Spinal cord injury (SCI) causes the irreversible loss of spinal cord parenchyma including astroglia, oligodendroglia and neurons. In particular, severe injuries can lead to an almost complete neural cell loss at the lesion site and structural and functional recovery might only be accomplished by appropriate cell and tissue replacement. Stem cells have the capacity to differentiate into all relevant neural cell types necessary to replace degenerated spinal cord tissue and can now be obtained from virtually any stage of development. Within the last two decades, many in vivo studies in small animal models of SCI have demonstrated that stem cell transplantation can promote morphological and, in some cases, functional recovery via various mechanisms including remyelination, axon growth and regeneration, or neuronal replacement. However, only two well-documented neural-stem-cell-based transplantation strategies have moved to phase I clinical trials to date. This review aims to provide an overview about the current status of preclinical and clinical neural stem cell transplantation and discusses future perspectives in the field.

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Bone marrow is the flexible tissue in the interior of bones. In humans, red blood cells are produced by cores of bone marrow in the heads of long bones in a process known as hematopoiesis.[2] On average, bone marrow constitutes 4% of the total body mass of humans; in an adult having 65 kilograms of mass (143 lbs), bone marrow typically accounts for approximately 2.6 kilograms (5.7lb). The hematopoietic component of bone marrow produces approximately 500 billion blood cells per day, which use the bone marrow vasculature as a conduit to the body's systemic circulation.[3] Bone marrow is also a key component of the lymphatic system, producing the lymphocytes that support the body's immune system.[4]

Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Additionally, bone marrow stem cells have been successfully transformed into functional neural cells,[5] and can also potentially be used to treat illnesses such as inflammatory bowel disease.[6]

The two types of bone marrow are "red marrow" (Latin: medulla ossium rubra), which consists mainly of hematopoietic tissue, and "yellow marrow" (Latin: medulla ossium flava), which is mainly made up of fat cells. Red blood cells, platelets, and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type; only around half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous ("spongy") material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of short bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.

The stroma of the bone marrow is all tissue not directly involved in the marrow's primary function of hematopoiesis.[2] Yellow bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

In addition, the bone marrow contains hematopoietic stem cells, which give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes).[7]

The bone marrow stroma contains mesenchymal stem cells (MSCs),[7] also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islets cells.

The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium.[9]Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.

The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells.[4] The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.

Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.[7]

Animal bone marrow has been used in cuisine worldwide for millennia, such as the famed Milanese Ossobuco.[citation needed]

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells.[10] Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.

To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia.[11]

On CT and plain film, marrow change can be seen indirectly by assessing change to the adjacent ossified bone. Assessment with MRI is usually more sensitive and specific for pathology, particularly for hematologic malignancies like leukemia and lymphoma. These are difficult to distinguish from the red marrow hyperplasia of hematopoiesis, as can occur with tobacco smoking, chronically anemic disease states like sickle cell anemia or beta thalassemia, medications such as granulocyte colony-stimulating factors, or during recovery from chronic nutritional anemias or therapeutic bone marrow suppression.[12] On MRI, the marrow signal is not supposed to be brighter than the adjacent intervertebral disc on T1 weighted images, either in the coronal or sagittal plane, where they can be assessed immediately adjacent to one another.[13] Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging,[14] though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process.[15]

Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.

The ratio between myeloid series and erythroid cells is relevant to bone marrow function, and also to diseases of the bone marrow and peripheral blood, such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of thalassemia.[16]

In a bone marrow transplant, hematopoietic stem cells are removed from a person and infused into another person (allogenic) or into the same person at a later time (autologous). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system.[17]

Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses,[5] and can also potentially be used for the treatment of other illnesses, such as inflammatory bowel disease.[6] In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat HIV in conjunction with antiretroviral drugs;[18][19] however, it was later found that HIV remained in the bodies of the test subjects.[20]

The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia. The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 12 days of recovery in the hospital.[21]

Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood.[22] An intravenous catheter is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the sternum, while the tibia is often used when taking samples from infants.[11] In newborns, stem cells may be retrieved from the umbilical cord.[23]

The earliest fossilised evidence of bone marrow was discovered in 2014 in Eusthenopteron, a lobe-finned fish which lived during the Devonian period approximately 370 million years ago.[24] Scientists from Uppsala University and the European Synchrotron Radiation Facility used X-ray synchrotron microtomography to study the fossilised interior of the skeleton's humerus, finding organised tubular structures akin to modern vertebrate bone marrow.[24]Eusthenopteron is closely related to the early tetrapods, which ultimately evolved into the land-dwelling mammals and lizards of the present day.[24]

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Bone marrow - Wikipedia

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J R Soc Med. 2004 Oct; 97(10): 465471.

Institute of Medical Sciences, University of Lincoln, UK

An area of research that today generates great optimism is the use of stem cells for therapy of human diseases. Much of the excitement centres on embryonic stem cells, but this approach remains controversial for ethical reasons; moreover, routine clinical application of this strategy is many years away. By contrast, haematopoietic stem cells from adult bone marrow are well characterized and have long been used therapeutically.1 An adult weighing 70 kg has a functional haematopoietic marrow volume of about 1.75 L and upon increased demands such as infection or haemorrhage it can increase sixfold.1,2 No moral controversy surrounds the use of these cells since they are either autologous or collected from a consenting donor. The potential applications of adult bone marrow cells have gained momentum with discoveries relating to the mesenchymal stem cell.

Adult bone-marrow-derived mesenchymal stem cells (MSC) are capable of differentiation along several lineages ().315 They are positive for CD29, CD44, CD105 and CD166, have a doubling time of about two days, expand in culture up to sixfold and their biological functions are not altered by ageing.3,15 lists some of the cytokine receptors expressed by these cells and the cytokines produced. Their features and properties are closely similar to those of counterpart cells isolated from fetal blood, liver and bone in the first and second trimesters, from amniotic fluid and umbilical cord blood, and from adult peripheral blood, compact bone and adipose tissue.2127 Moreover, a CD133-positive subpopulation of these cells, which can be expanded under defined conditions for more than one hundred population doublings without telomere shortening or karyotypic abnormality, has proved capable of differentiation not only into mesenchymal cell types (osteoblasts, chondrocytes, adipocytes, myocytes) but also into endothelium and cells with neuroectodermal phenotype and function.2830 Previously, adult marrow-derived stem cells were believed to yield a limited number of cell types whereas embryonic cells were totipotent. The discovery of these multipotent adult stem cells has clearly narrowed the gap: they offer a very promising and much more abundant potential resource for therapy of inherited or degenerative diseases and for repair of tissues such as cartilage, bone and myocardium.

What is the mechanism of stem cell differentiation? When the phenomenon was first explored, the possibility of cell fusion was mootedthat is, hybridization with other cells rather than true plasticity. Indeed, embryonic stem cells were seen to hybridize with brain cells to form tetraploid cells with pluripotent character.31 However, in-vitro and in-vivo studies of adult bone marrow stem cells suggest a rate of cell fusion too low to account for the transdifferentiation.32 Moreover, single euploid bone marrow MSC, never co-cultured with tissue-specific cells or embryonic cells, have been seen to differentiate into cells of the three germ layers;33in vivo, the use of bone marrow cells selectively expressing the enhanced green fluorescent protein ruled out fusion as a mechanism for the generation of functional pancreatic islet beta cells;34 and hepatocytes, cardiomyocytes, and pancreatic and endothelial cells have been described as physiologically either diploid or polyploid.3537 Certain cytokines, including interleukins (IL) 1, 4, and 13, tumour necrosis factor alpha and interferon gamma, are involved in the generation of normal multinucleated cells such as osteoclasts and Langhans giant cells;3840 thus, observations suggesting fusion of bone marrow cells with, for example, Purkinje neurons, cardiomyocytes and hepatocytes41 may instead simply reflect physiological polyploidy.

The direction in which bone marrow MSC differentiate is heavily influenced by cytokines (). For example, bone morphogenetic protein 6 (BMP-6) not only influences differentiation towards chondrogenesis or osteogenesis but may also serve to regulate the bone marrow environment via the effects of IL-6 on haematopoiesis and osteogenesis.50 Two possible mechanisms have been proposed for a regulatory role of BMP-6 in the human bone marrow microenvironment: (i) it might enhance the osteoblastic differentiation of human MSC; or (ii) it might reduce the osteoclastic differentiation of haematopoietic marrow cells by decreasing interleukin-6 production in bone marrow stroma. MSC coexpressing CD133 and fetal liver kinase 1 generated endothelial cells in the presence of vascular endothelial growth factor, and functional hepatocytes in the presence of fibroblast growth factor-4 and hepatocyte growth factor.29,30 Also, MSC coexpressing CD133, CD172 and nestin differentiated along a neural pathway in the presence of fibroblast growth factor or retinoic acid plus nerve growth factor.51,54 An MSC side-population with high efflux of DNA binding dye and expressing CD90 (Thy1) differentiated into mesangial renal cells.55

In-vitro differentiation conditions of human adult bone marrow mesenchymal stem cell

In animal models, transplanted bone marrow cells have been detected in skeletal and cardiac muscle,5658 vascular endothelium,58,59 liver,6062 lung, gut and skin epithelia,62 pancreatic beta cell islets,34,63 renal glomeruli,14,55 and neural tissue.33,6469 When bone-marrow-derived MSC were injected intracerebrally in acid-sphingomyelinase-deficient mice, the onset of neurological abnormalities was delayed and the animals lifespan was extended.70 Local transplantation of such cells is also reported to have regenerated bone7173 and myocardium.74,75 It is noteworthy that no donor-derived tumours have been seen in these animal modelswhereas with transplantation of undifferentiated embryonic stem cells teratoma development has been reported.76 The results also differ from those of undifferentiated embryonic stem cell transplantation in that engraftment and tissue-specific differentiation are achieved without pretransplantation measures to induce differentiation down the lineage desired. The ability of marrow-derived cells to populate numerous body tissuesbone, liver, cardiac muscle, colon, skinis well shown in patients who have received cells from gender-mismatched donors ().7784 A postmortem study revealed donor-derived neurons in the hippocampus and cerebral cortex of brain samples from women who had received bone marrow transplants from men.85 Deductions from such findings must be qualified by the observation that women who have carried male fetuses may show long-term mosaicism with male cells; nevertheless, the weight of the evidence is that donor bone-marrow-derived cells can migrate and give rise to tissues belonging to all three germ-cell layers.7785 It is noteworthy that, in the transdifferentiation of these adult marrow stem cells, there was no evidence of cell fusion.7785 Lately, work in mice indicated that such cells participate in skin regeneration and reconstitution and promote wound healing;8688 and one research group reports a pilot study in three patients indicating that locally applied autologous bone marrow cells enhanced dermal building and closure of long-term non-healing wounds.89

Migration of human adult bone marrow stem cells in gender-mismatched bone marrow transplantation patients

In animal models of myocardial infarction, stem cells were reported to participate in repair whether injected locally or stimulated in bone marrow by use of stem cell factor (SCF) and G-CSF.90 In man, a randomized placebo-controlled study revealed increased coronary collateral flow in patients treated with intracoronary GM-CSF (molgramostim) followed by two weeks of subcutaneous administration.91

In the past decade the use of G-CSF (filgrastim) has transformed the treatment of cancer by facilitating marrow reconstitution after myeloablative therapy. We must hope for a similar breakthrough in the management of coronary heart disease.

In allogeneic transplantation, mesenchymal stem cells in bone marrow play a key part in immunomodulation and the induction of tolerance. MSC suppress the proliferation of T-lymphocytes induced by cellular or non-specific mitogenic stimuli92 and negatively influence B-cell lymphopoiesis.93 Allogeneic/xenogeneic MSC transplants engraft in immunocompetent sheep and non-human primates.9497 When a patient was treated, after myeloablation, with both haematopoietic stem cells and cultured MSC from a mismatched donor, only grade I graft-versus-host disease (GvHD) was observed.98 That MSC can not only reduce GvHD but also facilitate haematopoietic engraftment is evidenced by the rapid haematopoietic recovery of patients with breast cancer who received autologous blood stem cells together with culture-expanded MSC after high-dose chemotherapy.99 In both clinical trials, MSC transplantation was well tolerated.

Osteogenesis imperfecta has been the focus of two studies in children. Allogeneic MSC transplantation, leading to successful osteoblast engraftment in 3 of 5 children with type III osteogenesis imperfecta, was associated with a 4477% increase in bone mineral content, improved linear growth and reduced fracture frequency.77,100 In another cohort of 6 children with type III osteogenesis imperfecta who had received earlier bone marrow transplantation, MSC infusions from the original donor resulted in a 50% improvement in their growth velocity.101 Similar improvements were observed in children with metachromatic leukodystrophy and Hurlers syndrome after repeated allogeneic marrow MSC infusions.102

Ten clinical studies have been reported on the effects of autologous bone marrow stem cell transplantation in patients with myocardial infarction or ischaemic heart failure ().103112 In three pilot studies, two of them randomized controlled trials, bone marrow cells infused via a coronary catheter a few days after acute myocardial infarction led to significant improvement in coronary flow reserve and left ventricular ejection fraction.104,105,111 In the remaining seven, marrow cells injected directly into the myocardium of patients with chronic ischaemic heart disease yielded benefits in ejection fraction and also angina score.103,106110,112

Clinical trials of adult bone marrow autotransplantation in ischaemic heart disease

Despite the impressive safety record of all these pilot clinical trials, the possibility of undesired differentiation into other tissues must be borne in mind in monitoring of future studies.

In the next decade, the approaches discussed above will clearly be developed and refined. Further avenues will open up. For example, bone-marrow-derived cells expressing stem cell factor have been shown to initiate endogenous pancreatic tissue regeneration in mice.113 If such cells could be used as pancreatic beta islet cell progenitors, there would be scope for autologous transplantation in patients with diabetes, avoiding the need for the immunosuppression necessary after allotransplantation and circumventing the scarcity of allogeneic material. Whereas the multipotent adult dermal stem cells from human scalp skin have shown mainly neural differentiation, suggesting a possible therapeutic role in neurodegenerative diseases,114,115 the bone marrow MSC show strong orientation towards bone, cartilage, endothelium and cardiac muscle.

In conclusion, the existing medical uses of bone marrow are likely to expand greatly with exploitation of the therapeutic potential of adult mesenchymal stem cells, with their capacity for many lines of differentiation. The next stage is to isolate the various subsets and investigate their mechanisms of differentiation and homing to tissues. This work has vast implications for human wellbeing, through cell and gene therapies, through tissue engineering and through immunotherapy.

1. Hassan HT, Gutensohn K, Zander AR, Kuhnl P. CD34 positive cell sorting and enrichment: applications in bloodbanking and transplantation. In: Recktenwald D, Radbruch A, eds. Cell Separation: Methods and Applications. New York: Marcel Dekker, 1998: 28392

9. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2002;174: 1120

73. Kadiyala S, Jaiswal N, Bruder SP. Culture-expanded bone marrow-derived mesenchymal stem cells regenerate a critical-sized bone defect. Tissue Eng 9197;3: 17385

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Adult bone-marrow stem cells and their potential in medicine

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The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the iAAA protease YME1L

These authors contributed equally to this work

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

SLP2 assembles with PARL and YME1L into the SPY complex in the mitochondrial inner membrane.

Assembly into SPY complexes modulates PARLmediated processing of PINK1 and PGAM5.

SLP2 restricts OMA1mediated processing of the OPA1.

Timothy Wai, Shotaro Saita, Hendrik Nolte, Sebastian Mller, Tim Knig, Ricarda RichterDennerlein, HansGeorg Sprenger, Joaquin Madrenas, Mareike Mhlmeister, Ulrich Brandt, Marcus Krger, Thomas Langer

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For years, the cornerstones of cancer treatment have been surgery, chemotherapy, and radiation therapy. Over the last decade, targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin)drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cellshave also emerged as standard treatments for a number of cancers.

Illustration of the components of second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 278090. doi:10.1158/1078-0432.CCR-11-1920)

And now, despite years of starts and stutter steps, excitement is growing for immunotherapytherapies that harness the power of a patients immune system to combat their disease, or what some in the research community are calling the fifth pillar of cancer treatment.

One approach to immunotherapy involves engineering patients own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

For example, in several early-stage trials testing ACT in patients with advanced acute lymphoblastic leukemia (ALL) who had few if any remaining treatment options, many patients cancers have disappeared entirely. Several of these patients have remained cancer free for extended periods.

Equally promising results have been reported in several small trials involving patients with lymphoma.

These are small clinical trials, their lead investigators cautioned, and much more research is needed.

But the results from the trials performed thus far are proof of principle that we can successfully alter patients T cells so that they attack their cancer cells, said one of the trial's leaders, Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

Adoptive cell transfer is like giving patients a living drug, continued Dr. Brentjens.

Thats because ACTs building blocks are T cells, a type of immune cell collected from the patients own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions.

The expanded population of CAR T cells is then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patients body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

Although adoptive cell transfer has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

This process builds on a similar form of ACT pioneered by Steven Rosenberg, M.D., Ph.D., and his colleagues from NCIs Surgery Branch for patients with advanced melanoma.

The CAR T cells are much more potent than anything we can achieve with other immune-based treatments being studied, said Crystal Mackall, M.D., of NCIs Pediatric Oncology Branch (POB).

Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism.

CAR T-cell therapy eventually may become a standard therapy for some B-cell malignancies like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article.

More than 80 percent of children who are diagnosed with ALL that arises in B cellsthe predominant type of pediatric ALLwill be cured by intensive chemotherapy.

For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are close to none, said Stephan Grupp, M.D., Ph.D., of the Childrens Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said.

Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous.

In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine.

Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy.

According to the most recent data from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the studys lead investigator, Daniel W. Lee, M.D., also of the POB.

Dr. Crystal Mackall

Our findings strongly suggest that CAR T-cell therapy is a useful bridge to bone marrow transplant for patients who are no longer responding to chemotherapy, Dr. Lee said.

Similar results have been seen in phase I trials of adult patients conducted at MSKCC and NCI.

In findings published in February 2014, 14 of the 16 participants in the MSKCC trial treated to that point had experienced complete responses, which in some cases occurred 2 weeks or sooner after treatment began. Of those patients who were eligible, 7 underwent a stem cell transplant and are still cancer free.

The NCI-led trial of CAR T cells included 15 adult patients, the majority of whom had advanced diffuse large B-cell lymphoma. Most patients in the trial had either complete or partial responses, reported James Kochenderfer, M.D., and his NCI colleagues.

Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable, Dr. Kochenderfer said. [NCI Surgery Branch researchers have also reported promising results from one of the first trials testing CAR T cells derived from donors, rather than the patients themselves, to treat leukemia and lymphoma.]

Other findings from the trials have been encouraging, as well. For example, the number of CAR T cells increased dramatically after infusion into patients, as much as 1,000-fold in some individuals. In addition, after infusion, CAR T cells were detected in the central nervous system, a so-called sanctuary site where solitary cancer cells that have evaded chemotherapy or radiation may hide. In two patients in the NCI pediatric trial, the CAR T-cell treatment eradicated cancer that had spread to the central nervous system.

If CAR T cells can persist at these sites, it could help fend off relapses, Dr. Mackall noted.

CAR T-cell therapy can cause several worrisome side effects, perhaps the most troublesome being cytokine-release syndrome.

The infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. With cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.

Cytokine-release syndrome is a common problem in patients treated with CAR T cells. In the POB and CHOP trials, patients with the most extensive disease prior to receiving the CAR T cells were more likely to experience severe cases of cytokine-release syndrome.

For most patients, trial investigators have reported, the side effects are mild enough that they can be managed with standard supportive therapies, including steroids.

The research team at CHOP noticed that patients experiencing severe reactions all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to two drugs that are approved to treat inflammatory conditions like juvenile arthritis: etanercept (Enbrel) and tocilizumab (Actemra), the latter of which blocks IL-6 activity.

The patients had excellent responses to the treatment, Dr. Grupp said. We believe that [these drugs] will be a major part of toxicity management for these patients.

The other two teams subsequently used tocilizumab in several patients. Dr. Brentjens agreed that both drugs could become a useful way to help manage cytokine-release syndrome because, unlike steroids, they dont appear to affect the infused CAR T cells activity or proliferation.

Even with these encouraging preliminary findings, more research is needed before CAR T-cell therapy becomes a routine option for patients with ALL.

We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics, Dr. Grupp said.

We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics.

Dr. Stephan Grupp

Several other trials testing CAR T cells in children and adults are ongoing and, with greater interest and involvement from the pharmaceutical and biotechnology sector, more trials testing CAR T cells are being planned.

Researchers are also studying ways to improve on the positive results obtained to date, including refining the process by which the CAR T cells are produced.

Research groups like Dr. Brentjens are also working to make a superior CAR T cell, including developing a better receptor and identifying better targets.

For example, Dr. Lee and his colleagues at NCI have developed CAR T cells that target the CD22 antigen, which is also present on most B cells, although in smaller quantities than CD19. The CD22-targeted T cells, he believes, could be used in concert with CD19-targeted T cells as a one-two punch in ALL and other B-cell cancers. NCI researchers hope to begin the first clinical trial testing the CD22-targeted CAR T cells in November 2014.

Based on the success thus far, several research groups across the country are turning their attention to developing engineered T cells for other cancers, including solid tumorslike pancreatic and brain cancers.

The stage has now been set for greater progress, Dr. Lee believes.

NCI investigators, for example, now have a platform to plug and play better CARs into that system, without a lot of additional R&D time, he continued. Everything else should now come more rapidly.

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Gene therapy and cell therapy are overlapping fields of biomedical research with the goals of repairing the direct cause of genetic diseases in the DNA or cellular population, respectively. These powerful strategies are also being focused on modulating specific genes and cell subpopulations in acquired diseases in order to reestablish the normal equilibrium. In many diseases, gene and cell therapy are combined in the development of promising therapies.

In addition, these two fields have helped provide reagents, concepts, and techniques that are elucidating the finer points of gene regulation, stem cell lineage, cell-cell interactions, feedback loops, amplification loops, regenerative capacity, and remodeling.

Gene therapy is defined as a set of strategies that modify the expression of an individuals genes or that correct abnormal genes. Each strategy involves the administration of a specific DNA (or RNA).

Cell therapy is defined as the administration of live whole cells or maturation of a specific cell population in a patient for the treatment of a disease.

Gene therapy: Historically, the discovery of recombinant DNA technology in the 1970s provided the tools to efficiently develop gene therapy. Scientists used these techniques to readily manipulate viral genomes, isolate genes, identify mutations involved in human diseases, characterize and regulate gene expression, and engineer various viral vectors and non-viral vectors. Many vectors, regulatory elements, and means of transfer into animals have been tried. Taken together, the data show that each vector and set of regulatory elements provides specific expression levels and duration of expression. They exhibit an inherent tendency to bind and enter specific types of cells as well as spread into adjacent cells. The effect of the vectors and regulatory elements are able to be reproduced on adjacent genes. The effect also has a predictable survival length in the host. Although the route of administration modulates the immune response to the vector, each vector has a relatively inherent ability, whether low, medium or high, to induce an immune response to the transduced cells and the new gene products.

The development of suitable gene therapy treatments for many genetic diseases and some acquired diseases has encountered many challenges and uncovered new insights into gene interactions and regulation. Further development often involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes.

While effective long-term treatments for anemias, hemophilia, cystic fibrosis, muscular dystrophy, Gauschers disease, lysosomal storage diseases, cardiovascular diseases, diabetes, and diseases of the bones and joints are elusive today, some success is being observed in the treatment of several types of immunodeficiency diseases, cancer, and eye disorders. Further details on the status of development of gene therapy for specific diseases are summarized here.

Cell therapy: Historically, blood transfusions were the first type of cell therapy and are now considered routine. Bone marrow transplantation has also become a well-established protocol. Bone marrow transplantation is the treatment of choice for many kinds of blood disorders, including anemias, leukemias, lymphomas, and rare immunodeficiency diseases. The key to successful bone marrow transplantation is the identification of a good "immunologically matched" donor, who is usually a close relative, such as a sibling. After finding a good match between the donors and recipients cells, the bone marrow cells of the patient (recipient) are destroyed by chemotherapy or radiation to provide room in the bone marrow for the new cells to reside. After the bone marrow cells from the matched donor are infused, the self-renewing stem cells find their way to the bone marrow and begin to replicate. They also begin to produce cells that mature into the various types of blood cells. Normal numbers of donor-derived blood cells usually appear in the circulation of the patient within a few weeks. Unfortunately, not all patients have a good immunological matched donor. Furthermore, bone marrow grafts may fail to fully repopulate the bone marrow in as many as one third of patients, and the destruction of the host bone marrow can be lethal, particularly in very ill patients. These requirements and risks restrict the utility of bone marrow transplantation to some patients.

Cell therapy is expanding its repertoire of cell types for administration. Cell therapy treatment strategies include isolation and transfer of specific stem cell populations, administration of effector cells, induction of mature cells to become pluripotent cells, and reprogramming of mature cells. Administration of large numbers of effector cells has benefited cancer patients, transplant patients with unresolved infections, and patients with chemically destroyed stem cells in the eye. For example, a few transplant patients cant resolve adenovirus and cytomegalovirus infections. A recent phase I trial administered a large number of T cells that could kill virally-infected cells to these patients. Many of these patients resolved their infections and retained immunity against these viruses. As a second example, chemical exposure can damage or cause atrophy of the limbal epithelial stem cells of the eye. Their death causes pain, light sensitivity, and cloudy vision. Transplantation of limbal epithelial stem cells for treatment of this deficiency is the first cell therapy for ocular diseases in clinical practice.

Several diseases benefit most from treatments that combine the technologies of gene and cell therapy. For example, some patients have a severe combined immunodeficiency disease (SCID) but unfortunately, do not have a suitable donor of bone marrow. Scientists have identified that patients with SCID are deficient in adenosine deaminase gene (ADA-SCID), or the common gamma chain located on the X chromosome (X-linked SCID). Several dozen patients have been treated with a combined gene and cell therapy approach. Each individuals hematopoietic stem cells were treated with a viral vector that expressed a copy of the relevant normal gene. After selection and expansion, these corrected stem cells were returned to the patients. Many patients improved and required less exogenous enzymes. However, some serious adverse events did occur and their incidence is prompting development of theoretically safer vectors and protocols. The combined approach also is pursued in several cancer therapies.

Further information on the progress and status of gene therapy and cell therapy on various diseases is listed here.

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Gene Therapy and Cell Therapy Defined | ASGCT - American ...

Uncategorized Comments Off on Gene Therapy and Cell Therapy Defined | ASGCT – American … | October 20th, 2015

OK, so now we know the problem. There are certain genes needed to make a cell turn into an ES cell. Since these genes are presumably off in a skin cell, we need to turn them on again. And have all of the skin cell genes shut off too.

The way the scientists decided to do this was to add back whatever genes are needed to erase the pattern in the skin cell. (These genes are off in a skin cell.) This is a lot easier than specifically turning on this small set of genes.

The way they decided to add back the genes was with a virus. A lot of gene therapy gets done this way.

Many viruses work by sticking themselves into a cell's DNA. What the scientists planned to do was to take out some of the nonessential virus DNA and put in the necessary genes.

We're all set except we don't yet have the genes. Scientists had figured out through various means that if they added 24 different genes to a skin cell, it would turn into an ES cell. Yikes!

That is way too many to do gene therapy. So they started taking one away at a time to find the really key ones. They finally settled on 4 genes. This is still an awful lot but it is at least doable.

Last year they added back these genes and got some promising results. The skin cells took on many of the properties of ES cells but not all of them. This is encouraging but not good enough.

To fix this, they changed the skin cells to make selecting the most ES-like ones easier to do. When they did this, they were able to grow cells that essentially looked like an ES cell.

As a final test, they added some of these cells to an early mouse embryo. The embryo grew into a pup that contained different cell types derived from the original embryo and the skin cells (a chimera). This test proved these cells had been turned into something that could be used as ES cells.

Cool. But it is not a slam dunk to get this to work in people. We don't know if these same 4 genes are the ones that work in people too. And around 20% of the mice died from cancers caused by one of the added genes.

But these are problems we can deal with. Of course we'll have to continue to use "real" ES cells to figure out the genes needed to turn skin cells into ES cells. In other words, we need to destroy embryos now to stop destroying them in the future.

This research will progress very quickly. Because the experiments are easier to do than cloning, little labs all over the world can tackle these kinds of questions with no government interference. Personalized medicine may be here sooner than we think.

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Embryonic stem cells from skin cells | Understanding Genetics

Skin Stem Cells Comments Off on Embryonic stem cells from skin cells | Understanding Genetics | October 16th, 2015

A patient has become the first in the UK to receive an experimental stem cell treatment that has the potential to save the sight of hundreds of thousands of Britons.

By December, doctors will know whether the woman, who has age-related macular degeneration, has regained her sight after a successful operation at Moorfields Eye Hospital in London last month. Over 18 months, 10 patients will undergo the treatment.

The transplant involves eye cells, called retinal pigment epithelium, derived from stem cells and grown in the lab to form a patch that can be placed behind the retina during surgery.

Related: Stem cell therapy success in treatment of sight loss from macular degeneration

The potential is huge. Although the first patients have the wet form of macular degeneration, the doctors believe it might also eventually work for those who have the dry form, who are the vast majority of the UKs 700,000 sufferers.

The surgery is an exciting moment for the 10-year-old London Project to Cure Blindness, a collaboration between the hospital, the UCL Institute of Ophthalmology and the National Institute for Health Research, which was formed to find a cure for wet age-related macular degeneration, the more serious but less common form of the disease.

Prof Pete Coffey of UCL, one of the founders of the London Project, said he would not be working on the new treatment if he did not believe it would work. He hopes it could become a routine procedure for people afflicted by vision loss, which is as common a problem among older people as dementia.

It does involve an operation, but were trying to make it as straightforward as a cataract operation, he said. It will probably take 45 minutes to an hour. We could treat a substantial number of those patients.

First they have to get approval. The trial is not just about safety, but also efficacy. There will be a regulatory review after the first few transplants to ensure all is going well.

The group of patients chosen have the wet form of the disease and experienced sudden loss of vision within about six weeks. The support cells in the eye, which get rid of daily debris and allow the seeing part to function have died.

There is a possibility of restoring their vision, said Coffey. The aim of the transplant is to restore the support cells so the seeing part of the eye is not affected by what would become an increasingly toxic environment, causing deterioration and serious vision loss. The surgery is being performed by retinal surgeon Prof Lyndon Da Cruz from Moorfields, who is also a co-founder of the London Project.

The team chose people with this dramatic vision loss to see whether the experimental stem cell therapy would reverse the loss of vision. But in those with dry macular degeneration, said Coffey, the process is far slower, which would mean doctors could choose the time to intervene if the treatment works.

Helping people to regain their sight has long been one of the most hopeful prospects for stem cell transplantation. Other research groups have been trialling the use of stem cells in people with Stargardts disease, which destroys the vision at a much earlier age.

Stem cells have moved from the drawing board into human trials with incredible speed, scientists say. The first embryonic stem cell was derived in 1989. Using them in eyes was always going to have a big advantage over other prospects, because it is possible to transplant them without an all-out attack by the immune system, as would happen in other parts of the body. Most people who have any sort of transplant have to take drugs that suppress the immune system for the rest of their lives.

Just like conventional medicines, stem cell therapies will very likely have to be developed and marketed by large commercial concerns. The London Project has the US drug company Pfizer on board.

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First UK patient receives stem cell treatment to cure loss ...

Uncategorized Comments Off on First UK patient receives stem cell treatment to cure loss … | October 5th, 2015

George Reed's heart wasn't doing so well: He's 71, and after suffering a heart attack years earlier, Reed had undergone open heart surgery and was put on multiple medications. But nothing seemed to help the dizziness and chest pain he experienced daily.

"I'd get dizzy and just fall over -- sometimes twice a day. I would run my head into the concrete. I was a bloody mess," the Perry, Ohio, native says. Despite his doctor's best efforts, Reed continued to experience angina, a type of chest pain that occurs when the heart doesn't get enough oxygen-rich blood; it can be accompanied by dizziness. So when he was recommended for an experimental study that would inject his own stem cells into his damaged heart, Perry signed on. "I needed something to change," he says.

Researchers gave Reed a drug commonly used in bone marrow transplants that stimulates the marrow to make more stem cells. Then they removed some of Reed's blood, isolated the stem cells and injected them into and around the damaged areas of his heart.

"The goal was to grow new blood vessels with stem cells from the patient's own body," says Dr. Tim Henry, a co-author of the study and director of research at the Minneapolis Heart Institute Foundation.

Within a few months, Reed, along with many of the other 100 or so patients at 26 hospital centers who'd received this stem cell treatment, reported feeling better than he had in years.

"When it started kicking in, I felt like a kid. I felt good," Reed says. He wasn't passing out and falling down anymore.

For Jay Homstad, 49, who was part of the Minnesota branch of the study, he felt the changes most in his ability to walk and be active.

"My activity level increased tenfold. Before, I struggled with chest pain every day. My activity level was about as close to zero as you could get. Now I can participate ... just in life. It may sound silly, but the best part is that in the wintertime I could go out and walk with my dog along the Red River. When you're walking through snow that is waist deep, you can tell there's a difference," Homstad says.

Homstad had had about a dozen surgeries and nine stents put in before he enrolled in the study, but he still struggled with angina daily. Within a few months of the stem cell shots, he could walk farther, and his chest pain subsided and was kept at bay for nearly four years.

"These are people for whom other treatment hasn't worked. They're debilitated by their chest pain, but their other options are really limited, that's why we picked them," says Henry. If the positive results seen in this study hold up in the next phase of the study, which is set to begin enrollment in the fall, this type of cardiac stem cell injection could be added to the arsenal of weapons against angina. The upcoming phase three trial has already been approved by the Food and Drug Administration.

Shot to the Heart, Before It's too Late

While several smaller studies have suggested that injecting stem cells into damaged heart tissue might be effective, this study, in its scope and rigor, was the first of its kind. A total of 167 patients were recruited and randomly assigned to receive a lower dose of stem cells, a higher dose or a placebo. The patients didn't know who got what treatment, and neither did the doctors treating them.

When tracked for a year after the injection, patients who received the lower dose of stem cells could last longer during a treadmill exercise than those who had received the placebo, and they averaged seven fewer episodes of chest pain in a week. To put this in perspective, a popular drug to treat angina, Ranolazine, reduced chest pain by fewer than two episodes a week in clinical trials.

Although the goal of the stem cell shots was to grow new blood vessels, it's impossible to tell if these stem cells were actually growing into blood vessels or if they were just triggering some other kind of healing process in the body, Henry says. Tests in animal models, however, do suggest that new blood vessels are forming, says Dr. Marco Costa, a co-author of the study and George Reed's doctor at UH Case Medical Center in Cleveland.

For now, the only gauge of the injections is improvement in symptoms.

Despite the positive results of the study, cardiologists remain "cautiously optimistic" about stem cells as a treatment for angina.

"The number of patients is relatively small, so this trial would probably not carry much scientific weight," says Dr. Jeff Brinker, a professor of cardiology at Johns Hopkins University. The results did justify the next, larger trial, he says, which would offer more answers as to whether this treatment is actually working the way researchers suspect.

The fact that lower doses of stem cells were puzzlingly more effective than larger ones is cause for caution, says Dr. Steve Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

"The jury is still out for stem cell therapies to treat heart disease," says Dr. Cam Paterson, a cardiologist at the University of North Carolina at Chapel Hill.

But the results so far provide cautious hope for heart patients like George Reed and Jay Homstad.

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Injecting the Heart With Stem Cells Helps Chest Pain - ABC ...

Cardiac Stem Cells Comments Off on Injecting the Heart With Stem Cells Helps Chest Pain – ABC … | September 13th, 2015

A new method for delivering stem cells to damaged heart muscle has shown early promise in treating severe heart failure, researchers report.

In a preliminary study, they found the tactic was safe and feasible for the 48 heart failure patients they treated. And after a year, the patients showed a modest improvement in the heart's pumping ability, on average.

It's not clear yet whether those improvements could be meaningful, said lead researcher Dr. Amit Patel, director of cardiovascular regenerative medicine at the University of Utah.

He said larger clinical trials are underway to see whether the approach could be an option for advanced heart failure.

Other experts stressed the bigger picture: Researchers have long studied stem cells as a potential therapy for heart failure -- with limited success so far.

"There's been a lot of promise, but not much of a clinical benefit yet," said Dr. Lee Goldberg, who specializes in treating heart failure at the University of Pennsylvania.

Researchers are still sorting through complicated questions, including how to best get stem cells to damaged heart muscle, said Goldberg, who was not involved in the new study.

What's "novel" in this research, he said, is the technique Patel's team used to deliver stem cells to the heart. They took stem cells from patients' bone marrow and infused them into the heart through a large vein called the coronary sinus.

Patel agreed that the technique is the advance.

"Most other techniques have infused stem cells through the arteries," Patel explained. One obstacle, he said, is that people with heart failure generally have hardened, narrowed coronary arteries, and the infused stem cells "don't always go to where they should."

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Stem Cells Show Promise in Heart Failure Treatment

Cardiac Stem Cells Comments Off on Stem Cells Show Promise in Heart Failure Treatment | August 1st, 2015

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Stem Cell Research is an amazing field right now, and promises to be a powerful and potent tool to help us live longer and healthier lives. Just last month, for example, Stem Cell Therapy was used to restore sight in patients with severe retinal deterioration, allowing them to see clearer than they had in years, or even decades.

Now, there is another form of Stem Cell Treatment on the horizonthis one of a very different form. Stem Cells have now been used as a mechanism to deliver medical treatment designed to eliminate cancer cells, even in hard to reach places. One issue with current cancer treatments is that, treatments that are effective at treating tumors on the surface of the brain cannot be performed safely when the tumor is deeper within the brains tissues.

Stem Cells have the fantastic ability to transform into any other kind of cell within the human body, given the appropriate stimulation. As of today, most of these cells come from Embryonic Lines, but researchers are learning how to backwards engineer cells in the human body, reverting them back to their embryonic state. These cells are known as Induced Pluripotent Stem Cells.

How Does This Stem Cell Cancer Treatment Work?

Using genetic engineering, it is possible to create stem cells that are designed to release a chemical known as Pseudomonas Exotoxin, which has the ability to destroy certain tumor cells in the human brain.

What is Pseudomonas Exotoxin?

Pseudomonas Exotoxin is a compound that is naturally released by a form of bacteria known as Pseudomonas Aeruginosa. This chemical is toxic to brain tumor cells because it prevents polypeptides from growing longer, essentially preventing the polypeptides from growing and reproducing. When used in a specific manner, this toxin has the ability to destroy cancerous and malignant tissue without negatively impacting healthy tissue. In addition to its potential as a cancer treatment, there is also evidence that the therapy could be used for the treatment of Hepatitis B.

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IPS Cell Therapy

IPS Cell Therapy Comments Off on IPS Cell Therapy | July 2nd, 2015

General Information About Prostate Cancer Key Points Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate. Signs of prostate cancer include a weak flow of urine or frequent urination. Tests that examine the prostate and blood are used to detect (find) and diagnose prostate cancer. Certain factors affect prognosis (chance of recovery) and treatment options. Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate.

The prostate is a gland in the male reproductive system. It lies just below the bladder (the organ that collects and empties urine) and in front of the rectum (the lower part of the intestine). It is about the size of a walnut and surrounds part of the urethra (the tube that empties urine from the bladder). The prostate gland makes fluid that is part of the semen.Enlarge

Anatomy of the male reproductive and urinary systems, showing the prostate, testicles, bladder, and other organs.

Prostate cancer is found mainly in older men. In the U.S., about 1 out of 5 men will be diagnosed with prostate cancer.

These and other signs and symptoms may be caused by prostate cancer or by other conditions. Check with your doctor if you have any of the following:

Other conditions may cause the same symptoms. As men age, the prostate may get bigger and block the urethra or bladder. This may cause trouble urinating or sexual problems. The condition is called benign prostatic hyperplasia (BPH), and although it is not cancer, surgery may be needed. The symptoms of benign prostatic hyperplasia or of other problems in the prostate may be like symptoms of prostate cancer.

Normal prostate and benign prostatic hyperplasia (BPH). A normal prostate does not block the flow of urine from the bladder. An enlarged prostate presses on the bladder and urethra and blocks the flow of urine.

The following tests and procedures may be used:

Digital rectal exam (DRE). The doctor inserts a gloved, lubricated finger into the rectum and feels the prostate to check for anything abnormal.

Transrectal ultrasound. An ultrasound probe is inserted into the rectum to check the prostate. The probe bounces sound waves off body tissues to make echoes that form a sonogram (computer picture) of the prostate.

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Prostate Cancer Treatment - National Cancer Institute

Uncategorized Comments Off on Prostate Cancer Treatment – National Cancer Institute | June 23rd, 2015

John W. McDonald, M.D., Ph.D. an associate professor of neurology at the Johns Hopkins University School of Medicine and director of the International Center for Spinal Cord Injury at Kennedy Krieger Institute taps into the bodys own repair mechanisms in search of treatments for spine injury.

Stem cells allow us to address questions Ive thought about forever. These are really exciting times for the repair of the nervous system, because we can move beyond mere correlation and get definitive answers.

Despite what I was taught in medical school, nervous system cells do divide and grow. Not all of them. But oligodendrocytes are the most prominent ones that do. If we were to follow newly born cells in an adult human brain for an hour, the majority of those cells would go on to become oligodendrocytes.

Injury and the consequence of injury disrupts the turning over of cells, basically because of reduced electrical activity, which oligodendrocytes depend on for survival and myelination.

Im convinced that endogenous stem cells in the spinal cordthose naturally born there by the million, every hour, even in spinal cord injured adultsrepresent an important therapeutic target.

Through the transplantation work were doing in mice, were learning a lot about the natural environment of cells in the nervous system. For example, mouse embryonic stem cells have the innate mechanism to overcome physical and chemical barriers. Their presence changes the microenvironment enough so that endogenous cells are able to cross barriers such as scars. We are working on figuring how to activate the same cues that cause those microenvironment changes without actually transplanting stem cells.

The whole nervous systemall the signaling between cellsruns by electrical activity. Were just now getting access to the imaging tools to be able to see and begin to understand it. If that ensemble of activity is disrupted by injury, what percent of connections remain, and how can we use what remains to recreate the orchestra?

New imaging methods now are confirming earlier animal studies that as much as 30 percent of connections can still remain below the level of spinal cord injury, even in the severe injury scenarios. This realizationthat we dont need to cure the nervous system, we just need partial repairis born out in people whove had bad spinal cord injuries who now can regain substantial function and even walk..

Our strategy is to maximize the physical integrity of your body so it can meet a cure halfway when a cure comes. We discovered that we can make a great impact on an individuals own spontaneous recovery by facilitating the bodys own micro-repair system.

What we do in lab is geared toward understanding these mechanisms of microrepair. We already know that myelination and birth of oligodendrocytes are incredibly dependent on electrical activity.

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Stem Cell Research at Johns Hopkins Medicine: Spinal ...

Spinal Cord Stem Cells Comments Off on Stem Cell Research at Johns Hopkins Medicine: Spinal … | May 31st, 2015

Fetal stem cells

The embryo is referred to as a fetus after the eighth week of development. The fetus contains stem cells that are pluripotent and eventually develop into the different body tissues in the fetus.

Adult stem cells present in all humans in small numbers. The adult stem cell is one of the class of cells that we have been able to manipulate quite effectively in the bone marrow transplant arena over the past 30 years. These are stem cells that are largely tissue-specific in their location. Rather than typically giving rise to all of the cells of the body, these cells are capable of giving rise only to a few types of cells that develop into a specific tissue or organ. They are therefore known as multipotent stem cells. Adult stem cells are sometimes referred to as somatic stem cells.

The best characterized example of an adult stem cell is the blood stem cell (the hematopoietic stem cell). When we refer to a bone marrow transplant, a stem cell transplant, or a blood transplant, the cell being transplanted is the hematopoietic stem cell, or blood stem cell. This cell is a very rare cell that is found primarily within the bone marrow of the adult.

One of the exciting discoveries of the last years has been the overturning of a long-held scientific belief that an adult stem cell was a completely committed stem cell. It was previously believed that a hematopoietic, or blood-forming stem cell, could only create other blood cells and could never become another type of stem cell. There is now evidence that some of these apparently committed adult stem cells are able to change direction to become a stem cell in a different organ. For example, there are some models of bone marrow transplantation in rats with damaged livers in which the liver partially re-grows with cells that are derived from transplanted bone marrow. Similar studies can be done showing that many different cell types can be derived from each other. It appears that heart cells can be grown from bone marrow stem cells, that bone marrow cells can be grown from stem cells derived from muscle, and that brain stem cells can turn into many types of cells.

Medically Reviewed by a Doctor on 1/23/2014

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Stem Cells Symptoms, Causes, Treatment - MedicineNet

Uncategorized Comments Off on Stem Cells Symptoms, Causes, Treatment – MedicineNet | May 5th, 2015

Autologous Adipose Tissue Derived Stromal Vascular Fraction Cells Application In Patients
The U.S. Stem Cell Clinic is founded on the principle belief that the quality of life for our patients can be improved through stem cell therapy. We are dedicated to providing safe and effective...

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Autologous Adipose Tissue Derived Stromal Vascular Fraction Cells Application In Patients - Video

Uncategorized Comments Off on Autologous Adipose Tissue Derived Stromal Vascular Fraction Cells Application In Patients – Video | April 30th, 2015

My Life After MS: Ep 2 part 1-How I Got Pregant
This is the Video Journal of Kristen Henry King, after recieving stem cell therapy to treat her MS. She #39;s is now a stem cell activist and is working hard to make sure that Stem Cell treatment...

By: Kristen Henry King

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My Life After MS: Ep 2 part 1-How I Got Pregant - Video

Uncategorized Comments Off on My Life After MS: Ep 2 part 1-How I Got Pregant – Video | April 20th, 2015

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Newswise PHILADELPHIA A new collaborative study describes a way that lung tissue can regenerate after injury. The team found that lung tissue has more dexterity in repairing tissue than once thought. Researchers from the Perelman School of Medicine at the University of Pennsylvania and Duke University, including co-senior authors Jon Epstein, MD, chair of the department of Cell and Developmental Biology, and Brigid L.M Hogan, Duke Medicine, along with co-first authors Rajan Jain, MD, a cardiologist and instructor in the Department of Medicine and Christina E. Barkauskas, also from Duke, report their findings in Nature Communications.

Its as if the lung cells can regenerate from one another as needed to repair missing tissue, suggesting that there is much more flexibility in the system than we have previously appreciated, says Epstein. These arent classic stem cells that we see regenerating the lung. They are mature lung cells that awaken in response to injury. We want to learn how the lung regenerates so that we can stimulate the process in situations where it is insufficient, such as in patients with COPD [chronic obstructive pulmonary disease].

The two types of airway cells in the alveoli, the gas-exchanging part of the lung, have very different functions, but can morph into each other under the right circumstances, the investigators found. Long, thin Type 1 cells are where gases (oxygen and carbon dioxide) are exchanged the actual breath. Type 2 cells secrete surfactant, a soapy substance that helps keep airways open. In fact, premature babies need to be treated with surfactant to help them breathe.

The team showed in mouse models that these two types of cells originate from a common precursor stem cell in the embryo. Next, the team used other mouse models in which part of the lung was removed and single cell culture to study the plasticity of cell types during lung regrowth. The team showed that Type 1 cells can give rise to Type 2 cells, and vice-versa.

The Duke team had previously established that Type 2 cells produce surfactant and function as progenitors in adult mice, demonstrating differentiation into gas-exchanging Type 1 cells. The ability of Type I cells to give rise to alternate lineages had not been previously reported.

We decided to test that hypothesis about Type 1 cells, says Jain. We found that Type 1 cells give rise to the Type 2 cells over about three weeks in various models of regeneration. We saw new cells growing back into these new areas of the lung. Its as if the lung knows it has to grow back and can call into action some Type 1 cells to help in that process.

This is one of the first studies to show that a specialized cell type that was thought to be at the end of its ability to differentiate can revert to an earlier state under the right conditions. In this case, it was not by using a special formula of transcription factors, but by inducing damage to tell the body to repair itself and that it needs new cells of a certain type to do that.

The team is also applying the approaches outlined in this paper to cells in the intestine and skin to study basic ideas of stem cell maintenance and differentiation to relate back to similar mechanisms in the heart. They also hope to apply this knowledge to such other lung conditions as acute respiratory distress syndrome and idiopathic pulmonary fibrosis, where the alveoli cannot get enough oxygen into the blood.

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Limber Lungs: One Type of Airway Cell Can Regenerate Another Lung Cell Type

Uncategorized Comments Off on Limber Lungs: One Type of Airway Cell Can Regenerate Another Lung Cell Type | April 13th, 2015

Rice University and Texas Children's Hospital scientists are using stem cells from amniotic fluid to promote the growth of robust, functional blood vessels in healing hydrogels.

In new experiments, the lab of bioengineer Jeffrey Jacot combined versatile amniotic stem cells with injectable hydrogels used as scaffolds in regenerative medicine and proved they enhance the development of vessels needed to bring blood to new tissue and carry waste products away.

The results appear in the Journal of Biomedical Materials Research Part A.

Jacot and his colleagues study the use of amniotic fluid cells from pregnant women to help heal infants born with congenital heart defects. Such fluids, drawn during standard tests, are generally discarded but show promise for implants made from a baby's own genetically matched material.

He contends amniotic stem cells are valuable for their ability to differentiate into many other types of cells, including endothelial cells that form blood vessels.

"The main thing we've figured out is how to get a vascularized device: laboratory-grown tissue that is made entirely from amniotic fluid cells," Jacot said. "We showed it's possible to use only cells derived from amniotic fluid."

In the lab, researchers from Rice, Texas Children's Hospital and Baylor College of Medicine combined amniotic fluid stem cells with a hydrogel made from polyethylene glycol and fibrin. Fibrin is a biopolymer critical to blood clotting, cellular-matrix interactions, wound healing and angiogenesis, the process by which new vessels branch off from existing ones. Fibrin is widely used as a bioscaffold but suffers from low mechanical stiffness and rapid degradation. Combining fibrin and polyethylene glycol made the hydrogel much more robust, Jacot said.

The lab used vascular endothelial growth factor to prompt stem cells to turn into endothelial cells, while the presence of fibrin encouraged the infiltration of native vasculature from neighboring tissue.

Mice injected with fibrin-only hydrogels showed the development of thin fibril structures, while those infused with the amniotic cell/fibrin hydrogel showed far more robust vasculature, according to the researchers.

Similar experiments using hydrogel seeded with bone marrow-derived mesenchymal cells also showed vascular growth, but without the guarantee of a tissue match, Jacot said. Seeding with endothelial cells didn't work as well as the researchers expected, he said.

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Amniotic stem cells demonstrate healing potential

Bone Marrow Stem Cells Comments Off on Amniotic stem cells demonstrate healing potential | April 10th, 2015

18 hours ago by Vicky Agnew

Inside the microscopic world of the mouse hair follicle, Yale Cancer Center researchers have discovered big clues about how stem cells regenerate and die. These findings, published April 6 in the journal Nature, could lead to a better understanding of how the stem cell pool is maintained or altered in tissues throughout the body.

Stem cells are undifferentiated cells that replenish themselves and, based on their tissue location, can become specialized cells such as blood or skin cells. The hair follicle is an ideal site for exploring stem cell behavior because it has distinct and predictable oscillations in the number and behavior of stem cells, said the study's lead author, Kailin R. Mesa, a third-year doctoral student in the lab of Valentina Greco, associate professor of genetics, cell biology, and dermatology.

Using live microscopic imaging to track stem cell behavior in the skin of living mice, researchers observed that the stem cell niche, or surrounding area, plays a critical role in whether stem cells grow or die.

"Prior to this, it wasn't clear whether stem cell regulation was intrinsic or extrinsic, and now we know it is external in that the niche instructs the stem cells," Mesa said. "In terms of cancer, we can next explore how we might perturb or change the niche in hopes of affecting the growth of cancer stem cells."

Also, researchers were surprised to find that the stem cells within the pool fed on other dying stem cells. This reveals a mechanism for removing dead cells, a process previously observed in mammary glands but never in the skin.

Explore further: Limited self-renewal of stem cells in the brain

More information: Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool, Nature, DOI: 10.1038/nature14306

Journal reference: Nature

Provided by Yale University

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Tiny hair follicle offers big clues about the life and death of stem cells

Skin Stem Cells Comments Off on Tiny hair follicle offers big clues about the life and death of stem cells | April 8th, 2015

PHILADELPHIA -- The American Association for Cancer Research (AACR) is honoring Owen N. Witte, MD, founding director of the Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research and distinguished professor of microbiology, immunology, and molecular genetics at the University of California, Los Angeles, with the 55th annual AACR G.H.A. Clowes Memorial Award at the AACR Annual Meeting 2015, to be held in Philadelphia, April 18-22.

Witte, who is also a Howard Hughes Medical Institute investigator and an elected fellow of the AACR Academy, is being recognized for his many contributions to the understanding of human leukemias, immune disorders, and epithelial cancer stem cells. Witte's work, which contributed to the development of several approved targeted therapies, has transformed the lives of patients with Philadelphia chromosome-positive leukemias and B-cell malignancies. He will present his lecture, "Finding Therapeutic Targets for Aggressive Prostate Cancer," Monday, April 20, 5:30 p.m. ET, in the Grand Ballroom of the Pennsylvania Convention Center.

The AACR and Eli Lilly and Company established the G.H.A. Clowes Memorial Award in 1961 to honor Dr. G.H.A. Clowes, a founding member of the AACR and research director at Eli Lilly. This award recognizes an individual with outstanding recent accomplishments in basic cancer research.

Witte's innovative work helped revolutionize modern cancer treatment by defining tyrosine kinases as crucial drug targets in human disease. Most notably, he pinpointed the molecular consequences of the Philadelphia (Ph) chromosome abnormality present in chronic myelogenous leukemia (CML) and related types of leukemia and defined the tyrosine kinase activity of the ABL gene product. These findings played a crucial role in the subsequent development of ABL kinase-targeted therapies, including imatinib (Gleevec), which remains the front-line treatment for Ph-positive CML.

In addition to his research involving ABL, Witte also co-discovered Bruton agammaglobulinemia tyrosine kinase (BTK). This particular kinase is essential for B-cell maturation and when mutated, results in the onset of the immunodeficiency disease, X-linked agammagloblulinemia. Recent studies involving this protein have resulted in the U.S. Food and Drug Administration approval of ibrutinib (Imbruvica), a selective BTK inhibitor, for the treatment of chronic lymphocytic leukemia mantle cell lymphoma, and Waldenstrm macroglobulinemia.

More recently, Witte's work has focused on defining the epithelial stem cell populations that contribute to prostate cancer. He is currently using mass spectrometry approaches to identify kinases that could be potential therapeutic targets for human prostate cancer.

"Much progress has been made in the area of personalized cancer medicine due to the dedication of scientists and physicians around the world, many of whom I've had the pleasure of working with through the AACR's innovative initiatives," said Witte. "But much more work is needed as we seek to understand cancer, which is not a single disease but rather many diseases that develop differently. I thank the AACR for their leadership in this effort and am honored to receive the Clowes Memorial Award."

An active AACR member, Witte has served on the AACR board of directors and several grant review committees. He is a past recipient of the AACR-Richard and Hinda Rosenthal Award and a co-leader of the Stand Up to Cancer Dream Team: Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer. Additionally, he is also serving an appointed term on the President's Cancer Panel.

Witte has been recognized throughout his career with numerous honors. He has received the Nakahara Memorial Lecture Prize, the Cotlove Lectureship from the Academy of Clinical Laboratory Physicians and Scientists, the de Villiers International Achievement Award from the Leukemia and Lymphoma Society, the Warren Alpert Prize, and is elected member of the Institute of Medicine, National Academy of Sciences, and fellow of the American Academy of Arts and Sciences and the American Academy of Microbiology.

Witte received his medical degree from Stanford University School of Medicine in California, and was a postdoctoral fellow at the Center for Cancer Research at the Massachusetts Institute of Technology in Cambridge. He joined the UCLA faculty in 1980.

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Dr. Owen Witte recognized with AACR G.H.A. Clowes Memorial Award

Uncategorized Comments Off on Dr. Owen Witte recognized with AACR G.H.A. Clowes Memorial Award | April 8th, 2015