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A recent finding by scientists from the Hospital for Sick Children, Toronto, and Duke University challenges long-held ideas about why our bones have a harder time healing as we age. Their research discovered that old mouse bones mend like youthful bones do when they’re exposed to young blood after a fracture.

 

“The traditional concept is that as you get older, your bone cells kind of wear out so they can’t heal as well, and we thought we’d find that during this study as well,” explains study co-author Benjamin Alman, of the Hospital for Sick Children. “But it turns out that it’s not the bone cells, it’s the blood cells. As you get older, the blood cells change the way they behave when you have an injury, and as a result the cells that heal bone aren’t able to work as efficiently.”

 

The researchers paired lab mice, one old and one young, and subjected them to bone fractures, but that wasn’t all they had in common. The living animals’ circulatory systems were also joined together by a 150-year-old surgical technique known as parabiosis. Scientists removed a layer of skin from each mouse and stitched the exposed surfaces together. As the animals healed their capillaries joined, enabling their two hearts to pump the same blood throughout the two bodies as a single system. Parabiosis, which has been gaining new popularity in aging research, allowed Alman and colleagues to see what impacts the circulating factors of the younger mouse’s blood had when introduced into the body of an older mouse.

 

The experiment, published this week in Nature Communications, suggests that young blood cells secrete some as-yet-unknown molecule, likely a protein or possibly some other chemical, that speeds up the healing of fractured bone. The molecule apparently does so by regulating levels of beta-catenin in bone cells known as osteoblasts. Keeping beta-catenin at the proper levels appears crucial for the formation of new high-density bone.

 

This ability is greatly diminished in older animals’ blood because it no longer secretes the molecule, whose exact chemical nature remains a mystery at this point. “My guess is that there are a number of proteins involved that are made differently as we get older, and that they are responsible for the difficulty in healing bone,” Alman says.

 

The findings could prove good news for aging humans, but healing our bones won’t require the type of transfusions used in the experiment—nor will it borrow the synthesized “True Blood” variety that may soon enter clinical trials. Sharing human blood in this manner raises a number of red flags ranging from practicality to possible medical complications.

Source: www.smithsonianmag.com

See on Scoop.itCardiovascular and vascular imaging


Abbott’s percutaneous MitraClip mitral valve repair device SUPERIOR to Pacemaker or Implantable Cardioverter Defibrillator (ICD) for reduction of Ventricular Tachyarrhythmia (VT) episodes

Reporter: Aviva Lev-Ari, PhD, RN

Abbott’s MitraClip can cut arrhythmias in half, according to data from Heart Rhythm conference

The researchers studied 50 patients before and after implantation of the MitraClip over 20 months. There were 68 sustained VT episodes in the patient prior to implantation, and 30 after. The number of long-lasting episodes (those with a cycle length of more than 300 milliseconds) recorded was 46 prior to implantation and 21 episodes following use of the MitraClip.

The number of non-significant VT episodes fell from 56 to 49 after implantation, a statistically insignificant difference.

“We can show that the MitraClip therapy results in a significant reduction in ventricular arrhythmia burden, especially in ICD patients,” said Dr. Cathrin Theis during the May 14 presentation, according to MassDevice.

Studies demonstrating efficacy of the MitraClip are crucial because the device got FDA’s approval in 2013 despite the results from its pivotal trial, which found that MitraClip posted almost no clinical benefits over traditional valve surgery after four years.

On top of this study comparing the device to ICDs, experts at the annual meeting of the American College of Cardiology said post market registry data collected on the MitraClip shows that the device is safe and effective, for the primary clinical benefit of a reduction in mitral regurgitation was achieved in 63.7% of patients.

The MitraClip is meant to treat mitral regurgitation, which is associated with ventricular tachyarrhythmia. Mitral regurgitation involves a leaky heart valve that lets blood flow backward and can cause irregular heartbeats, stroke or heart failure. MitraClip is delivered via catheter through the femoral vein in the leg, and it clips together parts of the mitral valve. The solution is meant to be less invasive than regular surgery.

“The market opportunity for mitral regurgitation is significant but still in its early stages, and MitraClip is the only product on the market to-date that can treat this disease in a minimally invasive way,” said Abbott CEO Miles White during its most recent earnings call.

He said sales of the device increased at a double-digit rate in both the U.S. and abroad.

– read the study
– here’s MassDevice‘s take

Related Articles:
Registry data shows Abbott’s MitraClip transcatheter valve is performing well in real-world settings
Abbott wins Medicare coverage, new tech add-on payments for MitraClip cardiology device
Abbott’s MitraClip heart valve device gains FDA’s long-awaited blessing
Four year results: Abbott’s MitraClip no better than surgery

SOURCE

http://www.fiercemedicaldevices.com/story/data-presented-cardiology-conference-show-abbotts-mitraclip-can-cut-arrhyth/2015-05-15?utm_campaign=AddThis&utm_medium=AddThis&utm_source=mailto#.VVsoG2yN4ik.mailto


Deadline of Friday, May 29, 2015 for Nomination for The US Leader in Precision Medicine Implementation across the Country

Reporter: Aviva Lev-Ar, PhD, RN

Nominate a White House Champion of Change for Precision Medicine

On January 30, 2015, President Obama launched the Precision Medicine Initiative: a bold new research effort that aims to revolutionize the way we treat disease and improve health. While most medicine is designed with the “average patient” in mind, the President’s Precision Medicine Initiative aims to take into account individual differences in people’s genes, environments, and lifestyles to improve patient’s health. By empowering patients, researchers, and providers to work together in developing individualized treatments, the Initiative could lead to powerful new discoveries and treatments for diseases such as cancer, diabetes, and many more.

In fact, there are many patients, researchers, companies, entrepreneurs, and health care providers across the country who are leading the way, generating and using data to make progress on our most pressing medical challenges. For example, at the age of 12, Elana Simon was diagnosed with a rare type of pediatric cancer that affected her liver. Determined to learn more about the disease, as a high school student, Elana set out to work with other patients and researchers to study the characteristics of this specific type of liver cancer. By working with a precise patient group instead of a more general population of all patients with liver cancer, Elana and her team identified the specific change in DNA that leads to the development of her cancer and are now developing the first diagnostic tests and clinical trials for the disease. Elana, whose cancer is now in remission, is just wrapping up her freshman year at Harvard University.

This is exactly the kind of data-driven approach in which the President’s Precision Medicine Initiative aims to invest. Just as we identify and match blood types for transfusions, and customize prescriptions for glasses and contacts to the individual, this initiative aims to usher in an era in which we are able to improve health and treat diseases like cystic fibrosis, heart disease, and cancer based upon the characteristics of individual patients.

As Elana’s story also makes clear, there is already incredible work being done in this groundbreaking area of medicine. That’s why we’re calling on you to help us identify and honor individuals or organizations that are leading the way in health research and discovery by nominating a Champion of Change for Precision Medicine by midnight on Friday, May 29.Nominees may include:

  • Researchers who are using a data-driven approach to improve treatments or uncover new insights to improve health.
  • Leaders who are empowering people to work together to share their data or build research cohorts to better understand their diseases.
  • Individuals who are developing innovative tools and techniques to harness and analyze health data.
  • Advocates who are working to ensure that patient data are handled in a way that ensures privacy and security.
  • Patients who have benefitted from a precision medicine approach to treatment and care and who are working to ensure that other Americans can benefit from this approach.

Click here to submit your nomination (be sure to choose Precision Medicine in the “Theme of Service” field of the nomination form).

We look forward to sharing the outstanding work that individuals and organizations across the country are doing to advance our understanding of health and disease.

Stephanie Devaney is the Project Manager for the Precision Medicine Initiative at the White House.

SOURCE

https://www.whitehouse.gov/blog/2015/05/18/nominate-white-house-champion-change-precision-medicine


Innovation in Cancer Biopharmaceutical Intelligence [4.7]

Writer and Curator: Larry H. Bernstein, MD, FCAP , Writer and Curator

http://pharmaceuticalintelligence.com/2015/05/19/larryhbern/Innovation_in_Cancer_Biopharmaceutical_Intelligence

Innovation in Cancer Biopharmaceutical Intelligence

The content of this article, with several interesting features is as follows:

4.7.1 Carmen Drahl..A Great Organic Chemist and Science Writer

4.7.2 Anthony Melvin Crasto

4.7.3 Amgen files ‘breakthrough’ leukemia drug in the US

(from Crasto’s site)

4.7.4 Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

(from Crasto selections)

4.7.5 The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy

(from Crasto – Natural Products)

4.7.6 A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis

(from Crasto_Organic synthesis)

4.7.7 Pauline Lau. Biochemist, Instrumental Analysis, Molecular and Clinical Diagnostics, and Pharmaceuticals

(a personal communication)

4.7.8  Kinetic and perfusion modeling of hyperpolarized 13C pyruvate and urea in cancer with arbitrary RF flip angles

(from Rad Bozov)

4.7.9 ZSTK 474

(Dr Anthony  Melvin Crasto)

4.7.1 Carmen Drahl. A Great Organic Chemist and Science Writer

Her eyes fit a stellar career path. She is a talent in organic and medicinal chemistry, and an informed reporter.

Extract from Dr. Anthony Melvin Castro,  Organic Chemistry

Carmen Drahl

Carmen Drahl

CARMEN DRAHL

Award-winning science communicator and social media power user based in Washington, DC.

Carmen Drahl is a multimedia science journalist and chemistry communicator based in Washington, DC.

ScienceAlum

ScienceAlum

A social media evangelist, Carmen started her first chemistry blog in 2006. Today, she regularly leverages Twitter, Facebook, and Google Plus Hangouts in her reporting.

Carmen has written about how life may have originated on Earth, explained how new medications get their names, and covered the ongoing issues plaguing the forensic science community. Her video on the food science behind 3D printed cocktail garnishes won the 2014 Folio Eddie Award for Best Association Video.

Until December 2014, Carmen worked at Chemical & Engineering News magazine. Her work has also been featured at Scientific American’s blog network, SiriusXM’s Doctor Radio, and elsewhere.

Carmen holds a Ph.D. in chemistry from Princeton University.

Ph.D. with Erik J. Sorensen.  She was on a team that completed the first total synthesis of abyssomicin C, a molecule found in small quantities in nature that showed hints of promise as a potential antibiotic. I constructed molecular probes from abyssomicin for proteomics studies of its biological activity.

M.A. with George L. McLendon worked toward developing a drug conjugate as a potential treatment for cancer. I synthesized a photosensitizer dye-peptide conjugate for targeting the cell death pathway called apoptosis.

Jacobus Fellowship Recipients - Carmen Drahl - Princeton

Jacobus Fellowship Recipients – Carmen Drahl – Princeton

Jacobus Fellowship Recipients – Carmen Drahl – Princeton

At a reception before the Alumni Day luncheon, President Tilghman (third from left) congratulated the winners of the University’s highest awards for students: (from left) Pyne Prize winners Lester Mackey and Alisha Holland; and Jacobus Fellowship recipients Sarah Pourciau, Egemen Kolemen and Carmen Drahl.

Specialties:

interviewing, science writing, social media, Twitter, Storify, YouTube, public speaking, hosting, video production, iPhone videography, non-linear video editing, blogging (WordPress and Blogger), HTML website coding

Carmen Drahl

By the time I discovered science blogs I knew my career goals were changing. I’d already been lucky enough to audit a science writing course at Princeton taught by Mike Lemonick from TIME, and thought that maybe science writing was a good choice for me. After reading chemistry blogs for a while I realized “Hey, I can do this!” and started my own blog, She Blinded Me with Science, in July 2006. It was the typical grad student blog, a mix of posts about papers I liked and life in the lab.

Carmen Drahl pic1

Carmen Drahl

At C&E News I’ve contributed to its C&ENtral Science blog, which premiered in spring 2008. I’ve experimented with a few different kinds of posts- observations and on-the-street interviews when

I run into something chemistry-related in DC, in-depth posts from meetings, and video demos of iPod apps. One of my favorite things to do is toy with new audio/video/etc technology for the blog.

Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial

Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.

Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown)

GSK2636771B-300x224

GSK2636771B-300×224

4.7.2 Anthony Melvin Crasto

Principal Scientist, Process research

Glenmark Generics Ltd.

Anthony Melvin Crasto Ph.D

Worlddrugtracker, Principal scientist, Process research, Glenmark-Generics Ltd & Founder of Several Linkedin Gps

IndiaPharmaceuticals
Glenmark Generics Ltd., Glenmark Pharmaceuticals

Previous
Glenmark Pharmaceuticals, Innovassynth, RPG Life Sciences

Education
Institute of Chemical Technology (UDCT)

December 2005 – Present (9 years 6 months) Mahape, Navimumbai, India,
email  amcrasto@gmail.com

Currently working with GLENMARK GENERICS LTD research centre as Principal Scientist, process research (bulk actives) at Mahape ,Navi Mumbai,and leading a team of scientists in developing APIs for regulated markets, this involves visualization and execution of novel routes, polymorphs, and developing intellectual property to protect the invention. This involves all aspects of synthesis in lab and commercialization on plant , support for DMF filing.

Currently involved in development of several targets for regulated markets. Provide support to US/European marketing team for developing and execution of new projects

Process Development :-

  • Providing guidance and support for process development for challenging of patents in regulated market.
  • Design patent non-infringing scalable synthetic routes/process and scale-up of API’s
  • Bench and Pilot scale synthesis transformations in hands on
  • Optimization of the process, ie,developing industrially feasible process.
  • Preparation of PDR, filing of patent and DMF
  • Lead a group of Scientists and Group Leaders(for docs).

Skill sets:- Technical skills:

Synthesis:

  • Development of novel synthetic routes/process for pharmaceuticals and successful implementation of the technology in pilot plant
  • Conducted various reactions at laboratory and production scales.
  • Synthesized various classes of compounds.
  • Experienced to work under cGMP condition

EX Hoechst Marion Roussel(SANOFI AVENTIS), RPG Life Sciences,Innovassynth, SEARLE,AGREVO,IOC

Glenmark Generics Ltd.

Research Activities Covered in Entire Career

1) Extensive range of chemistry and scale of manufacture from laboratory, scale up laboratory, pilot plant, plant scale including third party activity.

Applied intellectual and synthetic skills to the process development of pharmaceutical drugs/their intermediates, and natural products, neutraceuticals, mettalocenes, speciality chemicals, flavours and fragrances in the laboratory and monitor them during plant trials.

Act as a technology transfer man and provide all data required for transfer from lab to commercialization.

Use of Internet and manual literature search methods to decide on non-infringing route

Write DHR for API before implementation of novel route in the plant and assist for all batches for the DMF purposes, very well versed with IPR issues

Ability to develop novel routes for API,s and draft patents,well versed with polymorphism issues.

Several patents filed in US/EU

Total experience 23+ in industry.

Currently working as principal scientist and leading a team of scientists in developing APIs for regulated markets, this involves novel routes, polymorphs, and developing intellectual property to protect the invention. This involves all aspects of synthesis and commercialization and assist in providing support for DMF filing.

4.7.3 Amgen files ‘breakthrough’ leukemia drug in the US

Daily News | Sept 22, 2014

Selina Mckee

Biotechnology giant Amgen has filed its investigational cancer immunotherapy blinatumomab in the US for the treatment of certain forms of acute lymphoblastic leukaemia (ALL).

Specifically, the Biologic License Application seeks approval to market the drug for patients with Philadelphia-negative (Ph-) relapsed/refractory B-precursor forms of the aggressive blood/bone marrow cancer.

Blinatumomab is the first of Amgen’s BiTE antibody constructs, a novel immunotherapy approach under which antibodies are modified to engage two different targets simultaneously. The drug has already been awarded both ‘Orphan’ and ‘Breakthrough’ status by the Food and Drug Administration, indicating that it could offer a significant advance over available therapies on at least one clinically significant endpoint.

The submission includes data from a Phase II which successfully met its primary endpoint, showing a complete response (no leukaemia cells detectable with microscopy) rate of 43% in patients with relapsed/refractory ALL, including those with resistance to previous treatment approaches.

“Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL,” noted Anthony Stein, clinical professor, Haematology/Oncology at City of Hope, adding that “blinatumomab has the potential to significantly advance treatment options for patients living with this difficult-to-treat disease”.

In the US, it is estimated that more than 6,000 cases of ALL will be diagnosed in 2014. In adult patients with relapsed or refractory ALL, median overall survival is just three to five months, further highlighting the urgent need for new treatment options.

Read more at: http://www.pharmatimes.com/Article/14-09-22/Amgen_files_breakthrough_leukaemia_drug_in_the_US.aspx#ixzz3aL5d1ZnJ

Follow us: @PharmaTimes on Twitter

4.7.4 Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

By Ralph Turchiano on Aug 5, 2014 •

High doses of the herb American ginseng (Panax quinquefolius) over two months reduced cancer-related fatigue in patients more effectively than a placebo, a Mayo Clinic-led study found. Sixty percent of patients studied had breast cancer. The findings are being presented at the American Society of Clinical Oncology’s annual meeting.

Researchers studied 340 patients who had completed cancer treatment or were being treated for cancer at one of 40 community medical centers. Each day, participants received a placebo or 2,000 milligrams of ginseng administered in capsules containing pure, ground American ginseng root.

“Off-the-shelf ginseng is sometimes processed using ethanol, which can give it estrogen-like properties that may be harmful to breast cancer patients,” says researcher Debra Barton, Ph.D., of the Mayo Clinic Cancer Center.

At four weeks, the pure ginseng provided only a slight improvement in fatigue symptoms. However, at eight weeks, ginseng offered cancer patients significant improvement in general exhaustion — feelings of being “pooped,” “worn out,” “fatigued,” “sluggish,” “run-down,” or “tired” — compared to the placebo group.

4.7.5 The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy

Royal Jelly - queen larvae

Royal Jelly – queen larvae

Royal Jelly – queen larvae

Royal jelly is a honey bee secretion that is used in the nutrition of larvae, as well as adult queens.[1] It is secreted from the glands in the hypopharynx of worker bees, and fed to all larvae in the colony, regardless of sex or caste.[2]

When worker bees decide to make a new queen, because the old one is either weakening or dead, they choose several small larvae and feed them with copious amounts of royal jelly in specially constructed queen cells. This type of feeding triggers the development of queen morphology, including the fully developed ovaries needed to lay eggs.[3]

Other Common Names:  Apilak, Gelée Royale, Queen Bee Jelly

Royal Jelly has been called the “Crown Jewel” of the beehive that has become extremely popular since the 1950s as a wonderful source of energy and natural way to increase stamina; perhaps that is the reason why the Queen Bee is so strong and enduring.  It is also thought to be a great nutritional source of enzymes, proteins, sugars and amino acids, but there is no scientific proof to verify the supplement’s efficacy for its use as an overall health tonic.

Royal Jelly is a thick, milky material that is secreted from the hypopharyngea- salivary glands in the heads of the young nurse bees between the sixth and twelfth days of life, and when honey and pollen are combined and refined within the nurse bee, Royal Jelly is naturally created.  While all larvæ in a colony are fed Royal Jelly, it is the only food that is fed to the Queen Bee throughout her life; other adult bees do not consume it at all.  All female eggs may produce a Queen Bee, but this occurs only when – during the whole development of the larvæ – she is cared for and fed by this material – in large quantities.

As a result of this special nutrition, the Queen develops reproductive organs (while the worker bee develops traits that relate only to work, i.e., stronger mandibles, brood food, wax glands and pollen baskets).  The Queen develops in about fifteen days, while the workers require twenty-one; and finally, the Queen endures for several years, while workers survive only a few months. “10-2 HDA,” thought to be the principle active substance in Royal Jelly, makes the Queen Bee fifty percent larger than the other female worker bees and gives her incredible stamina, ovulation ability and longevity, living four to five years longer than worker bees who only live forty or more days.  Perhaps this is the reason why so many positive qualities have been attributed to Royal Jelly as a truly rare gift of nature, but it should be noted that there is no clinical evidence to support the claims.

There is even great controversy as to the constituents included in the supplement.  Most researchers claim that it includes all the B-vitamins and vitamins A, C, D and E; some disagree.  It does contain proteins, sugars, lipids (essential fatty acids), many essential amino acids, collagen, lecithin, enzymes and minerals, in addition to the very valuable 10-2-HDA (10-Hydroxy-2-Decenoic Acid).  It is said that Royal Jelly may be most effective when combined with honey.

The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy, etc., and recent studies indicated immuno-regulation and anti-malignancy activities.  It can promote the growth of T-lymphocyte subsets, Interleukin-2 and the generation of tumor necrosis factor.  Much research is being conducted on this valuable active constituent, which has exhibited positive physiological and pharmacological effects including vasodilative and hypotensive activities, antihypercholesterolemic activity and anti-inflammatory functions.

10-2-HDA (10-Hydroxy-2-Decenoic Acid)

10-2-HDA (10-Hydroxy-2-Decenoic Acid)

4.7.6  A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis
OCT 28, 2014

A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis,
C.H. Hornung, M.R. Mackley, I.R. Baxendale and S.V. Ley and, Org. Proc. Res. Dev., 2007, 11, 399-405.

http://pubs.acs.org/doi/abs/10.1021/op700015f

This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels−Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.

4.7.7 Pauline Lau. Biochemist, Instrumental Analysis, Molecular and Clinical Diagnostics, and Pharmaceuticals.

She was born on the China-Russian border, near the end of the rail line.  When they came to US her mother saw bagels and said, look – they have round bread.

At the meetings she always took us to the best Chinese restaurant, and said not to ask what’s in the food.  They always brought out a fish fresh from the tank and showed it to us.  When she went to Roche, where she became a legend. she got a house on the lake. They had to remove the roof to put a round banquet table in her house. At a meeting in Mexico, we saw the amazing too good to be true Monarch butterflies filling the trees.  Her photographic skills are suberb.  She’ll live to 100.

Carl Garber just retired and gave me the address.  I just found your photo calender!

Yes, I have been hiding in Taiwan for the past almost 10 years.  I moved from diagnostic to pharma and selling mostly biosimilar products to pharmaceutical emerging countries which has strong market growth comparing to US/EU.

Pauline Lau Group

Pauline Lau Group

Pauline Lau Group

Pauline Lau Group
http://www.gbimonthly.com/v9_2014/v9spreport_2014_2.html

I do not go back to US often now.  We have an office in Taipei.  Here is a recent magazine article about our company.  You will see few of my employees and I in front of our 28th floor office window.

I am rushing out for Singapore and will be meeting there for a few days.

4.7.8  Kinetic and perfusion modeling of hyperpolarized 13C pyruvate and urea in cancer with arbitrary RF flip angles

Naeim Bahrami, Christine Leon Swisher, Cornelius Von Morze, Daniel B. Vigneron, Peder E. Z. Larson
Department of Radiology and Biomedical Imaging, University of California – San Francisco, San Francisco, CA, USA
Quant Imaging MedSurg 2014; 4(1):24-32
http://dx.doi.org:/10.3978/j.issn.2223-4292.2014.02.02

Abstract: The accurate detection and characterization of cancerous tissue is still a major problem for the clinical management of individual cancer patients and for monitoring their response to therapy. MRI with hyperpolarized agents is a promising technique for cancer characterization because it can non-invasively provide a local assessment of the tissue metabolic profile. In this work, we measured the kinetics of hyperpolarized [1-13C] pyruvate and 13C-urea in prostate and liver tumor models using a compressed sensing dynamic MRSI method. A kinetic model fitting method was developed that incorporated arbitrary RF flip angle excitation and measured a pyruvate to lactate conversion rate, Kpl, of 0.050 and 0.052 (1/s) in prostate and liver tumors, respectively, which was significantly higher than Kpl in healthy tissues [Kpl =0.028 (1/s), P<0.001]. Kpl was highly correlated to the total lactate to total pyruvate signal ratio (correlation coefficient =0.95). We additionally characterized the total pyruvate and urea perfusion, as in cancerous tissue there is both existing vasculature and neovascularization as different kinds of lesions surpass the normal blood supply, including small circulation disturbance in some of the abnormal vessels. A significantly higher perfusion of pyruvate (accounting for conversion to lactate and alanine) relative to urea perfusion was seen in cancerous tissues (liver cancer and prostate cancer) compared to healthy tissues (P<0.001), presumably due to high pyruvate uptake in tumors. Keywords: Hyperpolarized carbon-13; metabolic imaging; cancer; perfusion; kinetic modeling; dynamic MRSI

Hyperpolarization is the nuclear spin polarization of a material far beyond thermal equilibrium conditions. The accurate and correct diagnosis and characterization of cancer is still a major problem for the clinical management of every kind of cancer patients, including individual prostate or liver cancer patients, and also in order to monitor their response to therapy (1-3). Magnetic resonance spectroscopic imaging (MRSI) with hyperpolarized 13C labeled substrates is a new method to study any cancers that may be able to simultaneously and noninvasively assess changes in metabolic intermediates from multiple biochemical pathways of interest. Recent studies have shown a large amount of potential applications of hyperpolarized (HP) 13C MRSI for the in vivo monitoring of cellular metabolism and the characterization of disease. The low natural abundance and sensitivity of 13C compared to protons poses a technical challenge using conventional approaches (4,5). Dynamic nuclear polarization (DNP) of 13C labeled pyruvate and subsequent rapid dissolution generates a contrast agent with a four order-of-magnitude sensitivity enhancement that is injected and gives the ability to monitor the spatial distribution of pyruvate and its conversion to lactate, alanine, and bicarbonate. The conversion of pyruvate to lactate catalyzed by the enzyme lactate dehydrogenase is of particular interest, as the kinetics of this process have been shown to be sensitive to the presence and severity of disease in preclinical models (6,7). HP MRSI can also be used to measure perfusion that in cancer can reflect spatially heterogeneous changes to existing vasculature and neovascularization as tumors surpass the normal blood supply, including microcirculatory disturbance in abnormal vessels. Tumor perfusion data in addition to the metabolic data available from spectroscopic imaging of 13C pyruvate would be of important value in exploring the complex relationship between perfusion and metabolism in cancer at both preclinical and clinical research levels (8-11). The primary purpose of this research was to study the dynamics of simultaneously injected HP [1-13C]-pyruvate and 13C-urea to provide improved characterization of cancerous tissues. To achieve rapid, 2 s temporal resolution, whole mouse MRSI we used a 18-fold accelerated compressed sensing acquisition and reconstruction with smaller flip angles for pyruvate and urea compared to lactate and alanine for efficient usage of the hyperpolarized magnetization by preserving the substrate. This flip angle scheme required using a modified kinetic model that accounts for arbitrary RF flip angles (12-15). Data was acquired in mice with prostate and liver cancer and comparisons were made to normal tissues such as kidney and healthy liver of the metabolite concentrations, including Urea, Pyruvate, and Lactate, the conversion constant (Kpl) between pyruvate to lactate, and the conversion constant (Kpa) between pyruvate to alanine. We also created novel parameterizations of the total pyruvate and urea perfusions in order to assess vascular delivery and tissue uptake. A key new feature of our modeling is the ability to detect metabolic conversion, magnetization exchange between compounds, and perfusion when using arbitrary RF flip angles for different compounds.

We observed a strong correlation between Kpl and the total lactate to total pyruvate ratio, as others have also shown. The ratio is a simpler calculation and easier to implement than the kinetic modeling. However, we have determined through simulation that the total lactate to total pyruvate ratio is highly influenced by the delivery time of pyruvate, so care should be taken when using this ratio if variable vascular delivery rates are expected. Both the kinetic modeling and metabolite ratio are highly influenced by the actual RF flip angles, and precise B1 calibration is important for quantitative measurements. Measurement of urea perfusion can be a marker vascular delivery since urea primarily stays in the vasculature. Liver is a very vascular organ and the opened capillary shape of liver vasculature likely caused high urea perfusion in liver. The kidneys are highly vascularized and are also responsible for concentrating urea for removal in the urine. In tumors, the tissue request for blood is high but in a more uncontrolled way because of the abnormality of blood vasculature and circulation inside most tumors. Thus the urea perfusion in tumors is likely more sporadic and random. Urea cannot perfuse well in some parts of tumor particularly in suspected necrotic regions. On the other hand, some parts of tumor have more metabolic activity and, therefore, these parts need more blood and more vessels, and consequently should have more urea perfusion. Our total pyruvate and urea perfusion parameterizations are different from conventional perfusion modeling, and were designed as a simple representation of the total amount of these compounds that are present in the tissue. In particular, the total pyruvate perfusion also includes any pyruvate or metabolic products that remain in the tissue, in addition to those present in the vasculature. The urea perfusion should primarily represent the vasculature delivery since it primarily stays in the vessels, while the total pyruvate perfusion can also be a marker for vascular delivery but also includes tissue uptake. We hypothesize that when the pyruvate perfusion is higher relative to urea perfusion it represents a higher amount of uptake of the pyruvate that is flowing into the tissue.

Conclusions In this study we fit metabolite T1 values, conversion rates, Kpa, and Kpl, and measured novel pyruvate and urea perfusion parameterizations across cancerous and normal tissues from data acquired with a multiband RF excitation, compressed sensing dynamic MRSI pulse sequence. Our modeling allowed for use of arbitrary RF flip angles between metabolites, which in turn allows for efficient usage of the hyperpolarized magnetization. We observed a high correlation between our Kpl fits and the total lactate to pyruvate signal ratio, suggesting either could be used to characterize pyruvate-lactate metabolism. Through the novel pyruvate and urea perfusion parameterizations we were able to quantify the increased uptake of pyruvate in cancerous tissues, which correlated with increased metabolic conversion to lactate. These provided a more complete characterization of cancerous tissue metabolism and perfusion.

4.2.9 ZSTK474

(Dr. Anthony Melvin Castro)

zstk474

zstk474

ZSTK474 is a cell permeable and reversible P13K inhibitor with an IC₅₀ at 6nm. It was identified as part of a screening library, selected for its ability to block tumor cell growth. ZSTK474 has shown strong antitumor activities against human cancer xenographs when administered orally to mice without a significant toxic effect.

Phosphatidylinositol 3-kinase (PI3K) has been implicated in a variety of diseases including cancer. A number of PI3K inhibitors have recently been developed for use in cancer therapy. ZSTK474 is a highly promising antitumor agent targeting PI3K. We previously reported that ZSTK474 showed potent inhibition against four class I PI3K isoforms but not against 140 protein kinases.

However, whether ZSTK474 inhibits DNA-dependent protein kinase (DNA-PK), which is structurally similar to PI3K, remains unknown. To investigate the inhibition of DNA-PK, we developed a new DNA-PK assay method using Kinase-Glo. The inhibition activity of ZSTK474 against DNA-PK was determined, and shown to be far weaker compared with that observed against PI3K. The inhibition selectivity of ZSTK474 for PI3K over DNA-PK was significantly higher than other PI3K inhibitors, namely NVP-BEZ235, PI-103 and LY294002.

PATENT                                                                                                          SUBMITTED GRANTED

Heterocyclic compound and antitumor agent containing the same as active ingredient [US7071189]                                                                                                                                                               2004-06-17   2006-07-04

Treatment of prostate cancer, melanoma or hepatic cancer [US2007244110]                                                                                                                                                                                                   2007-10-18

Heterocyclic compound and antitumor agent containing the same as effective ingredient [US7307077]                                                                                                                                                           2006-11-02   2007-12-11

Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient [us7750001]                                                                                                                                   2008-05-15   2010-07-06

Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy [us2011009405]                                                                                                                                                                       2011-01-13

Substituted pyrimidines and triazines and their use in cancer therapy [us2011053907]                                                                                                                                                                                     2011-03-03

Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient [us2010267700]                                                                                                                             2010-10-21

Amorphous body composed of heterocyclic compound, solid dispersion and pharmaceutical preparation each comprising the same, and process for production of the same [us8227463]                                                                                                                                                                                                                                                                                                                                                                                                                           2010-09-30    2012-07-24

Pyrazolo[1,5-a]pyridines and their use in cancer therapy
[us2010226881]                                                                                                                                                                                                                                                                                                 2010-09-09

Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy [us2010249099]                                                                                                                                                   2010-09-30


Circulating Tumor Cells in an NIH Study were Captured on a Microfluidic Chip

Reporter: Aviva Lev-Ari, PhD, RN

Microchip captures clusters of circulating tumor cells – NIH study

Researchers have developed a microfluidic chip that can capture rare clusters of circulating tumor cells, which could yield important new insights into how cancer spreads. The work was funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health.

Circulating tumor cells (CTCs) are cells that break away from a tumor and move through a cancer patient’s bloodstream. Single CTCs are extremely rare, typically fewer than 1 in 1 billion cells. These cells can take up residence in distant organs, and researchers believe this is one mode by which cancer spreads.

Continue to read

http://www.nih.gov/news/health/may2015/nibib-18.htm

 

nibib-18_l_b

 

Fluorescently labelled cancer cell cluster balancing on the tip of a post within Cluster-Chip.

Credit: Mehmet Toner, BioMicroElectroMechanical Systems Resource Center at MGH

 

SOURCE

http://www.nih.gov/news/health/may2015/nibib-18.htm


GE engineers have made a simple proof-of-concept 3D-printed mini jet engine that operates at 33,000 rotations per minute. The backpack-sized jet engine was built over the course of several years to test the technology’s abilities and to work on a side project together.

“We wanted to see if we could build a little engine that runs almost entirely out of additive manufacturing parts,” says one of the engineers.

The GE team couldn’t build the complexity of a whole commercial aircraft engine into their working model. Instead, they got plans for a simpler engine developed for remote control model planes and customized them for their 3D printing machines. Their final product measures around a foot long by about eight inches tall.

 

The team also designed and developed a fuel nozzle that will be additively manufactured for inclusion in the CFM LEAPjet engine for commercial single-aisle aircraft. The FAA recently approved the first 3D printed component for a version of the GE90 jet engine.

Source: www.kurzweilai.net

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY


Chinese search giant Baidu says it has invented a powerful supercomputer that brings new muscle to an artificial-intelligence technique giving software more power to understand speech, images, and written language.

The new computer, called Minwa and located in Beijing, has 72 powerful processors and 144 graphics processors, known as GPUs. Late Monday, Baidu released a paper claiming that the computer had been used to train machine-learning software that set a new record for recognizing images, beating a previous mark set by Google.

“Our company is now leading the race in computer intelligence,” said Ren Wu, a Baidu scientist working on the project, speaking at the Embedded Vision Summit on Tuesday. Minwa’s computational power would probably put it among the 300 most powerful computers in the world if it weren’t specialized for deep learning, said Wu. “I think this is the fastest supercomputer dedicated to deep learning,” he said. “We have great power in our hands—much greater than our competitors.”

Computing power matters in the world of deep learning, which has produced breakthroughs in speech, image, and face recognition and improved the image-search and speech-recognition services offered by Google and Baidu.

The technique is a souped-up version of an approach first established decades ago, in which data is processed by a network of artificial neurons that manage information in ways loosely inspired by biological brains. Deep learning involves using larger neural networks than before, arranged in hierarchical layers, and training them with significantly larger collections of data, such as photos, text documents, or recorded speech.

So far, bigger data sets and networks appear to always be better for this technology, said Wu. That’s one way it differs from previous machine-learning techniques, which had begun to produce diminishing returns with larger data sets. “Once you scaled your data beyond a certain point, you couldn’t see any improvement,” said Wu. “With deep learning, it just keeps going up.” Baidu says that Minwa makes it practical to create an artificial neural network with hundreds of billions of connections—hundreds of times more than any network built before.

 

A paper released Monday is intended to provide a taste of what Minwa’s extra oomph can do. It describes how the supercomputer was used to train a neural network that set a new record on a standard benchmark for image-recognition software. The ImageNet Classification Challenge, as it is called, involves training software on a collection of 1.5 million labeled images in 1,000 different categories, and then asking that software to use what it learned to label 100,000 images it has not seen before.

Software is compared on the basis of how often its top five guesses for a given image miss the correct answer. The system trained on Baidu’s new computer was wrong only 4.58 percent of the time. The previous best was 4.82 percent,reported by Google in March. One month before that, Microsoft had reportedachieving 4.94 percent, becoming the first to better average human performance of 5.1 percent.

Source: www.technologyreview.com

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY

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