Peptides offer fresh insights for cancer diagnosis and treatment

Genes and proteins play essential roles in the maintenance of health and the development of disease and are the focus of the fields of genomics and proteomics, respectively.

Genes, which are composed of 4 nucleic acids, provide the blueprint for constructing all living forms, while proteins, which are composed of some 20 amino acids, are the body’s tireless day laborers, building organs and tissues, forming a complex defense network of antibodies, transporting essential materials to far-flung destinations in the body and facilitating essential chemical reactions.BRCA1 is a human gene that produces tumor suppressor proteins, which repair damaged DNA and help maintain the stability of each cell’s genetic material. Mutations in this gene (and the related gene BRCA2), can disable this repair network, resulting in an increased risk of breast cancer. In the graphic, tumor-associated proteins resulting from mutations in BRCA1 are degraded into smaller fragments or peptides, which circulate in the bloodstream. These circulating peptides are then enriched using specialized nanoporous silica thin films or NanoTraps, then profiled using mass spectrometry to identify among four clinical groups. Such research may help clinicians determine which carriers of BRCA1 mutations are most likely to progress to breast cancer.Download Full Image

Less well known are the peptides, though they too are central players in life processes and can shed new light on a variety of diseases. Indeed, the rapidly expanding field of peptide research or peptidomics is poised to deliver fresh biological insights and new methods for the detection and treatment of a broad range of disorders, particularly cancer.

A new book, “The Enzymes: Peptidomics of Cancer-Derived Enzyme Products,” explores the peptidome in keen detail. The particular focus of the book is how peptides, small segments of linked amino acids, can provide researchers and clinicians with vital clues about cancer prognosis currently unavailable through conventional diagnostic methods.

Tony Hu, a researcher in Arizona State University’s Virginia G. Piper Biodesign Center for Personalized Diagnostics, co-edited the new book.

“Back in 2016, I was invited to UCLA to give a seminar. I talked with a professor there — Fuyuhiko Tamanoi — who served for many years as the editor for the book series ‘Enzyme,’” Hu said. “After he heard a bit about emerging peptide research, he decided it would make a fine topic for a new book, so we invited experts worldwide, from Europe, from China, Japan and the U.S. to explore different aspects of the peptidome.”

As Hu explained, the book is divided into three major areas. The first deals with the discovery of biomarkers — peptide signals present in blood or saliva that can be used for diagnostic purposes. The second part deals with peptide biofunction, which turns out to play a critical role in cancer. The third section is devoted to clinical application and regulation of peptide biomarkers. The book therefore spans research on the peptidome reaching from the laboratory bench to the patient bedside, making it the most comprehensive handbook of leading edge peptidomics to date.

Probing the peptidome

Peptides, like proteins, are composed of amino acids. They are generally far smaller molecules, typically composed of just 50 amino acids or less. They are often produced through the breakdown of larger, more complex proteins. This process of protein degradation is a common feature in cancer progression, invasion and metastasis. In the course of these processes, peptide byproducts of the tumor microenvironment circulate in the bloodstream, providing a potentially rich source of biomarkers for disease.

Although there are myriad cancer-specific proteins secreted by active tumors, which could potentially serve as biomarkers, the challenges of monitoring such proteins — particularly in a clinical environment — are often formidable due to fluctuations in their location and abundance. Hu believes that tumor-secreted peptides, which circulate in the blood, can provide an alternate window into underlying activity, providing more fine-grained diagnoses of a given cancer than can be gleaned from either the genes or proteins alone.

ASU researcher Tony Hu’s new book, “The Enzymes: Peptidomics of Cancer-Derived Enzyme Products,” focuses on the role of peptides in cancer detection and therapy. Photo by Deanna Dent/ASU Now

 A new field is born

“About 15 years ago, people started looking at peptides,” Hu said.

Peptides are a rich source of information about the proteins they are derived from and also can shed light on the body’s enzymatic network. As Hu explained, enzymatic activity is often a crucial component in cancer progression, but getting a precise handle on tumor-related enzyme activity has, until recently, proved challenging.

“We published a paper in Clinical Chemistry back in 2014,” Hu said. “There’s an enzyme that is pretty active at the local tumor site in breast cancer. When we profile this enzyme on the tumor tissue, it’s showing this dramatically increased expression compared to normal.”

The enzyme, however, dissolves in the blood and is undetectable. Testing such cancer patients shows blood enzyme levels close to normal.

This presents clinicians with two options: 1) Use a very invasive method to biopsy the tumor tissue in order to profile the enzyme directly, or 2) look at the peptide product produced by the enzyme, which can be profiled directly from the blood. When Hu and colleagues used this approach, they found a variation in peptide expression that precisely matched the enzyme activity at the tumor site. The results encouraged Hu that peptides indeed have much to tell us about underlying disease.

In other cases, the peptide itself is malfunctioning, which may be correlated with tumor progression. Further, peptides can provide vital clues concerning a tumor’s surrounding microenvironment, for example signaling a condition of low oxygen or hypoxia, an important precursor of cancer metastasis and an area of research Hu is currently involved in.

Another critical peptide under study is Hepcidin, a 25-amino acid peptide synthesized in the liver, which serves as the principle regulator of iron metabolism in vertebrates. It can also be used as a telltale indicator of elevated iron status, inflammation and infection associated with diseases including cancer and HIV.

In order to profile peptides from blood samples, mass spectroscopy is used, a technique allowing peptides to be accurately identified based on their molecular weights. Once an exotic technology confined to sophisticated laboratories, cutting-edge mass spec technology is now common in hospital settings around the world, further enabling peptide biomarker discovery to advance and enter routine clinical use.

Finding new avenues

As the authors note, specialized enzymes involved in protein degradation — known as proteases — are involved in all phases of cancer progression including early growth, angiogenesis, inflammation, survival and invasion. Their peptide byproducts offer insights into all of these processes. Evaluation of inflammation through peptide analysis could also be used as a rapid and direct indicator of drug toxicity in chemotherapy, a process that currently must rely on patient symptomatology.

Finally, advances in biotechnology have allowed a new class of safe and efficacious peptide drugs to be developed, furthering the aims of personalized medicine. Immunotherapy, in which the patients’ own immune system is used to attack cancer cells, is just one area where peptides are being applied therapeutically. The immune system responds to a cancer-linked peptide by mounting a robust defense — a technique currently being explored in the fight against prostate cancer.

“For these reasons, we believe peptides have been undervalued for a long time in cancer studies,” Hu said.

Accurate, early diagnostic and prognostic markers are still lacking for most cancers, posing the most significant challenge for successful diagnosis and treatment. Vital information, unavailable through proteomic study, is now becoming accessible through sensitive detection of circulating peptides. The new book throws light on an exciting and hopeful domain of research.

[“Source-asunow”]

Google Flights Expands ‘Tips’ to Offer Cheaper Hotel Bookings, Google Trips Now Shows Discounts

Google Flights Expands 'Tips' to Offer Cheaper Hotel Bookings, Google Trips Now Shows Discounts

HIGHLIGHTS

  • Tips on Google Flights will now suggest cost-effective hotel bookings
  • Google Flights was previously providing tips on flight bookings
  • Google Trips app offers access to deals through ‘Discounts’ feature

Making the experience better during this travel season, Google Flights has received a new update that expands the coverage of its Tips with enhanced machine learning efforts to make hotel bookings cost-effective. Google Trips, on the other hand, now comes with a Discounts feature.

Back in August, Google Flights was upgraded with Tips feature, which offered recommendations to save air travel costs. The feature was originally limited to flight bookings. But now, Google has used machine learning to provide you with tips even when you pick a hotel for your stay. You will receive tips above the results of your hotel bookings when room rates are higher than usual, or if the area is busier than usual due to a holiday or in case of any occupational instance such as a music concert or a business conference. All this will eventually help you avoid the busy dates and get the hotels at an affordable charge.

In addition to tips about the change in prices, you can opt for Hotel Price Tracking on your smartphone to get email price alerts about price drops on your choices of hotels. This new feature will also be available on the desktop version of Google Flights site in 2018.

Alongside the updated Google Flights, Google has brought a new version of the Google Trips app with the Discount feature. The new addition will give you instant access to deals on tickets and tours related to top attractions and activities. “Book and save on a tour of the Mayan ruins near Cancun, or get priority access to the top of the Eiffel Tower in Paris. No matter where you’re headed (and if you need ideas, read on), Trips makes it easy to browse and access fun stuff to do on your vacation without breaking the bank,” Google VP of Travel Products Richard Holden said in a blog post.

Deals through the Discount feature on Google Trips will surface for various top attractions, activities, and tours around your location in the coming days.

[“Source-gadgets.ndtv”]

Documents Offer Insight Into Soviet View Of JFK Assassination

Image result for Documents Offer Insight Into Soviet View Of JFK Assassination

American Lee Harvey Oswald and his Russian wife, Marina, pose on a bridge walk in Minsk during their stay in the Soviet Union. This is a 1964 handout photo from the Warren Commission.

AP

Was the Soviet Union involved in the 1963 assassination of President Kennedy?

Given Cold War tensions and the fact that shooter Lee Harvey Oswald had defected to the Soviet Union and lived there in the years leading up to the assassination, it’s a question that has long intrigued even the mildly conspiracy-minded.

Some 2,800 documents released by order of President Trump on Thursday provide some possible insights into how the assassination was viewed inside the Soviet Union.

That reaction appears to have been one of genuine surprise, as well as concern inside the Communist Party that the killing of Kennedy might be part of a larger right-wing coup to take over the U.S. government.

In a memo labeled “Top Secret” and dated Dec. 1, 1966 from FBI Director J. Edgar Hoover to Marvin Watson, a special assistant to President Lyndon Johnson, cites “[a] source who has furnished reliable information in the past and who was in Russia on the date of the assassination …”

The news, it says “was greeted by great shock and consternation and church bells were tolled in the memory of President Kennedy.”

The memo continues: “According to our source, officials of the Communist Party of the Soviet Union believed there was some well-organized conspiracy on the part of the “ultraright” in the United States to effect a ‘coup.’ They seemed convinced that the assassination was not the deed of one man but that it arose out of a carefully planned campaign in which several people played a part.”

The Soviets were fearful that the assassination would be used to play on “anticommunist sentiments” in the U.S. to “stop negotiations with the Soviet Union, attack Cuba and thereafter spread war.”

Oswald, a former U.S. Marine, went to the Soviet Union in 1959 and married there. Apparently disenchanted with Soviet life, he returned to U.S. soil less than two years later after apparently trying to commit suicide.

The FBI memo, citing the unnamed source, says “Soviet officials claimed that Lee Harvey Oswald had no connection whatsoever with the Soviet Union. They described him as a neurotic maniac who was disloyal to his own country and everything else.”

The same single source reported that the KGB, the Soviet intelligence agency, “issued instructions to all of its agents to immediately obtain all data available concerning” President Johnson. The memo said that in the months after Kennedy’s death, the KGB had come into “possession of data purporting to indicate that President Johnson was responsible for the assassination of the late President John F. Kennedy.”

In a different memo, this one from the CIA Director of Security to CIA Headquarters, originally classified “Secret” and dated March 11, 1964, refers to a George M. Lesnik, a former KGB agent who was in Moscow on the day of the Kennedy assassination.

After hearing the news, he “dashed to his office” to look at Oswald’s file. “When he found the file he reviewed it and found that Oswald had not been used or even approached for use by the Russian intelligence.” Lesnik claimed that he then called others in the KGB who said they were unaware that Oswald had been cultivated in any way before returning to the United States.

[“Source-npr”]

Neighbors, ‘relative’ offer insights about Joseph Jakubowski

JANESVILLE—Neighbors said Joseph Jakubowski was quiet and polite and kept to himself in the few years they knew him.

Another woman, who characterized herself as a “relative” of Jakubowski’s, on Monday said Jakubowski had fallen on hard times in the past few months after he’d apparently lost his job at a local retail store and was unable to find other work or assistance.

Police believe Jakubowski mailed an anti-government manifesto to the president April 4, burglarized a rural Janesville gun shop and then vanished. Investigators continued an intensive local and national manhunt Monday.

Monday afternoon, a woman who pulled a car into Jakubowski’s last known residence at 811 Glen St. told The Gazette she would speak only on condition of anonymity because of safety concerns. She would only identify herself as a “relative” of Jakubowski’s.

The woman painted a picture of Jakubowski as a man who’d been struggling to find equilibrium after she said he’d lost his job at a local Best Buy store then hurt his back doing a pick-up job roofing houses.

“He lost his job, and he couldn’t find another job,” the woman said. “Couldn’t find work. Couldn’t get any help. Couldn’t get food stamps. Couldn’t get nothing. Hurt his back. What do you do?”

Despite those troubles, the woman said, Jakubowski had a history—even recently—of trying to help other people.

The woman said Jakubowski recently had helped mow people’s lawns, and he’d tackle handyman work and repair other people’s cars.

“He helped a gentleman that was taking organs from one hospital to the other that couldn’t get to his job because his car wouldn’t start. He changed the starter so that he could get to work that night,” the woman said.

The woman said she wasn’t sure what would have prompted Jakubowski to mail a 161-page manifesto to President Trump, then burglarize a gun shop, steal more than a dozen high-end guns, and then set his car on fire and disappear, as police believe. But she said it’s not the Joseph Jakubowski she knows.

“I don’t know what happened, or why he snapped. But Joe’s a good person down deep in his heart. Nobody’s printing anything good about him,” the woman said.

The woman said the last time she’d communicated with Jakubowski was at the end of March, when he indicated he planned to move out of the home on Glen Street.

“Joe was making a life for himself. He was making a good life. He just hit a really bad, hard run,” she said.

The woman said two other families live at 811 Glen St. She said one of the families recently moved in, and they don’t know Jakubowski. The woman would not disclose how she knew that information.

The Gazette on Monday knocked on the door to the upper level of the home where Jakubowski apparently lived for about two years, according to police and court records. No one answered.

Jakubowski is a longtime Janesville resident. A 1999 Janesville Parker High School yearbook in Gazette archives shows Jakubowski’s photo, and it has an image of him in uniform as a member of the high school concert band. Jakubowski was a freshman at Parker at the time.

Crystal Duran told The Gazette earlier she knew Jakubowski while growing up near Mercy Hospital and at Parker High School, where she saw him bullied.

“When we were younger, everybody was always picking on him all the time,” she said. “Kids beat him up at school.”

Duran said she never saw him do anything to prompt the bullying.

Jakubowski is well known to local police after minor scrapes with the law, mostly through his many traffic citations.

But in 2008, Jakubowski repeatedly pulled on an officer’s holstered sidearm during a fight with the officer in Janesville, according to a criminal complaint. Three officers eventually subdued him. He was charged with trying to disarm an officer and was sentenced to probation.

Police weren’t releasing much background information about the life of Jakubowski, and beyond characterizing his manifesto as broadly anti-government, police haven’t given much information about insights they’ve developed on Jakubowski’s mental state.

Sheriff Robert Spoden on Monday said the sheriff’s office was still interviewing people Jakubowski knows to gain insights into the man who police consider an armed and dangerous fugitive. He said investigators are working with FBI personality profile experts to try to piece together a clearer picture of Jakubowski’s personality and his mental state in the days leading up to him vanishing.

Spoden said he couldn’t highlight investigators’ findings because he didn’t want to compromise an ongoing investigation.

Jakubowski has been “highly agitated by national politics recently,” according to associates investigators have spoken to, Spoden said earlier.

“When you look at the (manifesto), it is a laundry list of injustices he believes government and society and the upper class have put … onto the rest of the citizens,” Spoden said.

Carol Austin, a landlord at the Glen Street house next door to Jakubowski, and Phil Scriven, one of Austin’s tenants, were outside doing yard work Monday. Both told The Gazette that in the two years Jakubowski lived next door, they’d had limited contact with the man, but they both characterized Jakubowski as “quiet” and “polite.”

Jakubowski once came by to borrow some oil and a set of wrenches from Scriven. Scriven said Jakubowski returned the tools promptly and thanked Scriven.

Scriven said he doesn’t know much about Jakubowski, who he said “stayed to himself and minded his own business.”

Scriven said he knew Jakubowski liked to drink soda—Mountain Dew, especially.

Scriven said it’s been a tense set of days for neighbors who’ve seen SWAT teams set up outside residences on Glen Street a few times.

“To see cops walking around carrying rifles in the neighborhood, all that commotion, it’s been unnerving to say the least, Scriven said. “We’ve had onlookers, sometimes 60 to 70 of them pulling up and down the street when police are here.

“It’s just been unsettling.”

[“Source-gazettextra”]