Does Adjunctive Preladenant Reduce “Off” Time in Parkinson Disease?


Phase II, dose-finding trial results suggest a modest reduction in “off” time, with acceptable safety.

Effective treatment of motor symptoms in patients with Parkinson disease becomes more difficult with disease progression, and physicians often struggle to balance multiple medications to limit motor fluctuations without causing or exacerbating dyskinesias. Adenosine 2A (A2A) receptor antagonists such as preladenant and istradefylline are a novel class of agents being developed as adjuncts to dopaminergic therapy, with the goal of shortening daily “off” time (periods during which Parkinson symptoms return as medication wears off) without worsening dyskinesias. In a manufacturer-funded and designed, phase II, double-blind, dose-finding trial involving 253 patients, researchers evaluated the efficacy and safety of adjunctive preladenant at doses of 1, 2, 5, or 10 mg twice daily compared with placebo; randomization was performed based on an adaptive protocol. The primary outcome measure was change in mean daily “off” time from baseline to 12 weeks, as reported in diaries maintained by participants.

At 12 weeks, adjusted mean total daily “off” time was reduced from baseline by 1.0 hour in the 5-mg group (P=0.049) and by 1.2 hours in the 10-mg group (P=0.019). In addition, dyskinesias did not seem to increase in association with reductions in “off” time (although the study was not adequately powered for such analysis). Preladenant was well tolerated at all doses.

Comment: These results should be interpreted with caution, as fewer than 50 patients in each group completed the trial. Furthermore, a reduction of about 1 hour in total daily “off” time barely crosses the threshold of what can be considered clinically meaningful and is roughly equivalent to reductions achieved with entacapone and rasagiline. Although this drug is likely to have only modest clinical impact, the addition of novel nondopaminergic agents is eagerly anticipated. A larger, phase III trial is required to test preladenant’s efficacy definitively.

Source: Journal Watch Neurology

Long-Term Outcomes of Ductal Carcinoma in Situ


Breast-conserving treatments for DCIS are associated with excellent prognoses.

Incidence of ductal carcinoma in situ (DCIS) has risen substantially during the last 2 decades as a result of screening mammography. However, mammographically detected DCIS is often clinically silent and substantially less extensive than the large DCIS lesions that once were common at diagnosis. In addition, therapeutic approaches to DCIS have evolved: For most patients, breast conservation (i.e., lumpectomy and radiation therapy with or without tamoxifen as appropriate) is feasible.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 and B-24 trials were designed to assess outcomes of breast-conserving treatments for DCIS. In the B-17 trial, 818 patients with localized DCIS were randomized to lumpectomy only (LO) or lumpectomy plus radiation therapy (LRT). In the B-24 trial, 1804 patients were randomized to LRT with or without tamoxifen. Now, NSABP investigators provide long-term data from B-17 (median follow-up, 207 months) and B-24 (median follow-up, 163 months) in participants who did or did not experience invasive ipsilateral breast tumor recurrence (I-IBTR). The key issue addressed was influence of I-IBTR on overall outcomes by treatment mode.

Fifteen-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10% for LRT plus placebo (B-24), and 8.5% for LRT plus tamoxifen. I-IBTR (but not DCIS recurrence) was associated with excess risk for death (hazard ratio, 1.75; P<0.001). Risk for dying of breast cancer in either trial (with or without I-IBTR) was very low: 15-year cumulative incidence was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT plus placebo (B-24), and 2.3% for LRT plus tamoxifen.

Comment: That invasive ipsilateral breast tumor recurrence ultimately affects survival should not come as a revelation. On a more positive note, these data reaffirm that optimal treatment of DCIS attenuates risk for death from breast cancer. In short, breast-conserving treatment for DCIS is associated with excellent long-term prognosis.

Source: Journal Watch Oncology and Hematology

Hypnobirthing


Hypnobirthing is a birthing method that uses self-hypnosis and relaxation techniques to help a woman feel prepared, narrow her focus, and reduce her awareness of fear, anxiety and pain during childbirth.

If you’re tense or afraid during labor, stress hormones can redirect blood flow to your limbs, heart and brain — the fight-or-flight reaction — and waste precious energy. Hypnobirthing may counteract this process by preventing the release of stress hormones, which potentially reduces the pain of labor.

Hypnobirthing classes typically begin during the third trimester of pregnancy. While specific programs differ, they generally teach participants to use a combination of music, visualization, positive thinking and words to relax the body and control sensations during labor.

Research examining the benefits of hypnobirthing is limited. A 2004 research review found insufficient evidence to show that the technique is effective. A 2006 research review, however, found that hypnobirthing reduced the use of pain medication during labor.

If you’re interested in finding out more about hypnobirthing, talk to your health care provider. He or she may recommend a certified childbirth educator or other professional who can help you determine if hypnobirthing is right for you.

source: mayo clinic

Nanoprocessing


Introducing the world’s first programmable nanoprocessor

As electronic components have continued to shrink to smaller and smaller sizes, we have been rapidly approaching the nanoscale. Indeed, we have already seen the creation of simple logic circuits from semiconductor nanowires. However, despite the success of these novel architectures, the goal must be to build nanoscale equivalents of the microprocessors we are all familiar with. Researchers from Harvard and The MITRE Corporation have recently achieved this, with the development of the world’s first programmable nanoprocessor [Yan et al., Nature (2011) 470, 240].

Dr Shamik Das and co-workers used a bottom-up approach to fabricate logic tiles consisting of Ge/Si nanowires covered in layers of aluminium and zinc oxide, producing a series of non-volatile field effect transistors (FETs). The diameter of the wires was just 30 nm. Each tile consists of two arrays of nanowires, resulting in 496 FETs over an area of 960 µm2. However, previous studies have demonstrated that it could be possible to dramatically reduce this size by a factor of 103.
To construct the processor Dr Das explained to Materials Today that the Ge/Si nanowires are first fabricated using a nanocluster-catalyzed growth method, before being printed onto a substrate. “This printing innovation enables the fabrication of large arrays of aligned nanowires upon the target substrate.  Such aligned-nanowire arrays are crucial to the production of scalable nanowire nanoprocessor systems. Following the printing of nanowire arrays, lithographic techniques such as EBL [electron beam lithography] and RIE [reactive ion etching] are used to define contacts and interconnects”.
“The overall fabrication process deftly combines bottom-up techniques that define the most critical, sub-lithographic features with top-down methods [are used for]for the larger-scale structures.  As a result, the process should be scalable for the fabrication of extended, integrated systems consisting of a great number of the nanoprocessor tiles demonstrated in the present work”.
The team demonstrated that the same tile could be reprogrammed to function as a full adder, full subtractor, multiplexer and demultiplexer, as by applying a gate bias to an FET, it could be forced to act as an active transistor, or a passive connection. The tiles could also be connected together to drive subsequent elements, such that much more complex architectures could be realized.
Possible applications include integration into embedded sensors and small medical devices. According to Das, their ultimate goal is “is the demonstration of a complete, ultra-tiny nanoprocessor that can carry out energy-efficient, real-time control of such applications”.
source: material today/nanotechnology

A nanostar is born


New platinum catalysts for cheap and stable fuel cells

Proton exchange membrane fuel cells, also known as polymer electrolyte membrane fuel cells (PEMFCs), offer a way to power future emission-free vehicles, by providing stationary and portable power sources. However, the high cost and low durability of platinum catalysts are two major challenges hindering their commercialization. Researchers from the University of Western Ontario, and General Motors Research and Development Center have now discovered a new catalyst, platinum nanostars, that could make fuel cells more cost-effective and stable. [S. H. Sun et al., Angew Chem Int Ed (2011) 50, 422].
Pt is the most effective catalyst for fuel (usually hydrogen) oxidation at the anode and oxygen reduction reaction (ORR) at the cathode. The ORR is considerably slower than the oxidation of H2, and requires more catalyst. But Pt is expensive and relatively rare, and so has pushed up the price of fuel cells. At present, the most widely used cathode catalysts consist of fine particles of Pt supported on carbon black supports. In contrast to Pt nanoparticles, one-dimensional structures of Pt, such as nanowires, exhibit additional advantages associated with their anisotropy and unique structure.
Star-like single-crystal platinum nanostructures were produced, each with several nanowire arms with diameters of ~4 nm on carbon black. The carbon supported star-like Pt nanostructures (star-like PtNW/C) were synthesized in an environmentally friendly process, which does not require high temperatures, organic solvents, surfactants or complicated electrochemical deposition apparatus, by reducing a Pt precursor (H2PtCl6) with formic acid (HCOOH) in aqueous solution at room temperature.
The star-like PtNW/C showed greatly improved activity and durability compared to a state-of-the-art commercial catalyst made of Pt nanoparticles on carbon. More interestingly, the durability can be further improved by eliminating the carbon support.
The key reason this strategy works relies on the combination of a multi-armed network structure and the one-dimensional shape of the arms. This helps the activity and durability. In addition, the few surface defects and the preferential exposure of certain crystal facets further improves the activity. The increased activity and durability means that the amount of Pt needed on an electrode can be reduced, which could significantly lower the cost and increase the durability of PEMFCs.
soure: material today/naotechnology

One way sound


Introducing the tunable acoustic diode

Diodes, in the form of thermionic valves and semiconductor devices have helped revolutionize electronics. Their defining property is that they only allow current to flow through them in one direction. Over the last 10 years several studies have been published on producing rectifying diodes for other propagating phenomena, including sound. Such a system was experimentally demonstrated late last year by a group of Chinese researchers [Liang et al., Nature (2010) 9, 989]. Now, just a few months later a separate Chinese team has succeeded in producing an alternative acoustic diode system, which can also be switched on and off [Li et al., Phys Rev Lett (2011) 106, 084301].
Both systems rely on acoustic metamaterials; so called sonic crystals that only allow certain frequencies of sound to propagate. In the original acoustic diode, one side of the sonic crystal was combined with a highly non-linear (NL) material, capable of changing the frequency of incident sound waves. As the sonic crystal only lets certain frequencies propagate through it, only sound waves converted by the NL materials could pass through.
The new system uses a slightly different process. One side of the sonic crystal is given a different periodicity, producing a corrugated diffraction structure. This results in a change of the spatial frequency. Lu and Chen told Materials Today that “Compared to the previous acoustic diode, our device leads to a totally linear unidirectional effect with higher efficiency, broader bandwidth, and much less power consumption.”
The diode consist of square steel rods in air, each having a width of 4 mm and a spacing of 3 mm. Toward one side of the sonic crystal, rods were removed to create a stepped diffraction structure, such that the rods were eventually separated by 38 mm. As the square rods broke the rotational symmetry of the unit cell, it was possible to tune the acoustic scattering by rotating the orientation of the blocks. A rotation of 45o allowed the diode to be switched off, such that sound was able to propagate in both directions.
The researchers believe that a similar methodology could be used to construct an on-chip isolator for acoustic waves, but also “extended to hypersonic frequencies whereby the device could be applied to manipulate the heat flow”. The researchers are also considering the possibility of producing “an acoustic transistor to manipulate, amplify and switch the incident waves by [using] acoustic or light waves”.

Marking diabetes


author: Joanne Kotz, Senior Editor

A Massachusetts team has identified amino acid1 and triacylglyceride2 signatures that can predict increased risk of developing type 2 diabetes. The researchers now plan to look at whether the signatures can distinguish which prediabetic patients will benefit from lifestyle changes or therapeutic intervention. The key unknown is whether a cutoff value for the signatures can be identified that will prospectively predict an individual’s risk or response to treatment.

“We know that the current tools for diagnosing diabetes—glucose and HbA1c—are not particularly good at predicting diabetes,” said Steven Watkins, CSO of Tethys Bioscience Inc. “This is because changes in the blood levels of these markers tend to occur late in the disease process.”

Tethys markets PreDx DRS, an assay that predicts an individual’s risk of developing diabetes. The test is conducted in a CLIA-certified laboratory and incorporates seven circulating biomarkers including glucose and hemoglobin A1c (HbA1c).

In a search for other early markers of type 2 diabetes, a team led by researchers from Massachusetts General Hospital and the Broad Institute of MIT and Harvard conducted two studies. One looked at levels of metabolites, and the other looked at levels of lipids in the blood of 378 participants in the Framingham Offspring Study.

“For a person off the street, what would be a cutoff level that constitutes a danger sign?”

Christopher Newgard
Duke University School of Medicine

At the time of an examination conducted from 1991–1995, none of the participants had diabetes but all were judged to be at high risk for the disease. Out of this cohort, only half went on to develop diabetes over the next 12 years.

The Massachusetts team set out to identify the markers that could help better predict who would go on to develop the disease.

In serum samples from the 1991–1995 examinations, the team used mass spectrometry to identify metabolites or lipids that were present in different concentrations in the blood of people who went on to develop diabetes compared with in the blood of those who did not.

In the first study, three amino acids—isoleucine, tyrosine and phenylalanine—were present at higher levels in the serum of people who later developed diabetes. In the study analyzing lipid levels, triacylglycerides (TAGs) with shorter chain length and fewer double bonds were present at higher levels in the blood of people who later developed diabetes than TAGs with longer chain length or more double bonds.

After controlling for age, sex, BMI and fasting glucose, the top quartile of patients with the highest amino acid signature had a sixfold greater risk of developing diabetes than those having a signature in the bottom quartile.

Similarly, top-quartile TAG signature patients had a 4.3-fold higher risk of becoming diabetic than bottom-quartile TAG signature patients.

Results from the metabolite study were published in Nature Medicine, and results from the lipid study were published in The Journal of Clinical Investigation.

“A relationship between branched-chain amino acids or triacylglyceride composition and diabetic processes has been known for a while, but this is the first large-scale clinical validation of the observation,” said Watkins.

Risk prediction

The predictive power of these signatures for diabetes risk is real but relatively modest, said Watkins. Thus, he thinks the markers likely will need to be combined with other measures to provide clinically useful predictive power.

“These papers report intriguing markers,” said Michael Milburn, CSO of Metabolon Inc. “Determining how practical they are is really the next step.”

Metabolon is developing a test for insulin resistance that measures three metabolites and can be used to predict the risk of developing diabetes and other diseases. Milburn said the company hopes to launch the test around year end.

Because the current studies normalized for glucose levels, they did not directly test how these signatures compared to the predictive power of glucose levels, noted Milburn. Thus, he said it will be important to conduct additional studies to see how these signatures perform compared with current clinical standards such as glucose measurements.

In addition, Milburn thinks there will be challenges in moving from looking at a whole population to demonstrating clinical utility for a particular individual.

This is a key question to be addressed, agreed Christopher Newgard, professor of pharmacology and cancer biology and director of the Sarah W. Stedman Nutrition and Metabolism Center at the Duke University School of Medicine. “For a person off the street, what would be a cutoff level that constitutes a danger sign?” he asked.

Robert Gerszten and Thomas Wang, who co-led both studies, said the Massachusetts team now plans to run additional studies in larger, heterogeneous populations to examine how their findings can be generalized to individuals with a variety of backgrounds, for instance, different ethnicities and age groups.

Gerszten is director of the clinical and translational research program at the MGH heart center, associate professor of medicine at Harvard Medical School and a senior associate at the Broad Institute. Wang is associate director of the heart failure and transplantation program at MGH and associate professor of medicine at Harvard Medical School.

Another angle being pursued by the team is to determine whether the amino acid and TAG signatures are independent of one another and whether they could be combined to predict diabetes risk more accurately. “The early look is that the signatures are not highly correlated, so they may well add information to each other, but this still needs to be proven formally,” said Gerszten.

“These papers report intriguing markers. Determining how practical they are is really the next step.”

Michael Milburn
Metabolon Inc.

Therapy guide

Markers that more accurately predict the risk of an individual developing diabetes would clearly be useful clinical tools, but the real home run would be markers that can guide the individual treatment of prediabetic patients.

Prediabetes encompasses multiple different metabolic dysfunctions, including insulin resistance, β cell dysfunction and dyslipidemia. These different conditions are “poorly differentiated with current tests,” said Milburn, and an important future direction is identifying markers for each of these distinct conditions that can help predict response to different types of treatments.

There are some hints that the amino acid signature may be up to that task.

Newgard cited a 2010 study that looked mechanistically at the insulin-sensitizing action of thiazolidinediones.3 In obese, insulin-resistant rats, the extent of tissue-specific transcriptional changes in the branched-chain amino acid pathway correlated with efficacy of four thiazolidinediones, including Avandia rosiglitazone from GlaxoSmithKline plc and Actos pioglitazone from Takeda Pharmaceutical Co. Ltd.

“Where we now need to go is to overlay pharmacotherapies that are available today on top of our understanding of the predictive nature of these amino acid signatures,” said Newgard.

Watkins agreed that a next step will be determining whether interventions that change the marker concentrations lead to positive outcomes in individual patients.

Indeed, Gerszten said the Massachusetts team is planning to look at whether the amino acid or TAG signature can predict response to intervention. The team plans to look at drug and lifestyle intervention studies for prediabetics to see if either signature correlates with response.

Gerszten told SciBX that the team would be “interested in partnering with pharma to identify patient subsets that are most at risk for disease and/or most likely to derive benefit from therapeutic interventions.”

Patent applications have been filed covering both diagnostic and therapeutic applications for the results reported in both papers and are available for licensing, said Gerszten.

source: sciBX

Alternatives to Lung Transplantation: Lung Volume Reduction for COPD


Emphysema is disabling and progressive and hallmarked by decreased exercise tolerance and impaired quality of life. Surgical interventions that reduce lung volume have been the focus of multiple interventions for decades; however, until recently, limited evidence has documented their effectiveness. Lung volume reduction surgery (LVRS) underwent rigorous study in the National Emphysema Treatment Trial (NETT), which demonstrated its short-term and long-term effectiveness, associated morbidity and mortality, and the essential factors that predict LVRS success or failure. This article summarizes the major results of the NETT and briefly reviews newer bronchoscopic lung volume reduction techniques that show promise as alternative treatments for select patients with COPD undergoing consideration for lung transplantation.

source: clinic of chest medicine


Nicotinamide Inhibits Growth of Carcinogen Induced Mouse Bladder Tumor and Human Bladder Tumor Xenograft Through Up-Regulation of RUNX3 and p300


Acetylation of chromatin interacting proteins is central to the epigenetic regulation of gene expression. Various tumor suppressors are inactivated by abnormal epigenetic modification. A great deal of effort has been devoted to developing anticancer agents that reactivate silenced tumor suppressors by modulating chromatin structure. Studies show that histone deacetylase inhibitors can act as anticancer agents and several histone deacetylase inhibitors are currently in clinical trials. We noted that the tumor suppressor RUNX3 is inactivated by promoter hypermethylation in human bladder cancer. We investigated whether reactivation of RUNX3 could suppress bladder cancer development in an animal model.

Materials and Methods

We analyzed RUNX3 reactivation and protein stabilization by a mild inhibitor of class III histone deacetylases, nicotinamide, by immunoprecipitation and immunoblot. Mouse bladder tumor was induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The effect of nicotinamide on Runx3 methylation status and tumor growth was measured.

Results

Nicotinamide induced RUNX3 expression at the transcriptional and posttranslational levels in a carcinogen induced mouse bladder tumor model and in human bladder tumor xenografts. Nicotinamide effectively inhibited the growth and progression of bladder tumors without decreasing body weight.

Conclusions

Results suggest that nicotinamide has preventive and therapeutic effects on tumorigenesis through multiple mechanisms of RUNX3 expression up-regulation.

source: the journal of urlogy


Testicular Cancer


Germ cell tumor is the most frequent malignant tumor type in young men, with a steep rise in incidence in recent years. The majority of patients with advanced disease will be cured, but there is a need to improve the outcome of poor-risk patients. For this patient category, and for patients who relapse following standard, first-line, cisplatin-based chemotherapy, the role of high-dose chemotherapy (HDCT) is still a matter of debate. With cure rates > 90% in the whole group of testicular cancer patients, long-term morbidity has become increasingly important.

Objective

Highlights of the American Society of Clinical Oncology 2010 Annual Meeting pertinent to these key issues in the field of testicular cancer are discussed.

Conclusions

The role of HDCT as first-line treatment of stage I seminoma in poor-prognosis patients or in second-line therapy as salvage treatment has not been established. The clinical approach to stage I seminoma patients varies considerably between European countries, such as Scandinavian countries and Spain. Long-term testicular cancer survivors are at increased risk of cardiovascular disease, particularly after treatment with chemo- and radiotherapies.

Take Home Message

High-dose chemotherapy has not been shown to be superior in first-line treatment of stage I seminoma in poor-prognosis patients or as a salvage regimen in second-line therapy. Prospective trials, adequately powered to detect a clinically meaningful difference, are needed to address these questions.

source: European urology supplement