Archive for May, 2012


Platelets are a rich source of growth factors that can be applied to facial aesthetics

The use of platelet-rich plasma for rejuvenation and augmentation is discussed by Dr Sabine Zenker

Dermal stimulation and augmentation continues to grow within the facial aesthetics industry. A bioresorbable material such as hyaluronic acid (HA) is
commonly used. Many exogenous fillers rely on an autologous fibrotic response for volume augmentation—but disadvantages include the transient effects of temporary, resorbable
fillers and foreign body reactions such as persistent erythema and swelling and encapsulation, granuloma formation and chronic or delayed infections. An autologous source for soft tissue augmentation is therefore a desirable alternative.
Human growth factors (GFs) have been extensively investigated, but there are now clinical applications of individual GFs: keratinocyte growth factor (Kepivance, Sweden) for oral
mucositis; and platelet derived growth factor (Regranex, UK) for non-healing diabetic wounds. But applied outside their normal environment, these exogenous GFs may have untoward effects— for example, the FDA introduced a black box warning on becaplermin in 2008 for increased cancer mortality. The safety of palifermin has so far not been established.
Platelets
Platelets are an excellent source of GFs in their naturally-occurring and biologically determined ratio, and are successful in acute wound healing. The application of platelet-rich plasma (PRP) has been proven to enhance early wound healing and
healing in diabetic ulcers. Concentrated platelet preparations have been used clinically since the 1990s to simulate the native wound healing environment compared with that after isolated growth factor application. There is also substantial clinical proof
of PRP in other areas of medicine—platelet gel is widely used inorthopaedics and oromaxillofacial surgery.
Platelet recovery systems have been developed where erythrocytes are separated from white cells and platelets in distinct fractions. Platelet pellets are resuspended in recovered plasma, usually with 6–7 times the normal concentration of platelets in peripheral blood. This concentration is an autologous source of growth factors. After injection into the dermis and subcutaneous layers, the platelets are activated endogeneously by the
body’s own coagulation factors such as thrombine and collagen.
This leads to platelet degranulation, releasing platelet GFs such as PGDF, ILGF, EGF and TGF-beta. Activated platelets also release proteins such as the adhesive glycoproteins fibrin, fibronectin and vitronectin. These proteins and GFs interact with cells
in the subcutaneous tissues, such as fibroblasts, endothelial cells and stem cells and after binding to their cellular receptors, they activate intracellular signaling events—mediating cell proliferation,migration, survival and production of extracellular matrix proteins. This results in tissue rejuvenation. For the enhancement of skin texture, glow and hydration,
PRP is applied via superficial dermal injection using a mesotherapy technique. When used as a filler, PRP is injected dermally or subdermally to volumise and reshape the skin. The autologous character of this agent means there are minimal side effects, but these usually take form of mild bruising, swelling or, theoretically, infection. Contraindications include pregnancy, breast feeding, autoimmune or blood disease and cancer.
There are several kits for PRP harvesting, including MyCells, Selphyl and Regen. The MyCells kit is designed for autologous PRP re-injection and has been approved by the FDA, the Medical Device Committee of the European Union and by the Israeli
health ministry. PRP for facial rejuvenation is currently injected in three countries: Japan, England and Israel.

Studies
There is poor clinical data available to prove the safety and efficacy of PRP injections. An initial pilot study of 10 women showed that PRP injections for facial rejuvenation is an effective way to address some of the more difficult areas on the face, around the eyes and the neck.
MyCells performed a clinical investigation in Japan, the UK and Israel with over 400 patients. In this study, the clinical effects and potential side effects of MyCells PRP skin rejuvenation were evaluated. The patients were facially injected with the MyCells PRP skin rejuvenation kit. Follow up was performed three to six months after primary injections. Treatment was performed for the following indications and techniques:
• Layer specific transplant
• “Tenting” of the skin
• “Cul-de-sac” and needle bevel up
• Over-correction up to 50%
• Serial treatments, providing an accumulative effect
• Minimal-trauma technique using a long needle

Patients were treated with intradermal injection using long 30G needles, injected in deep folds or wrinkles using the linear threading technique, and with superficial injection using the mesotherapy technique. Following injection, Auriderm XO gel (vitamin K) was applied.
Patients were reviewed at three-monthly intervals. Results were age-dependent. Younger patients less than 35 years were found to respond quickly with the main indication being skin rejuvenation and prevention—treatment every 12-24 months should suffice.
Patients up to 45 years required a second treatment 9-12 months later and annual booster injections. Patients aged 50–60 years required a second treatment at six months, a third at one year and three months, with a touch up two years after the first treatment. Patients over 60 needed a second treatment at three months, a third at nine months and a fourth treatment 1.5 years later. Over-corrections were performed on 30-50% of patients.
My clinical experience with PRP has shown that this modality may be an alternative or adjunctive therapy for tissue regeneration to any of the existing therapies. Its application for superficial or deep dermal stimulation leads to skin rejuvenation and global facial volumisation.
This biostimulation is safe, creates an immediate and long lasting volumetric effect and a natural result. It is easy to perform and the procedure has virtually no side-effects and high levels of patients satisfaction.

References:
Bhanot S, Alex JC. “Current applications of platelet gels in facial
plastic surgery.” Facial Plast Surg. 2002 Feb;18(1):27-33.
Choukroun et al. “Influence of Platelet Rich Fibrin (PRF) on proliferation
of human preadipocytes and tympanic keratinocytes: A
new opportunity in facial lipostructure (Coleman`s technique) and
tympanoplasty?”
Dougherty EJ. “An evidence-based model comparing the costeffectiveness
of platelet-rich plasma gel to alternative therapies for
patients with non-healing diabetic foot ulcers.” Adv Skin Wound
Care. 2008 Dec;21(12):568-75.
Ebisawa K, Kato R, Okada M, Kamei Y, Mazlyzam AL, Narita Y,
Kagami H, Ueda M. “Cell therapy for facial anti-aging.” Med J
Malaysia. 2008 Jul; 63 Suppl A:41.
Epply BL, Pietrzak WS, Blanton M. “Platelet-rich plasma: a review
of biology and applications in plastic surgery.” Plast Reconstr Surg.
2006 Nov;118(6):147e-159e.
Hom DB, Linzie BM, Huang TC. “The healing effects of autologous
platelet gel on acute skin wounds.” Arch Facial Plast Surg 2007;
9:174- 183.
Kim JH, Park C, Park HM. “Curative effect of autologous plateletrich
plasma on a large cutaneous lesion in a dog.” Vet Dermatol.
2009 Jan 21 [Epub ahead of print].
Martínez-Zapata MJ, Martí-Carvajal A, Solà I, Bolibar I, Angel
Expósito J, Rodriguez L, García J. “Efficacy and safety of the use
of autologous plasma rich in platelets for tissue regeneration: A
systematic review.” Transfusion. 2009 Jan;49(1):44-56. Epub 2008
Oct 14. Review.
Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE,
Georgeff KR. “Platelet-rich plasma: Growth factor enhancement
for bone grafts.” Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1998;85:638-646)
Mazzucco L, Balbo V, Cattana E, Borzini P. “Platelet-rich plasma and
platelet gel preparation using Plateltex.” Blood Transfusion Centre
and Biotechnology Laboratory, Ospedale SS Antonio e Biagio, Alessandria,
Italy, Vox SanguinisVox Sanguinis (2008) ORIGINAL PAPER
©2008 The Author(s) Journal compilation ©2008 Blackwell Publishing
Ltd. DOI: 10.1111/j.1423-0410.2007.01027.x
Mishra A, Woodland J et al. “Treatment of tendon and muscle using
platelet-rich plasma.” Clin Sports Med 28 (2009) 113-115
Mishra A, Tummala P, King A, Lee B, Kraus M, Tse V, Jacobs CR.
“Buffered platelet-rich plasma enhances mesenchymal stem cell
proliferation and chondrogenic differentiation.” Tissue Eng Part C
Methods. 2009 Feb 13. [Epub ahead of print]
Mojalla A, Foyatier J-L. “The effects of different factors on the
survival of transplanted adipocytes.” Ann Chir Plast Esthét 2004;
49:426-436
Seung-Who et al. “Engineered Adipose tissue formation enhanced
by basic fibroblast growth factor and a mechanically stable environment.”
Cell transplantation 2007; 16:421-434
Sclafani AP, Romo T, Ukrainsky G, McCormick SA, Litner J, Kevy
SV, Jacobson MS. “Modulation of wound response and soft tissue
ingrowth in synthetic and allogeneic implants with platelet concentrate.”
Arch Facial Plast Surg 2005; 7: 163- 169.
Yuksel et al. “Increased free fat-graft survival with the long-term,
local delivery of insuline, insuline-like growth factor-1 and basic
fibroblastic growth factor by PLAG/PEG microspheres.” Plast Reconstr.
Surg 2000; 105:1712

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Sotatercept (formerly called ACE-011) is an investigational protein therapeutic that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron is developing sotatercept in collaboration with Celgene Corporation for the treatment of anemia caused by chemotherapy and chronic kidney disease.

Mechanism of Action

Sotatercept, the first in a novel class of anemia therapies, is a soluble fusion protein consisting of the extracellular domain of activin receptor type IIA (ActRIIA) linked to the Fc protein of human IgG1. Sotatercept binds with high affinity to activin A and other proteins in the TGF-β superfamily and inhibits signaling through the ActRIIA receptor.

Sotatercept increases hemoglobin levels and RBCs by a novel mechanism: it is not an erythropoietin (EPO)-based product or EPO-mimetic, does not bind the EPO receptor, but rather targets a pathway that is fundamentally distinct from EPO.  In preclinical studies, administration of sotatercept or a mouse version of the molecule to mice and cynomolgus monkeys was associated with increases in erythropoiesis and total red cell mass.  The precise actions of sotatercept underlying the promotion of erythropoiesis are under investigation.

Sotatercept also affects bone formation.  One of the functions of activin A is to inhibit bone growth.   Activin A signaling through ActRIIA suppresses activity of cells responsible for building bone (osteoblasts) and stimulates cells responsible for breaking down bone (osteoclasts). By blocking signaling through ActRIIA, sotatercept stimulates bone formation. In numerous animal models of diseases involving bone loss, sotatercept significantly increased bone mineral density, improved bone architecture, and increased bone formation rate and bone mechanical strength.  Similar effects were observed in experimental models of cancer-related bone loss (multiple myeloma and breast carcinoma) where treatment with a mouse form of sotatercept resulted in a significant reduction in tumor-induced osteolytic lesions. In the myeloma model, restoration of bone remodeling had a significant indirect effect on tumor burden and increased survival.

Acceleron and Celgene are developing sotatercept in anemia indications where the product’s unique pharmacology could potentially provide an innovative and differentiated alternative to existing anemia therapies.

Disease Overview

Anemia, a deficiency of healthy RBCs, is a debilitating condition that often accompanies chemotherapy or chronic kidney disease.  Patients with anemia typically experience fatigue and weakness, which impairs their quality of life and may limit their ability to receive optimal care.

Treatments for anemia include iron repletion, blood transfusion, and recombinant growth factors called erythropoietin stimulating agents (ESAs).  ESAs are currently the only approved drugs that stimulate the production of RBCs.

Clinical Need

ESAs have been used extensively to treat anemia. Recent studies of ESAs have shown an increased risk of mortality arising from exposure to high levels of recombinant erythropoietin and its derivatives, which may stimulate tumor progression, cause premature mortality, and increase the occurrence of thromboembolic events.  The safety concerns with ESAs have prompted substantial restrictions to their approved uses for the management of patients with cancer and kidney disease.

Sotatercept represents a new approach to anemia treatment.   Clinical trials in patients with CIA and CKD are currently underway to study its potential as a safe, effective treatment for anemia.

Clinical Trials

Acceleron is developing sotatercept together with Celgene Corporation for patients who suffer from anemia.  Sotatercept is currently being studied as a treatment for chemotherapy-induced anemia (CIA) and chronic kidney disease-related (CKD) anemia.

Phase 2/ 3 Study for Chemotherapy-Induced Anemia in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).   For information on this trial, please click here.

Phase 2 Study for Anemia in Patients with End-stage Renal Disease on Dialysis.   For information on this trial, please click here

In Phase 1 clinical studies in healthy volunteers, sotatercept was generally well tolerated, and, consistent with observations in preclinical studies, increased levels of hemoglobin and hematocrit, biomarkers of bone formation, and bone mineral density. The most common clinically significant adverse events observed included increased hemoglobin and increased hematocrit, which were pharmacologic effects of the drug, and also headache, all of which were manageable and reversible.

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals’ genes permanently from the embryonic stage – an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director María Blasco, have proved that mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal’s genes. And they have done so using gene therapy, a strategy never before employed to combat ageing. The therapy has been found to be safe and effective in mice.

The results are published today in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Eduard Ayuso and Fátima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autònoma de Barcelona (UAB), treated adult (one-year-old) and aged (two-year-old) mice, with the gene therapy delivering a “rejuvenating” effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals’ health, delaying the onset of age-related diseases – like osteoporosis and insulin resistance – and achieving improved readings on ageing indicators like neuromuscular coordination.

The gene therapy utilised consisted of treating the animals with a DNA-modified virus, the viral having been replaced by those of the telomerase enzyme, with a key role in ageing. Telomerase repairs the extremes of chromosomes, known as telomeres, and in doing so slows the cell’s and therefore the body’s biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study “shows that it is possible to develop a telomerase-based anti-ageing gene therapy without increasing the incidence of cancer”, the authors affirm. “Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage”, they add.

‘Resetting’ the biological clock

Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result, stops dividing and ages or dies. Telomerase gets round this by preventing telomeres from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell’s biological clock.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal – in fact several studies have shown that telomerase expression is the key to the immortality of tumour cells.

It is precisely this risk of promoting tumour development that has set back the investigation of telomerase-based anti-ageing therapies.

In 2007, Blasco’s group proved that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the , by causing their cells to express telomerase and, also, extra copies of cancer-resistant genes. These animals live 40% longer than is normal and do not develop cancer.

The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.

Also important is the kind of virus employed to carry the telomerase gene to the cells. The authors selected demonstrably safe viruses that have been successfully used in gene therapy treatment of haemophilia and eye disease. Specifically, they are non-replicating viruses derived from others that are non-pathogenic in humans.

This study is viewed primarily as “a proof-of-principle that telomerase is a feasible and generally safe approach to improve healthspan and treat disorders associated with short telomeres”, state Virginia Boccardi (Second University of Naples) and Utz Herbig (New Jersey Medical School-University Hospital Cancer Centre) in a commentary published in the same journal.

Although this therapy may not find application as an anti-ageing treatment in humans, in the short term at least, it could open up a new treatment option for ailments linked with the presence in tissue of abnormally short telomeres, as in some cases of human pulmonary fibrosis.

More healthy years

As Blasco says, “ageing is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell ageing, we could prevent these diseases”.

With regard to the therapy under testing, Bosch explains: “Because the vector we use expresses the target gene (telomerase) over a long period, we were able to apply a single treatment. This might be the only practical solution for an anti-ageing therapy, since other strategies would require the drug to be administered over the patient’s lifetime, multiplying the risk of adverse effects”.

Provided by Centro Nacional de Investigaciones Oncologicas (CNIO)

Scientist uses bone cell progenitors derived from human embryonic stem cells to grow compact bone tissue in quantities large enough to repair centimeter-sized defects

Dr. Darja Marolt, an Investigator at The New York Stem Cell Foundation (NYSCF) Laboratory, is lead author on a study showing that human embryonic stem cells can be used to grow bone tissue grafts for use in research and potential therapeutic application. Dr. Marolt conducted this research as a post-doctoral NYSCF –Druckenmiller Fellow at Columbia University in the laboratory of Dr. Gordana VunjakNovakovic.

The study, published in the early online edition of Proceedings of the National Academy of Sciences during the week of May 14th, is the first example of using bone cell progenitors derived from human embryonic stem cells to grow compact bone tissue in quantities large enough to repair centimeter-sized defects. When implanted in mice and studied over time, the implanted bone tissue supported blood vessel ingrowth, and continued development of normal bone structure, without demonstrating any incidence of tumor growth.

Dr. Marolt’s work is a significant step forward in using pluripotent stem cells to repair and replace bone tissue in patients. Bone replacement therapies are relevant in treating patients with a variety of conditions, including wounded military personnel, patients with birth defects, or patients who have suffered other traumatic injury. Since conducting this work as proof of principle at Columbia University, Dr. Marolt has continued to build upon this research as an Investigator in the NYSCF Laboratory, developing bone grafts from induced pluripotent stem (iPS) cells. iPS cells are similar to embryonic stem cells in that they can also give rise to nearly any type of cell in the body, but iPS cells are produced from adult cells and as such are individualized to each patient. By using iPS cells rather than embryonic stem cells to engineer tissue, Dr. Marolt hopes to develop personalized bone grafts that will avoid immune rejection and other implant complications.

The New York Stem Cell Foundation has supported Dr. Marolt’s research throughout her career, first through a NYSCF – Druckenmiller Fellowship to fund her post-doctoral work at Columbia University, and now with a NYSCF – Helmsley Investigator Award at The New York Stem Cell Foundation Laboratory. “The continuity of funding provided by NYSCF has allowed me to continue my research uninterrupted, making progress more quickly than would have otherwise been possible,” Dr. Marolt said.

Provided by New York Stem Cell Foundation

Abstract

Plasma beta-endorphin, prolactin (PRL), FSH and LH were measured in 17 volunteer male subjects at rest and under the stress caused by a long-distance nordic ski race. The race induced increased levels of beta-endorphin and PRL in all skiers. The changes in PRL with exercise were significantly related to the changes in beta-endorphin (r = 0.69, p less than 0.001). Furthermore, the highly trained skiers training over 150 km.week-1 of nordic ski showed consistently higher post-exercise beta-endorphin and PRL levels than the moderately trained skiers who trained for 20 km.week-1. In addition the race induced slight falls in FSH and LH; however plasma gonadotropin levels did not show any correlation with plasma beta-endorphin concentrations and did not differ between the two groups of skiers. These results suggest that endogenous opioid peptides may modulate PRL secretion in heavy exercise, since they are of minor importance in the release of FSH and LH in such a situation. The observations also suggest that the degree of previous training and the exercise intensity do seem to be responsible for the hormonal changes.

PMID:
2969335
[PubMed – indexed for MEDLINE]