Blood Test for Early Detection of Pancreatic Cancer

A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the United States are diagnosed with pancreatic cancer — the fourth leading cause of cancer death — every year. The blood biomarkers, detailed today in Science Translational Medicine, correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.

The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumors can be surgically removed.

A team led by Ken Zaret, PhD, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology, and Gloria Petersen, PhD, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier.

Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said. The authors anticipate that health care providers will use the early-detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first-degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.

Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”


How To Capture Quickly Cancer Markers

A nanoscale product of human cells that was once considered junk is now known to play an important role in intercellular communication and in many disease processes, including cancer metastasis. Researchers at Penn State have developed nanoprobes to rapidly isolate these rare markers, called extracellular vesicles (EVs), for potential development of precision cancer diagnoses and personalized anticancer treatments.

Lipid nanoprobes

Most cells generate and secrete extracellular vesicles,” says Siyang Zheng, associate professor of biomedical engineering and electrical engineering. “But they are difficult for us to study. They are sub-micrometer particles, so we really need an electron microscope to see them. There are many technical challenges in the isolation of nanoscale EVs that we are trying to overcome for point-of-care cancer diagnostics.”

At one time, researchers believed that EVs were little more than garbage bags that were tossed out by cells. More recently, they have come to understand that these tiny fat-enclosed sacks — lipids — contain double-stranded DNA, RNA and proteins that are responsible for communicating between cells and can carry markers for their origin cells, including tumor cells. In the case of cancer, at least one function for EVs is to prepare distant tissue for metastasis.

The team’s initial challenge was to develop a method to isolate and purify EVs in blood samples that contain multiple other components. The use of liquid biopsy, or blood testing, for cancer diagnosis is a recent development that offers benefits over traditional biopsy, which requires removing a tumor or sticking a needle into a tumor to extract cancer cells. For lung cancer or brain cancers, such invasive techniques are difficult, expensive and can be painful.

Noninvasive techniques such as liquid biopsy are preferable for not only detection and discovery, but also for monitoring treatment,” explains Chandra Belani, professor of medicine and deputy director of the Cancer Institute,Penn State College of Medicine, and clinical collaborator on the study.

We invented a system of two micro/nano materials,” adds Zheng. “One is a labeling probe with two lipid tails that spontaneously insert into the lipid surface of the extracellular vesicle. At the other end of the probe we have a biotin molecule that will be recognized by an avidin molecule we have attached to a magnetic bead.”


Light Makes OscillatorTo Oscillate Indefinitely

Researchers have designed a device that uses light to manipulate its mechanical properties. The device, which was fabricated using a plasmomechanical metamaterial, operates through a unique mechanism that couples its optical and mechanical resonances, enabling it to oscillate indefinitely using energy absorbed from light.

metamaterialThis work demonstrates a metamaterial-based approach to develop an optically-driven mechanical oscillator. The device can potentially be used as a new frequency reference to accurately keep time in GPS, computers, wristwatches and other devices, researchers said. Other potential applications that could be derived from this metamaterial-based platform include high precision sensors and quantum transducers..

Researchers engineered the metamaterial-based device by integrating tiny light absorbing nanoantennas onto nanomechanical oscillators. The study was led by Ertugrul Cubukcu, a professor of nanoengineering and electrical engineering at the University of California San Diego. The work, which Cubukcu started as a faculty member at the University of Pennsylvania and is continuing at the Jacobs School of Engineering at UC San Diego, demonstrates how efficient light-matter interactions can be utilized for applications in novel nanoscale devices.

Metamaterials are artificial materials that are engineered to exhibit exotic properties not found in nature. For example, metamaterials can be designed to manipulate light, sound and heat waves in ways that can’t typically be done with conventional materials.

Metamaterials are generally considered “lossy” because their metal components absorb light very efficiently. “The lossy trait of metamaterials is considered a nuisance in photonics applications and telecommunications systems, where you have to transmit a lot of power. We’re presenting a unique metamaterials approach by taking advantage of this lossy feature,” Cubukcu said. The researchers also point out that because the plasmomechanical metamaterial can efficiently absorb light, it can function under a broad optical resonance. That means this metamaterial can potentially respond to a light source like an LED and won’t need a strong laser to provide the energy.

Using plasmonic metamaterials, we were able to design and fabricate a device that can utilize light to amplify or dampen microscopic mechanical motion more powerfully than other devices that demonstrate these effects. Even a non-laser light source could still work on this device,” said Hai Zhu, a former graduate student in Cubukcu’s lab and first author of the study.

Optical metamaterials enable the chip-level integration of functionalities such as light-focusing, spectral selectivity and polarization control that are usually performed by conventional optical components such as lenses, optical filters and polarizers. Our particular metamaterial-based approach can extend these effects across the electromagnetic spectrum,” adds Fei Yi, a postdoctoral researcher who worked in Cubukcu’s lab.

The research was published in the journal Nature Photonics.


Teeth: nanoparticles increase the efficiency of bacterial killing more than 5,000-fold

The bacteria that live in dental plaque and contribute to tooth decay often resist traditional antimicrobial treatment, as they can “hide within a sticky biofilm matrix, a glue-like polymer scaffold.

A new strategy conceived by University of Pennsylvania researchers took a more sophisticated approach. Instead of simply applying an antimicrobial to the teeth, they took advantage of the pH-sensitive and enzyme-like properties of iron-containing nanoparticles to catalyze the activity of hydrogen peroxide, a commonly used natural antiseptic. The activated hydrogen peroxide produced free radicals that were able to simultaneously degrade the biofilm matrix and kill the bacteria within, significantly reducing plaque and preventing the tooth decay, or cavities, in an animal model.

Beautiful woman smile. Dental health care clinic.Even using a very low concentration of hydrogen peroxide, the process was incredibly effective at disrupting the biofilm,” said Hyun (Michel) Koo, a professor in the Penn School of Dental Medicine’s Department of Orthodontics  and the senior author of the study, which was published in the journal Biomaterials. “Adding nanoparticles increased the efficiency of bacterial killing more than 5,000-fold.”



So Strong And Thousands Of Times Thinner Than A Sheet Of Paper

Scientists and engineers are engaged in a global race to make new materials that are as thin, light and strong as possible. These properties can be achieved by designing materials at the atomic level, but they are only useful if they can leave the carefully controlled conditions of a lab. Researchers at the University of Pennsylvania have now created the thinnest plates that can be picked up and manipulated by hand. Despite being thousands of times thinner than a sheet of paper and hundreds of times thinner than household cling wrap or aluminum foil, their corrugated plates of aluminum oxide spring back to their original shape after being bent and twisted.


The researchers’ plates are strong enough to be picked up by hand and retain their shape after being bent and squeezed
Like cling wrap, comparably thin materials immediately curl up on themselves and get stuck in deformed shapes if they are not stretched on a frame or backed by another material.

Being able to stay in shape without additional support would allow this material, and others designed on its principles, to be used in aviation and other structural applications where low weight is at a premium.


How To Prevent Tooth Decay

Therapeutic agents intended to reduce dental plaque and prevent tooth decay are often removed by saliva and the act of swallowing before they can take effect. But a team of researchers has developed a way to keep the drugs from being washed away.
Dental plaque is made up of bacteria enmeshed in a sticky matrix of polymers — a polymeric matrix — that is firmly attached to teeth. The researchers, led by Danielle Benoit at the University of Rochester and Hyun Koo at the University of Pennsylvania’s School of Dental Medicine, found a new way to deliver an antibacterial agent within the plaque, despite the presence of saliva.


We had two specific challenges,” said Benoit, an assistant professor of biomedical engineering. “We had to figure out how to deliver the anti-bacterial agent to the teeth and keep it there, and also how to release the agent into the targeted sites.

To deliver the agent—known as farnesol—to the targeted sites, the researchers created a spherical mass of particles, referred to as a nanoparticle carrier. They constructed the outer layer out of cationic — or positively charged—segments of the polymers. For inside the carrier, they secured the drug with hydrophobic and pH-responsive polymers.
The positively-charged outer layer of the carrier is able to stay in place at the surface of the teeth because the enamel is made up, in part, of HA (hydroxyapatite), which is negatively charged. Just as oppositely charged magnets are attracted to each other, the same is true of the nanoparticles and HA. Because teeth are coated with saliva, the researchers weren’t certain the nanoparticles would adhere. But not only did the particles stay in place, they were also able to bind with the polymeric matrix and stick to dental plaque.

Since the nanoparticles could bind both to saliva-coated teeth and within plaque, Benoit and colleagues used them to carry an anti-bacterial agent to the targeted sites. The researchers then needed to figure out how to effectively release the agent into the plaque. They find that the nanoparticles release the drug when exposed to cavity-causing eating habits.
The findings have been published in the journal ACS Nano.

Using Nanocarriers, Drugs Attack Acute Lung Injury

Pulmonary inflammation can cause shallow breathing and the lungs to become brittle in patients who experience multiple blood transfusions, sepsis, lung surgery and acute lung trauma. This complication can leave patients on ventilators, which can further traumatize the lungs, and often results in a mortality rate of 30 to 40 percent. To date, no medication has been successful at preventing or mitigating the damage caused by lung inflammation. Now, a multidisciplinary research team led by David Eckmann, MD, PhD, Horatio C. Wood Professor of Anesthesiology at the University of Pennsylvania and professor of Bioengineering in Penn’s School of Engineering and Applied Science, has found that when delivered by a microscopic transporter called a nanocarrier, steroids can access the hard-to-reach lung endothelial cells that need it most and are successful at preventing inflammation in mice. This proof-of-concept study is published in PLOS One.

Acute Lung Injury

This is a treatment that benefits entirely from targeted delivery or it tends not to have any significant therapeutic benefit,” says Eckmann. “That’s part of the challenge with this disorder: we have been uncertain to this point whether it was the medication or its delivery mechanism that wasn’t working. Our results in mouse models show beyond a shadow of a doubt that the drugs can be effective, we just needed to improve delivery,” says Eckmann. Acute lung injury develops as a result of direct or indirect trauma to the lungs. It compromises the hard-to-reach pores that enable gas exchange between the epithelial and endothelial barriers in the lungs.


Mimicking Onion To Deliver Drugs

One of the defining features of cells is their membranes. Each cell’s repository of DNA and protein-making machinery must be kept stable and secure from invaders and toxins. Scientists have attempted to replicate these properties, but, despite decades of research, even the most basic membrane structures, known as vesicles, still face many problems when made in the lab. They are difficult to make at consistent sizes and lack the stability of their biological counterparts. Now, University of Pennsylvania researchers, led by professor Virgil Percec, of the Department of Chemistry in Penn’s School of Arts & Sciences, have shown that a certain kind of dendrimer, a molecule that features tree-like branches, offers a simple way of creating vesicles and tailoring their diameter and thickness. Moreover, these dendrimer-based vesicles self-assemble with concentric layers of membranes, much like an onion.

By altering the concentration of the dendrimers suspended within, the researchers have shown that they can control the number of layers, and thus the diameter of the vesicle, when the solution is injected in water. Such a structure opens up possibilities of releasing drugs over longer periods of time, with a new dose in each layer, or even putting a cocktail of drugs in different layers so each is released in sequence.
The researchers created “onion” dendrimersomes, which have multiple concentric membranes, each made of two layers of dendrimers
The problem,” Percec said, “is that once you remove the proteins and the other elements of a real biological membrane, they are unstable and don’t last for a long time. It’s also hard to control their permeability and their polydispersity, which is how close together in size they are. The methodologies for producing them are also complicated and expensive.”
If you want to deliver a single drug over the course of 20 days,” Perce said, “you could think about putting one dose of the drug in each layer and have it released over time. Or you might put one drug in the first layer, another drug in the second and so on. Being able to control the diameter of the vesicles may also have clinical uses; target cells might only accept vesicles of a certain size.

The study was published in Proceedings of the National Academy of Sciences.

How to Produce Hydrogen From Water At Low Cost

Cheaper clean-energy technologies could be made possible thanks to a new discovery. Research team members led by Raymond Schaak, a professor of chemistry at Penn State, have found that an important chemical reaction that generates hydrogen from water is effectively triggered — or catalyzed — by a nanoparticle made of nickel and phosphorus, two inexpensive elements that are abundant on Earth. The results of the research will be published in the Journal of the American Chemical Society. Schaak explained that the purpose of this nanoparticle is to help produce hydrogen from water — a process that is important for many energy-production technologies including fuel cells and solar cells. “Water is an ideal fuel, because it is cheap and abundant, but we need to be able to extract hydrogen from it,” Schaak said. Hydrogen has a high energy density and is a great energy carrier, Schaak explained, but it requires energy to produce. To make its production practical, scientists have been hunting for a way to trigger the required chemical reactions with an inexpensive catalyst. Platinum works, but it is expensive and relatively rare, so Schaak and his team have been searching for alternative materials.

hydrogen-electric carThere were some predictions that nickel phosphide might be a good candidate, and we already had been working with nickel phosphide nanoparticles for several years,” Schaak said. “It turns out that nanoparticles of nickel phosphide are indeed active for producing hydrogen and are comparable to the best known alternatives to platinum.”


How to diagnose directly Lyme

Early diagnosis is critical in treating Lyme disease. However, nearly one quarter of Lyme disease patients are initially misdiagnosed because currently available serological tests have poor sensitivity and specificity during the early stages of infection. Misdiagnosed patients may go untreated and thus progress to late-stage Lyme disease, where they face longer and more invasive treatments, as well as persistent symptoms. A nanotechnology-inspired technique developed by researchers at the University of Pennsylvania may lead to diagnostics that can detect the organism itself.

lyme anibody
An illustration of a Lyme antibody attached to a carbon nanotube
Lyme disease is an infection transmitted by the bite of ticks carrying the spiral-shaped bacterium Borrelia burgdorferi. The disease was named for Lyme, Connecticut, the town where it was first diagnosed in 1975 after a puzzling outbreak of arthritis. The organism was named for its discoverer, Willy Burgdorfer. The effects of this disease can be long-term and disabling unless it is recognized and treated properly with antibiotics.


Protein Passport to Past Immune System

The body’s immune system exists to identify and destroy foreign objects, whether they are bacteria, viruses, flecks of dirt or splinters. Unfortunately, nanoparticles designed to deliver drugs, and implanted devices like pacemakers or artificial joints, are just as foreign and subject to the same response. Now, researchers at the University of Pennsylvania School of Engineering and Applied Science and Penn’s Institute for Translational Medicine and Therapeutics have figured out a way to provide a “passport” for such therapeutic devices, enabling them to get past the body’s security system.
protein passport

From your body’s perspective,” said the student Rodriguez, member of the research team led by professor Dennis Discher, “an arrowhead a thousand years ago and a pacemaker today are treated the same — as a foreign invader. “We’d really like things like pacemakers, sutures and drug-delivery vehicles to not cause an inflammatory response from the innate immune system.


Electronics without Current

Researchers at Tampere University of Technology, Finland, will explore paths toward a completely new way of designing and making logic circuits that consume no current and can be written and read with light. The key idea behind the project is the so-called quantum dot cellular automaton (QCA). In QCAs, pieces of semiconductor so small that single electronic charges can be measured and manipulated are arranged into domino like cells. Like dominos, these cells can be arranged so that the position of the charges in one cell affects the position of the charges in the next cell, which allows making logical circuits out of these “quantum dominos”. But, no charge flows from one cell to the next, i.e. no current. This, plus the extremely small size of QCAs, means that they could be used to make electronic circuits at densities and speeds not possible now. However, realisation of the dots and cells and making electrical connections to them has been a huge challenge.
Professors Donald Lupo from Department of Electronics, Mircea Guina and Tapio Niemi from Optoelectronics Research Centre (ORC), and Nikolai Tkachenko and Helge Lemmetyinen from Department of Chemistry and Bioengineering, want to investigate a completely new approach. They want to attach tailor-made molecules, optical nanoantennas, to the quantum dots, which can inject a charge into a dot or enable charge transfer between the dots when light of the right wavelength shines on them.
Laser light is emitted from the end of a cadmium sulfide nanowire.

Simultaneously, researchers at the University of Pennsylvania have made an important advance in this frontier of photonics, fashioning the first all-optical photonic switch out of cadmium sulfide nanowires. Moreover, they combined these photonic switches into a logic gate, a fundamental component of computer chips that process information. The research was conducted by associate professor Ritesh Agarwal and graduate student Brian Piccione of the Department of Materials Science and Engineering in Penn’s School of Engineering and Applied Science. Post-doctoral fellows Chang-Hee Cho and Lambert van Vugt, also of the Materials Science Department, contributed to the study.