atherosclerosis refers to the build-up of plaque, or fatty deposits, in the artery walls, which, over time, restricts blood flow through the arteries. This can cause blood clots, resulting in a heart attack or stroke, depending on which artery -- coronary or carotid, respectively -- the plaque accumulates in.

The study found that chronic exposure to ozone was associated with a progression of thickening of the main artery that supplies blood to the head and neck. It also revealed a higher risk of carotid plaque, a later stage of arterial injury that occurs when there's widespread plaque buildup in the intima and media, the innermost two layers of an artery wall.

"We used statistical models to capture whether there are significant associations between ozone exposure and these outcomes," said Wang, who is also a faculty member in the UB RENEW (Research and Education in eNergy, Environment and Water) Institute. "Based on this model, it suggests that there is an association between long-term exposure to ozone and progression of atherosclerosis."

While the study finds an association between air pollution and atherosclerosis, researchers aren't clear on why. "We can show that there is an association between ozone exposure and this outcome, but the biological mechanism for this association is not well understood," Wang said.

The study is unique in its focus on ozone exposure rather than particulate matter.

Particle pollution comes from a variety of human and natural activities. Examples include vehicle exhaust, fossil fuel burning and agricultural and industrial operations and processes. Smog is a harmful byproduct of such activities.

That shouldn't be confused with the ozone layer in Earth's upper atmosphere, which shields us from much of the sun's ultraviolet radiation.

Ground-level ozone, however, causes serious health problems. When breathed in, it aggressively attacks lung tissue by chemically reacting with it, according to the American Lung Association.

Wang's study -- which includes researchers from the University of Washington and the University of Wisconsin-Madison -- has policy implications for the U.S., where the Environmental Protection Agency in 2015 lowered the federal health standards for ozone.

"Most attention to air quality in the United States has focused on particulate matter air pollution," Wang said. "However, ozone concentrations within metropolitan areas are not positively correlated with particulate matter pollution. In addition, mean ozone levels -- as reported in this paper -- are not declining in the United States, probably due to the worsening of climate change."

The EPA reports that particulate matter concentrations have decreased across the nation as efforts are made to reduce vehicle emissions and use clean energy.

Ozone, however, is much trickier, Wang notes. "For policy in the U.S., the focus should be on how to effectively control ozone concentration, which may be harder because it's a secondary pollutant," he said. "With climate change getting worse, this issue may become amplified."

The incidence of early onset colorectal cancer has increased nearly 50 percent in the last 30 years. A University of Colorado Cancer Center study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago aimed to identify factors that may aid in earlier diagnosis and treatment of the disease.

"The rising incidence of colorectal cancer in young adults is concerning," says Gurprataap Sandhu, MD, fellow at the CU Cancer Center. "In addition to trying to identify the cause of this increase, it is crucial to diagnose these patients at an earlier stage to improve clinical outcomes."

The results of the study found that there was a high incidence of advanced stage cancer and prolonged rectal bleeding history before diagnosis in young-onset patients with colorectal cancer. More than half of the 173 patients presented with rectal bleeding before diagnosis. On average, 294 days passed between the first time the patient noticed rectal bleeding and the time they were diagnosed. By the time of diagnosis, 37.8 percent of the patients were Stage IV.

"Our results show that young adult patients present with a much higher rate of Stage IV colorectal cancer compared to patients who are older than years of age," says Sandhu. "This is especially significant as Stage IV patients have a much worse prognosis and are typically incurable with a few exceptions."

Traditionally colorectal cancer screening starts at 50 years of age. However, the American Cancer Society (ACS) dropped the recommended screening age for average risk patients to 45 in response to the increase of early onset diagnoses.

"The finding of prolonged bleeding prior to diagnosis was a surprising. It is possible that the bleeding was attributed to hemorrhoids initially, leading to potential delay in seeking medical attention and ultimately diagnostic workup," says Sandhu. "Patients and primary care physicians should be made aware this finding in order to facilitate timely referral for colonoscopy which may lead to earlier diagnosis, less advanced disease at diagnosis, and improved outcomes."

More about early onset colorectal cancer

Colorectal cancer diagnoses in young people (under 50 years old) have been increasing significantly in the last decades. The reasons behind this are unclear but theories include the rising obesity in children, a decrease in childhood physical activity, and changes in the microbiome due to exposure to antibiotics.

According to a survey conducted by the Colorectal Cancer Alliance;

82% of young cancer survivors were initially misdiagnosed

73% were diagnosed at a later stage

50% felt their symptoms were ignored

62% did not have a family history

67% saw at least two doctors before being diagnosed

If caught early, the average five-year survival rate for patients with colorectal cancer is 90 percent. This drops to 14 percent if diagnosed at later stages.

PHILADELPHIA--People with attractive faces are often seen as more trustworthy, socially competent, better adjusted, and more capable in school and work. The correlation of attractiveness and positive character traits leads to a "beautiful is good" stereotype. However, little has been understood about the behavioral and neural responses to those with facial abnormalities, such as scars, skin cancers, birthmarks, and other disfigurements. A new study led by Penn Medicine researchers, which published today in Scientific Reports, uncovered an automatic "disfigured is bad" bias that also exists in contrast to "beautiful is good."

"Judgements on attractiveness and trustworthiness are consistent across cultures, and these assumptions based on facial beauty are made extremely quickly. On the other hand, people with facial disfigurement are often targets of discrimination, which seems to extend beyond the specific effects of lower overall attractiveness and may tie in more with the pattern of results with stigmatized groups," said the study's lead author Anjan Chatterjee, MD, a professor of Neurology, and director of the Penn Center for Neuroaesthetics. "In order to right any discrimination, the first step is to understand how and why such biases exist, which is why we set out to uncover the neural responses to disfigured faces."

Neuroimaging studies show that seeing attractive faces evokes brain responses in reward, emotion, and visual areas compared to seeing faces of average attractiveness. Specifically, attractive faces evoke greater neural responses as compared to faces of average attractiveness in ventral occipito-temporal cortical areas, which process faces and other objects. Additionally, attractiveness correlates with increased activations in the anterior cingulate cortex and medial-prefrontal cortex--areas which are associated with rewards, empathy, and social cognition.

The researchers set out to evaluate the behavioral and brain reactions to disfigured faces and investigate whether surgical treatment mitigates these responses. In two experiments, the researchers used a set of photographs of patients with different types of facial anomalies, before and after surgical treatment, to test whether people harbor a "disfigured is bad" bias and to measure neural responses.

In the first experiment, a behavioral study with 79 participants, the researchers tested if people harbor implicit biases against disfigured faces and if such implicit biases were different from consciously aware, self-reported explicit biases. The behavioral experiment consisted of an implicit association test (IAT) and an explicit bias questionnaire (EBQ) to identify whether people have a negative bias for disfigured faces. For the IAT, the researchers used the set of before and after photographs as a stimulus. The EBQ consisted of 11 questions which query conscious biases against people with facial disfigurements. While the team found no indication of an explicit bias, they found that non-disfigured faces were preferred in the IAT. This bias was particularly robust for men.

In a follow up functional MRI (fMRI) study with 31 participants, researchers tested brain responses to the same picture pairs. Participants judged the gender of each photograph they viewed. The researchers found increased neural responses in visual regions of the brain (the ventral occipito-temporal cortical areas) and decreases in regions associated with empathy (the anterior cingulate and medio-prefrontal cortex).

In sum, the authors found that people have implicit negative biases against people with disfigured faces, without knowingly harboring such biases. The diminished neural responses in the anterior cingulate cortex suggests that people are less empathetic when looking at individuals with disfigurement--this is also a potential neural marker of dehumanization, as diminished neural responses in the anterior cingulate cortex is also observed in response to other stigmatized people, such as the homeless and drug addicts.

"The emphasis of attractiveness and its association with positive attributes highlights the pervasive effect of appearance in social interaction. Chatterjee said. "While we found that corrective surgery mitigates negative social and psychological responses to people with facial anomalies, we are also exploring alternative strategies to minimize bias towards people with facial conditions."

A new study, published in 'Antimicrobial Agents and Chemotherapy' conducted by a University of Liverpool led research consortium, has helped develop a new treatment option for some multi-drug resistant (MDR) infections.

Antimicrobial Resistance (AMR) is a global and serious threat to human health that is making previously easy to treat infections harder to treat, and, according to the World Health Organisation, the cause of 25,000 deaths annually in European Union alone.

Gram-negative bacteria (GNB) are a group of medically important bacteria that can cause severe infections in patients throughout the NHS. They are increasingly resistant to multiple antibiotics and in some cases untreatable. The emergence of MDR Gram-negative bacteria is a serious and growing threat to public health.

Carbapenems are a class of highly effective antibiotic agents commonly used for the treatment of severe or high-risk bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Carbapenems are usually administered via intravenous injection, which requires hospitalisation and placement of an intravenous catheter.

Tebipenem pivoxil hydrobromide (SPR994)is a new carbapenem being developed by Spero Therapeutics that is being developed as an oral antimicrobial agent. Such a treatment may facilitate earlier discharge from hospital or the possibility of treating complex infections in the community.

The consortium, led by Professor William Hope from the University of Liverpool's Centre for Antimicrobial Pharmacodynamics, used a range of experimental model systems to identify the appropriate dosage to study in a large Phase III registration clinical trial of patients with complicated urinary tract infections. This Phase III trial is global multicentre study that is currently recruiting patients. The team used a combination of laboratory models that are a mimic of human disease and combine this with a range of mathematical and statistical techniques to predict an appropriate dosage. Such an approach maximises the chance that the right dose is studied the first time.

An accelerated drug development program of this type ensures that new antibiotics are available to patients in the NHS at the earliest opportunity and provides new options for the treatment of infections for which there are currently few if any therapeutic choices.

Professor Hope, said: "The program, conducted in collaboration with Spero Therapeutics, is a leading example of the principal mission of the Centre for Antimicrobial Pharmacodynamics, which is to accelerate the development of new antibiotics for patients with AMR.

"Working with Spero Therapeutics enabled the considerable experience in antimicrobial drug development in the consortium to be utilized and ensures that tebipenem can be a future treatment option for patients in the NHS and around the world."

"We are fortunate to work with the Centre for Antimicrobial Pharmacodynamics on the dose selection for our pivotal Phase 3 clinical trial as its design has greatly benefited from their experitise," said Tom Parr, Chief Scientific Officer of Spero Therapeutics. "At Spero we are committed addressing the serious unmet need of multi-drug resistant infections and look forward to providing updates on our Phase III trial of SPR994 in complicated urinary tract infections."