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Electrophilic Stress, Membranes, and Aging

Posted: July 3, 2011 at 3:55 pm

You may recall that composition of cell membranes is strongly correlated to species longevity – the idea being that some membranes are more resistant to the damage of reactive oxygen species than others, and that damage resistance at the cellular level ultimately translates into a longer-lived animal. Here is more on that topic: “This review begins with the premise that an organism’s life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species(ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated with membrane peroxidizability and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via nontargeted reactions with cellular macromolecules and (ii) modulate signaling pathways that control longevity-assurance mechanisms.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/21708248

Recommendation and review posted by Fredricko

Considering Why Type 2 Diabetes is an Age-Related Condition

Posted: July 3, 2011 at 3:55 pm

Type 2 diabetes is the poster child for an avoidable age-related condition: barring the worst of genetic bad luck, calorie restricted, well exercised people will not suffer from type 2 diabetes. But this is, undeniably, an age-related illness. Becoming ever more obese and sedentary will hasten the onset of diabetes into ever earlier years of life, but older obese and sedentary people are still far more likely to suffer type 2 diabetes than are equally overweight and sedentary younger counterparts. So while failing to take care of your health at any age is just another form of self-harm, there are other, less avoidable processes taking place at the level of cells and organs that make older people more vulnerable.

Here is an open access paper that reviews what researchers presently know of the decline of insulin-producing beta cells in the pancreas – which turns out to be not enough, as is still true of so much of our biochemistry. There are changes, cataloged and identified, but the chains of causation for those changes are poorly understood at best.

Type 2 Diabetes and the Aging Pancreatic Beta Cell

An increased incidence of diabetes is observed with age, and there are many possibly reasons for this. One of these is that the beta cell has reduced proliferative capacity and in diabetic individuals this is further confounded by higher rates of beta cell apoptosis. The currently known underlying mechanisms behind the reduction in beta cell proliferation observed with age include reduced expression of cell cycle activators, increased expression of cell cycle inhibitors, reduced pdx1 expression, and increased amylin aggregation. Studying aging in the non-diabetic rodent and human models is currently a developing field; therefore very few broad conclusions can be drawn. Further study in these areas is important as they could indicate targets for preventing or slowing the progression of diabetes with age.

I look on this as a good illustration of why the detailed, tissue by tissue, understand everything approach to repairing aging is doomed to take a very long time indeed. This is but one population of vital cells in one organ, one of the most studied forms of cell in past decades, and the research community remains far from a complete understanding as to how and why they fail with age.

Better strategies to deal with aging exist – such as SENS – and need to gain wider support and adoption. SENS-like approaches work around the challenge posed by the sheer complexity of human biochemistry by focusing on the known common mechanisms of aging, the root causes from which there is good reason to believe all other changes descend. Repairing these root causes is the fast path to the first generation of rejuvenation biotechnology, and that, in my eyes, is the only real shot at building viable interventions in the aging process that will arrive in time to help us.

Recommendation and review posted by Fredricko

In vivo cell trafficking just took a leap forward

Posted: July 3, 2011 at 3:55 pm


Today Celsense, Inc. and the University of Pittsburgh Cancer Center announced that the FDA has authorized the use of the Cell Sense imaging reagent for use in a phase I clinical trial of a dendritic cell caccine to treat colorectal cancer patients.

This is the first FDA authorization of the use of Cell Sense in patients. Cell Sense is a novel perfluorocarbon tracer agent used to safely and efficiently label cells ex vivo without the use of transfection agents. Labeled cells are then transplanted into the patient enabling researchers and clinicians to non-invasively track the administration and migration of therapeutic cells using MRI. Applications include tracking cells in immunotherapy or regenerative medicine as well as the diagnosis of inflammatory sites by tracking selected populations of immune cells.

Cell Sense has been studied extensively in preclinical testing with many different human cell types including human cells in animals. For instance, in 2009 a paper was published in Informa’s Cytotherapy, in which Celsense’s novel perfluorocarbon tracer agent (product “Cell Sense”) was used to label human DCs ex vivo for the purpose of tracking the cells in vivo post-transplant by 19F MRI. The paper provided an assessment of the technology and demonstrated that human DCs were effectively labeled without significant impact on cell viability, phenotype or function. Furthermore, the labeled dendritic cells were clearly detected in vivo by 19F MRI in a model system, with the labeled cells being shown to migrate selectively towards draining lymph node regions within 18 hours after transplant.

Many investigators looking at various ways to label cells to enable in vivo imaging have expressed concern that the FDA would delay the regulatory progress of their therapeutic candidates if an imaging modality was introduced.

This concern is based on numerous reports of MRI contrast reagents, such as the commonly investigated USPIO (ultrasmall superparamagnet iron oxide), deleteriously affecting the cells (see recent paper in Cell Transplantation).

“We believe that the authorization of this IND will alleviate such concerns and lower the barriers for adoption. The agency’s tangible support for bringing new technologies to bear in the translation of cell-based therapeutics is very encouraging,” s Charlie O’Hanlon, President and CEO of Celsense.

While there have been approved uses of imaging reagents (e.g., Feridex, etc) with cell therapies in other countries (e.g. Isreal), I believe this may be the first FDA-sanctioned use of a particle-based imaging label with a cell-based therapy. Other approaches to cellular imaging include nuclear imaging reagents and genetically modifying cells with reporter genes such as those provided by CellSight Technologies.

Imaging labels are capable of providing investigators with data demonstrating where the cells go, at what volumes, and for how long they stay at the target location.

The industry has been keen to see these kinds of technologies clinically employed but different cell-based labels have created their own technical, clinical, and/or regulatory hurdles. I’m hopeful that Celsense and others like them are now ushering us into a new era where we will eventually be able to use various technologies to monitor and collect valuable data concerning cells after they have been administered as a therapy to a patients.

Additional resources on the topic of imaging for cell therapies:

CIRM recently hosted a webinar – “CIRM/RMC Webinar: Imaging Technology for Cellular Therapies. One of the speakers, Dr. Shahriar Yaghoubi from CellSight Technologies, provides an overview of cell therapy imaging with emphasis on PET. Click hear for the archived playback.

A very interesting article posted today on Harvard’s StemBook website. “In-vivo Stem Cell Imaging – Regulatory Challenges and Advances“. Nice overview intel from J. Bulte and a snapshot into E. Wirth’s (of Geron) perspective re: stem cell imaging.

A new book from CRC Press edited by Dara Kraitchman and Joe Wu will be out soon. It gathers together different methods for comparison. The issue will remain the sensitivity of the methods to track few cells. “Stem Cell Labeling for Delivery and Tracking Using Non-Invasive Imaging“.

MRI contrast agents can change stem cell proliferation

There s also a very informative discussion thread on the topic in the Cell Therapy Industry group on LinkedIn.

Recommendation and review posted by Fredricko

Close Encounters of Science and Medicine

Posted: July 3, 2011 at 3:55 pm

From medicine to science

When I was about 3 or 4 years old, I got very sick. I stayed in bed for many weeks and every day a nurse would come to give me a penicillin shot. The pain from shots turned into fear, in time fear turned into a plan for revenge. When I got better I demanded to have my own syringe and cruelly treated all teddy bears and dolls. If they didn’t look sick I made them sick, just to perform surgeries, sew wounds and give shots. I even offered my service to family members; unfortunately, they stubbornly kept on being healthy.

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Recommendation and review posted by Fredricko

Lifeline Cell Technology’s FibroLife Media Used to Cultivate Tissue-Engineered Blood Vessels for Cytograft Tissue Engineering

Posted: July 3, 2011 at 3:55 pm


International Stem Cell Corporation’s (ISCO) subsidiary, Lifeline Cell Technology (Lifeline), contributed a critical role in developing and manufacturing a cell culture media that is suitable to grow the blood vessels used by Cytograft Tissue Engineering. 
As seen in the American Heart Association‘s innovative forum for late breaking science, “Emerging Science Series” webinar – Focus on Thrombosis and Vascular Biology, Cytograft’s technology has shown positive clinical results in the extensive market for vascular grafts; a market that exceeds 500,000 patients. 
Applications for this technology include vascular shunts for hemodialysis for patients with kidney disease, lower limb circulation problems and coronary artery bypass grafts. If approved in further upcoming clinical trials, Lifeline’s medium will be made for Cytograft to clinical grade in Lifeline’s cGMP media manufacturing facilities.
Coverage of this important story has been reported by the following media:

Forbes  

Wall Street Journal

CNN
http://thechart.blogs.cnn.com/2011/06/28/engineers-create-human-blood-vessels-from-skins-cells/ 

About International Stem Cell Corporation
International Stem Cell Corporation is focused on the therapeutic applications of human parthenogenetic stem cells and the development and commercialization of cell-based research and cosmetic products. ISCO’s core technology, parthenogenesis, results in the creation of pluripotent human stem cells from unfertilized oocytes (eggs). hpSCs avoid ethical issues associated with the use or destruction of viable human embryos. ISCO scientists have created the first parthenogenic, homozygous stem cell line that can be a source of therapeutic cells with minimal immune rejection after transplantation into hundreds of millions of individuals of differing genders, ages and racial background. This offers the potential to create the first true stem cell bank, UniStemCell™. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary Lifeline Cell Technology, and cell-based skin care products through its subsidiary Lifeline Skin Care. More information is available at http://www.internationalstemcell.com.

To subscribe to receive ongoing corporate communications, please click on the following link:http://www.b2i.us/irpass.asp?BzID=1468&to=ea&s=0.

Forward-looking Statements
Statements pertaining to anticipated developments, product development and marketing plans, and other opportunities for the company and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as “will,” “believes,” “plans,” “anticipates,” “expects,” “estimates,”) should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, competition, regulatory approvals, need and ability to obtain future capital, application of capital resources among competing uses, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company’s business, particularly those mentioned in the cautionary statements found in the company’s Securities and Exchange Commission filings. The company disclaims any intent or obligation to update forward-looking statements.

http://cts.businesswire.com/ct/CT?id=bwnews&sty=20110629005531r1&sid=14230&distro=ftp
International Stem Cell Corporation
Jeffrey Janus
President and CEO, Lifeline Cell Technology
760-940-6383
[email protected]


Recommendation and review posted by Fredricko

International Stem Cell Corporation’s Lifeline Cell Technology Subsidiary Expands Sales and Distribution While Enhancing Manufacturing Capability and Clinical Product Opportunities

Posted: July 3, 2011 at 3:55 pm

International Stem Cell Corporation (OTCBB:ISCO) (http://www.intlstemcell.com), the first company to perfect a method of creating human “parthenogenetic” stem cells derived from unfertilized human eggs, reports that its wholly owned subsidiary, Lifeline Cell Technology (Lifeline), grew 2011 first quarter product sales by 35% and gained well over 200 new customers compared with the prior year through new product introductions and the development of worldwide distribution channels. Lifeline also made significant progress in its strategy to expand its product applications into manufacturing human tissues and cells for clinical use. Lifeline Cell Technology develops, manufactures and markets the Lifeline® brand of cell culture products used by researchers to grow human cells for basic and pre-clinical research. Lifeline also fulfills an important role in parent ISCO’s long-term strategy to be a leading developer and manufacturer of human cells and human-cell-based products for clinical applications.


Lifeline’s chief executive officer, Jeffrey Janus, stated, “Our product sales growth was largely due to the development and launch of more than 30 new products in 2010, including products that allow researchers to study human stem cells. Lifeline also opened new distribution channels in Japan, India, Taiwan, South Korea and Singapore and has achieved significant sales in those new markets. Importantly, we have also moved closer to validating the feasibility of ISCO’s strategic plan as our proprietary FibroLife® media is being used to cultivate tissue-engineered blood vessels for Cytograft Tissue Engineering in Novato, California. Cytograft’s vessels are expected to be used as coronary grafts for coronary bypass procedures, as peripheral grafts to prevent lower limb amputations and as living tissue shunts for hemodialysis patients.”


Cytograft’s technology was recently featured at the American Heart Association’s conference of emerging technology and can be viewed on the AHA’s “Emerging Science Series Webinar” at scientificsessions.org/emergingscience.


Cytograft’s chief executive officer, Todd McAllister, Ph.D., said, “Cytograft’s clinical programs are going forward in Phase III trials and we are excited to be working with Lifeline as one of our key media developers and suppliers as we transition to commercialization and as we develop our next generation platform.”


In anticipation of producing clinical grade products, Lifeline recently moved into new laboratory facilities that are capable of cGMP level manufacturing. Said Janus, “Lifeline Cell Technology provides ISCO the capacity to develop and manufacture human cell-based products for growing field of regenerative medicine, while at the same time generating revenue in the research market. The Cytograft opportunity is but one example of many potential clinical applications for Lifeline’s products.”


About International Stem Cell Corporation
International Stem Cell Corporation is focused on the therapeutic applications of human parthenogenetic stem cells and the development and commercialization of cell-based research and cosmetic products. ISCO’s core technology, parthenogenesis, results in the creation of pluripotent human stem cells from unfertilized oocytes (eggs). hpSCs avoid ethical issues associated with the use or destruction of viable human embryos. ISCO scientists have created the first parthenogenic, homozygous stem cell line that can be a source of therapeutic cells with minimal immune rejection after transplantation into hundreds of millions of individuals of differing genders, ages and racial background. This offers the potential to create the first true stem cell bank, UniStemCell™. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary Lifeline Cell Technology, and cell-based skin care products through its subsidiary Lifeline Skin Care. More information is available at http://www.internationalstemcell.com.


To subscribe to receive ongoing corporate communications, please click on the following link:http://www.b2i.us/irpass.asp?BzID=1468&to=ea&s=0.


Forward-looking Statements
Statements pertaining to anticipated developments, product development and marketing plans, and other opportunities for the company and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as “will,” “believes,” “plans,” “anticipates,” “expects,” “estimates,”) should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, competition, regulatory approvals, need and ability to obtain future capital, application of capital resources among competing uses, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company’s business, particularly those mentioned in the cautionary statements found in the company’s Securities and Exchange Commission filings. The company disclaims any intent or obligation to update forward-looking statements.


http://cts.businesswire.com/ct/CT?id=bwnews&sty=20110629005531r1&sid=14230&distro=ftp
International Stem Cell Corporation
Jeffrey Janus
President and CEO, Lifeline Cell Technology
760-940-6383
[email protected]

or:
Lippert/Heilshorn & Associates
Don Markley
310-691-7100
[email protected]

Recommendation and review posted by Fredricko


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