The Use of Inhaled Prostaglandins in Patients With ARDS

OBJECTIVE:  This study aimed to determine whether inhaled prostaglandins are associated with improvement in pulmonary physiology or mortality in patients with ARDS and assess adverse effects.

METHODS:  The following data sources were used: PubMed, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, reference lists, conference proceedings, and Studies selected included randomized controlled trials and nonrandomized studies. For data extraction, two reviewers independently screened titles and abstracts for eligibility. With regard to data synthesis, 25 studies (two RCTs) published over 21 years (1993-2014) were included. The PROSPERO registration number was CRD42014013180.

RESULTS:  One randomized controlled trial showed no difference in the change in mean Pao2 to Fio2 ratio when comparing inhaled alprostadil to placebo: 141.2 (95% CI, 120.8-161.5) to 161.5 (95% CI, 134.6-188.3) vs 163.4 (95% CI, 140.8-186.0) to 186.8 (95% CI, 162.9-210.7), P = .21. Meta-analysis of the remaining studies demonstrated that inhaled prostaglandins were associated with improvement in Pao2 to Fio2 ratio (16 studies; 39.0% higher; 95% CI, 26.7%-51.3%), and Pao2(eight studies; 21.4% higher; 95% CI, 12.2%-30.6%), and a decrease in pulmonary artery pressure (−4.8 mm Hg; 95% CI, −6.8 mm Hg to −2.8 mm Hg). Risk of bias and heterogeneity were high. Meta-regression found no association with publication year (P = .862), baseline oxygenation (P = .106), and ARDS etiology (P = .816) with the treatment effect. Hypotension occurred in 17.4% of patients in observational studies.

CONCLUSIONS:  In ARDS, inhaled prostaglandins improve oxygenation and decrease pulmonary artery pressures and may be associated with harm. Data are limited both in terms of methodologic quality and demonstration of clinical benefit. The use of inhaled prostaglandins in ARDS needs further study.

Hubble sees a ‘behemoth’ bleeding atmosphere around a warm exoplanet (Update)

“What we can see is a large cloud of hydrogen gas absorbing the light from a red dwarf star as its exoplanet, GJ 436b, passes in front. The cloud is created as of result of x-rays emitted from the red dwarf burning off GJ 436b’s upper atmosphere.”The cloud forms a comet-like tail as a result of ultraviolet light coming from the star pushing on the hydrogen and causing it to spiral outwards. “Around 1000 metric tonnes of hydrogen are being burnt off from GJ 436b’s atmosphere every second; which equates to only 0.1 percent of its total mass every billion years. The same process is likely to be much stronger on other exoplanets, where the entire atmosphere could be removed or evaporated to destruction”. 

Astronomers using NASA’s Hubble Space Telescope have discovered an immense cloud of hydrogen dubbed “The Behemoth” bleeding from a planet orbiting a nearby star. The enormous, comet-like feature is about 50 times the size of the parent star. The hydrogen is evaporating from a warm, Neptune-sized planet, due to extreme radiation from the star.

This phenomenon has never been seen around an exoplanet so small. It may offer clues to how other planets with hydrogen-enveloped atmospheres could have their outer layers evaporated by their parent star, leaving behind solid, rocky cores. Hot, rocky planets such as these that roughly the size of Earth are known as Hot-Super Earths.

“This cloud is very spectacular, though the evaporation rate does not threaten the planet right now,” explains the study’s leader, David Ehrenreich of the Observatory of the University of Geneva in Switzerland. “But we know that in the past, the star, which is a faint red dwarf, was more active. This means that the planet evaporated faster during its first billion years of existence because of the strong radiation from the young star. Overall, we estimate that it may have lost up to 10 percent of its atmosphere over the past several billion years.”

The planet, named GJ 436b, is considered to be a “Warm Neptune,” because of its size and because it is much closer to its star than Neptune is to our sun. Although it is in no danger of having its atmosphere completely evaporated and stripped down to a rocky core, this planet could explain the existence of so-called Hot Super-Earths that are very close to their stars.

These hot, rocky worlds were discovered by the Convection Rotation and Planetary Transits (CoRoT) and NASA’s Kepler space telescope. Hot Super-Earths could be the remnants of more massive planets that completely lost their thick, gaseous atmospheres to the same type of evaporation.

Artist impression showing the warm, Neptune-size exoplanet GJ 436b at the beginning of its transit across the surface of its parent star, a red dwarf that is half the diameter of the Sun. The planet is 33x closer to its parent star than the Earth is to Sun, heating the atmosphere to the point it expands and escape the planet attraction. The star is, however, 40x fainter than the Sun, allowing the evaporating atmosphere to form a giant cloud surrounding and trailing the planet, much like a comet. Credit: D.Ehrenreich / V. Bourrier (Université de Genève) / A. Gracia Berná (Universität Bern)

Because the Earth’s atmosphere blocks most ultraviolet light, astronomers needed a space telescope with Hubble’s ultraviolet capability and exquisite precision to find “The Behemoth.”

“You would have to have Hubble’s eyes,” says Ehrenreich. “You would not see it in visible wavelengths. But when you turn the ultraviolet eye of Hubble onto the system, it’s really kind of a transformation, because the planet turns into a monstrous thing.”

Because the planet’s orbit is tilted nearly edge-on to our view from Earth, the planet can be seen passing in front of its star. Astronomers also saw the star eclipsed by “The Behemoth” hydrogen cloud around the planet.

Ehrenreich and his team think that such a huge cloud of gas can exist around this planet because the cloud is not rapidly heated and swept away by the radiation pressure from the relatively cool red dwarf star. This allows the cloud to stick around for a longer time. The team’s findings will be published in the June 25 edition of the journalNature.

Evaporation such as this may have happened in the earlier stages of our own solar system, when the Earth had a hydrogen-rich atmosphere that dissipated over 100 to 500 million years. If so, the Earth may previously have sported a comet-like tail.

GJ 436b resides very close to its star – less than 2 million miles—and whips around it in just 2.6 Earth days. In comparison, the Earth is 93 million miles from our sun and orbits it every 365.24 days. This exoplanet is at least 6 billion years old, and may even be twice that age. It has a mass of around 23 Earths. At just 30 light-years from Earth, it’s one of the closest known extrasolar planets.

This artist’s concept shows “The Behemoth,” an enormous comet-like cloud of hydrogen bleeding off of a warm, Neptune-sized planet just 30 light-years from Earth. Also depicted is the parent star, which is a faint red dwarf named GJ 436. The hydrogen is evaporating from the planet due to extreme radiation from the star. A phenomenon this large has never before been seen around any exoplanet. Credit: NASA, ESA, and G. Bacon (STScI)

Finding “The Behemoth” could be a game-changer for characterizing atmospheres of the whole population of Neptune-sized planets and Super-Earths in ultraviolet observations. In the coming years, Ehrenreich expects that astronomers will find thousands of this kind of planet.

The ultraviolet technique used in this study also may also spot the signature of oceans evaporating on smaller, more Earth-like planets. It will be extremely challenging for astronomers to directly see water vapor on those worlds, because it’s too low in the atmosphere and shielded from telescopes. However, when water molecules are broken by the stellar radiation into hydrogen and oxygen, the relatively light hydrogen atoms can escape the planet. If scientists spot this hydrogen evaporating from a planet that is slightly more temperate and less massive than GJ 436b, it could be an indication of an ocean on the surface.

Novel Drug Ups Function in Patients With LEMS | Medpage Today

Amifampridine phosphate slowed disease worsening in autoimmune neuromuscular disorder.

  • An investigational drug improved muscle strength and function in patients with Lambert-Eaton myasthenic syndrome (LEMS), researchers reported here.

In a randomized, controlled trial, amifampridine phosphate (Firdapse) slowed disease worsening compared with placebo, according to Shin Oh, MD, of the University of Alabama at Birmingham, and colleagues.

The drug “should be the standard symptomatic drug in LEMS on the basis of this study,” Oh said during a presentation at the American Academy of Neurology annual meeting.

LEMS is a rare autoimmune disease characterized by proximal muscle weakness. Autoantibodies attack voltage-gated calcium channels, causing a reduction in the amount of acetylcholine released by nerves.

The condition can mimic myasthenia gravis, but it has a different etiology and course, Oh said. It is estimated to affect some one in 100,000 patients, and about half of cases also develop small-cell lung cancer.

Although Firdapse has been approved in Europe since December 2009, there is no FDA-approved drug for symptomatic treatment in the U.S., although some drugs are used to mitigate symptoms, including pyridostigmine (Mestinon), compounded 3.4-DAP, and guanidine.

However, Firdapse won both orphan drug and breakthrough therapy designation from the FDA in 2013.

To evaluate its efficacy in LEMS, Oh and colleagues conducted a phase III multicenter, double-blind, placebo-controlled trial of 38 patients at 14 sites.

The primary endpoints were a quantitative exam of muscle strength called QMG score and outcomes on the Subjective Global Impression (SGI) test. Secondary endpoints were Clinical Global Impression-Improvement (CGI-I) and 25-foot walk test.

Oh and colleagues found greater disease worsening as measured by QMG score in placebo patients compared with those on the drug over a 2-week period (2.2 versus 0.4,P=0.0452).

Placebo patients also had greater worsening as measured by SGI score (-2.6 versus -0.8,P=0.028).

For secondary outcomes, placebo patients also had greater worsening compared with drug patients in terms of CGI scores (4.7 versus 3.6, P=0.0267).

 However, there was no significant change in 25-foot walking scores between the two groups.

Oh noted that drug-treated patients had a positive, rapid response that was seen within 8 days of starting on the drug, and an excellent overall response rate throughout the study.

Given the results, the researchers conducted an open-label extension phase in which 34 of 38 patients stayed at the same or lower dose for up to 2 years. That study is ongoing.

There were no serious adverse events attributable to the drug, which was generally safe and well tolerated. The side effects were benign, consisting of perioral and digital paresthesia, gastrointestinal disorders, and infections.

Jaydeep Bhatt, MD, of NYU Langone Medical Center in New York City, who was not involved in the study, called the trial well-designed and said it demonstrates that the drug can “provide patients with [LEMS] a real treatment choice for improving the walking and breathing difficulties they typically have.”

“These positive findings will hopefully lead to an FDA-approved therapy for this rare disease,” Bhatt said.

Get ready for the leap second – it could be the last one ever

ROGER PENROSE appears baffled by my tardiness, eyeing my sweat-beaded brow with what I can only assume is pity. “I found it very easily,” says the University of Oxford mathematician. “It’s a straight walk up from South Kensington tube.” The irony is not lost on either of us. I had not only arrived late to a meeting about time measurement; I had got lost on the streets of west London trying to find the Royal Institute of Navigation.

That was last year, at the first gathering of a committee to oversee the world’sfirst public consultation about leap seconds. It was to be Penrose‘s only appearance: after half an hour he pulled out, suggesting the committee was skirting the real problem with time.

The latest leap second will occur at the end of Tuesday, 30 June.

Cancer Biology

Why Research on Cancer Biology Is Critical to Progress against the Disease

Research on the biology of cancer starts with the simplest of questions: What is—and isn’t—normal?

To understand how cancer develops and progresses, researchers first need to investigate the biological differences between normal cells and cancer cells. This work focuses on the mechanisms that underlie fundamental processes such as cell growth, the transformation of normal cells to cancer cells, and the spread, or metastasis, of cancer cells.

Knowledge gained from such studies deepens our understanding of cancer and produces insights that could lead to the development of new clinical interventions. For example, studies of cell signaling pathways in normal cells and cancer cells have contributed greatly to our knowledge about the disease, revealing molecular alterations that are shared among different types of cancer and pointing to possible strategies for treatment.

The last few decades of basic research in cancer biology have created a broad base of knowledge that has been critical to progress against the disease. In fact, many advances in the prevention, diagnosis, and treatment of cancer would not have occurred without the knowledge that has come from investigating basic questions about the biology of cancer.

Opportunities in Cancer Biology Research

Scientists today have a growing understanding of the biology of a vast array of cancers driven by various mutations and across many body sites. New data and research approaches have created opportunities for researchers to study in detail many aspects of cancer biology, including how the normal biological programs of cell proliferation and death are altered during cancer and how the immune system responds to tumors.

The discovery of tumor stem cells in a range of cancers has created opportunities for researchers to identify these rare cells in both solid tumors and hematologic cancers, as well as to investigate the role of these cells at different stages of disease.

The recognition that the cancer cell is in a symbiotic relationship with the tumor microenvironment has created opportunities to study the interactions of cancer cells within the tumor or the host microenvironment. Researchers are now studying the molecular mechanisms and signaling pathways of cancer cell development, proliferation, and metastasis.

Growing interest in the microbiome, the community of microorganisms and viruses that inhabit the human body, has led researchers to investigate the role of the human microbiome in the initiation and progression of tumors.

New genetic technologies developed over the past decade have helped researchers examine the functional effects of genetic alterations that underlie the development of cancer. These tools have also been used to study epigenetic changes associated with cancer, mechanisms of DNA damage and repair, and gene regulation in cancer cells.

The introduction of increasingly powerful structural biology approaches have allowed researchers to characterize the structures of mutant proteins involved in cancer, such as RAS, and other molecules in greater detail than had been possible previously.

There are also opportunities to explore cancer biology through systems biology approaches. Researchers use a variety of information and tools, such as mathematical modeling, to describe the complex interactions among components of a biological system and make predictions that help guide and further refine experimental science.

Challenges in Cancer Biology Research

Basic research in cancer biology is often viewed as “high risk,” in part because the clinical applications of a given research project might not be clear at the outset. However, knowledge gained from studying cancer cell biology not only improves our understanding of the disease but is essential for the development of clinical advances that benefit patients, as recent progress in the areas of immunotherapy and cancer vaccines illustrates.

Nonetheless, because of the uncertainty about the outcomes of basic research in cancer biology, this area of research receives relatively little funding from sources that are driven by profit. For this reason, federal funding for cancer biology research is critical.

Collaboration across disciplines is increasingly necessary to better understand key mechanisms in cancer. Therefore, some investigators may need to develop tools and strategies for sharing and communicating research results.

NCI’s Role in Cancer Biology Research

NCI supports and directs research on the biological differences between normal cells and cancer cells through a variety of programs and approaches. For example, the Division of Cancer Biology (DCB) supports extramural researchers who are using a variety of methods to study cancer biology.

In addition to many of the topics mentioned above, DCB supports research on:

  • the metabolism of cancer cells, the responses of cancer cells to stress, and mechanisms involved in control of the cell cycle
  • biological agents (such as viruses and bacteria), host factors (such as obesity, co-morbid conditions, and age), and behaviors (such as dietary intake) that may cause or contribute to the development of cancer
  • immune regulation of the development and spread of tumors and approaches to improve immune targeting and destruction of cancer cells
  • genomic instability and related molecular, cytogenetic, and chromosomal effects during induction and progression to malignancy
  • the role of the microenvironment created by inflammation and the inflammatory signaling molecules in the formation and progression of tumors
  • processes and molecular targets where there is potential for therapeutic or preventive intervention
  • the effects of hypoxia on tumor cell invasion and metastasis
  • the role of somatic stem cells in determining tumor progression and metastatic behavior, and control of the stem cell niche by tumor microenvironment

NCI-supported research programs in cancer biology include the:

  • Physical Sciences in Oncology Network
    The goal of this initiative is to promote and foster the convergence of physical science and cancer research. Small transdisciplinary teams of physical scientists (engineers, physicists, mathematicians, chemists, and computer scientists) and cancer researchers (cancer biologists, oncologists, and pathologists) collaborate on solving problems such as determining which cell is the cell of origin for brain and hematopoietic tumors and exploring the use of three-dimensional images of single cells as cancer signatures.
  • Tumor Microenvironment Network (TMEN)
    The centers in this network focus on expanding our understanding of the role of the tumor microenvironment in cancer initiation, progression, and metastases. The goal of this initiative is to better understand the composition of the stroma in normal tissues and to learn how the tumor and stroma interact in cancer.
  • Barrett’s Esophagus Translational Research Network (BETRNet)
    This multidisciplinary, multi-institutional collaboration was established to better understand Barrett esophagus and to prevent esophageal adenocarcinoma. BETRNet aims to better understand esophageal adenocarcinoma (EA) biology; examine research opportunities associated with its precursor lesion, Barrett Esophagus; improve EA risk stratification and prediction; and provide strategies for EA prevention. The overriding goal is to decrease the incidence, morbidity, and mortality of this cancer.
  • Alliance of Glycobiologists for Detection of Cancer
    This consortium of tumor glycomics laboratories and their research partners study the cancer-related dynamics of complex carbohydrates. This program, which NCI sponsors with the National Institute of General Medical Sciences and the National Heart, Lung and Blood Institute, aims to study the structure and function of glycans in relation to cancer.
  • Molecular and Cellular Characterization of Screen-Detected Lesions Initiative
    The goal of this program is to undertake a comprehensive molecular and cellular characterization of tumor tissue, cell, and microenvironment components to distinguish screen-detected early lesions from interval and symptom-detected cancers. Researchers use various technologies and approaches to determine both the cellular and molecular phenotypes of early lesions, with the goal of better predicting the fate of early lesions.

NCI’s Centers of Excellence bring together intramural researchers from NCI’s Center for Cancer Research and Division of Cancer Epidemiology and Genetics to develop new projects and initiatives in various areas of cancer biology, including:

  • Chromosome Biology
    The experts affiliated with this center study the mechanisms involved in chromosome function through diverse research that includes mapping the dynamic changes of the genome and transcriptome during the development of cancer and translational research for the early diagnosis of cancer.
  • Integrative Cancer Biology and Genomics
    This center’s goal is to use advanced analytic technologies to define homogenous clusters of patients, who can then be treated with appropriate therapies. The researchers in this center build upon the immense amount of basic research data available in an effort to shorten the time between discovery and patient benefit by bringing together expertise in five areas: biomarkers and molecular targets, genomic approaches, human genomics and genetics, cancer inflammation, and integrative/systems biology and bioinformatics.