Neoplastic stem cells: current concepts and clinical perspectives.

Science.gov (United States)

Schulenburg, Axel; Brämswig, Kira; Herrmann, Harald; Karlic, Heidrun; Mirkina, Irina; Hubmann, Rainer; Laffer, Sylvia; Marian, Brigitte; Shehata, Medhat; Krepler, Clemens; Pehamberger, Hubert; Grunt, Thomas; Jäger, Ulrich; Zielinski, Christoph C; Valent, Peter

2010-11-01

Neoplastic stem cells have initially been characterized in myeloid leukemias where NOD/SCID mouse-repopulating progenitors supposedly reside within a CD34+/Lin- subset of the malignant clone. These progenitors are considered to be self-renewing cells responsible for the in vivo long-term growth of neoplastic cells in leukemic patients. Therefore, these cells represent an attractive target of therapy. In some lymphoid leukemias, NOD/SCID mouse-repopulating cells were also reported to reside within the CD34+/Lin- subfraction of the clone. More recently, several attempts have been made to transfer the cancer stem cell concept to solid tumors and other non-hematopoietic neoplasms. In several of these tumors, the cell surface antigens AC133 (CD133) and CD44 are considered to indicate the potential of a cell to initiate permanent tumor formation in vivo. However, several questions concerning the phenotype, self-renewal capacity, stroma-dependence, and other properties of cancer- or leukemia-initiating cells remain to be solved. The current article provides a summary of our current knowledge on neoplastic (cancer) stem cells, with special emphasis on clinical implications and therapeutic options as well as a discussion about conceptual and technical limitations. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Increasing Hematopoietic Stem Cell Yield to Develop Mice with Human Immune Systems

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Juan-Carlos Biancotti

2013-01-01

Full Text Available Hematopoietic stem cells (HSCs are unique in their capacity to give rise to all mature cells of the immune system. For years, HSC transplantation has been used for treatment of genetic and neoplastic diseases of the hematopoietic and immune systems. The sourcing of HSCs from human umbilical cord blood has salient advantages over isolation from mobilized peripheral blood. However, poor sample yield has prompted development of methodologies to expand HSCs ex vivo. Cytokines, trophic factors, and small molecules have been variously used to promote survival and proliferation of HSCs in culture, whilst strategies to lower the concentration of inhibitors in the culture media have recently been applied to promote HSC expansion. In this paper, we outline strategies to expand HSCs in vitro, and to improve engraftment and reconstitution of human immune systems in immunocompromised mice. To the extent that these “humanized” mice are representative of the endogenous human immune system, they will be invaluable tools for both basic science and translational medicine.

Non-neoplastic disorders of the esophagus

International Nuclear Information System (INIS)

Hong, Min Ji; Kim, Young Tong

2013-01-01

Non-neoplastic disorders of the esophagus include esophagitis, esophageal diverticulum, esophageal injury, foreign body, fistulous formation between the esophagus and the surrounding structures and mucocele. Since these disorders have variable symptoms and radiologic findings, it needs to differentiated from other disorders other than esophageal diseases. Being knowledgeable of CT findings suggest that these disorders can help diagnose non-neoplastic disorders of the esophagus. The purpose of this pictorial essay is to review the CT appearance of non-neoplastic disorders of the esophagus.

Biological Characteristics of Caspase-14 and Its Expression in Neoplastic Diseases in the View of Translational Medicine

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Kang-sheng LIU

2016-06-01

Full Text Available Caspase-14, a member of caspase family, only exists in mammals. As the most divergent member in the family of mammalian caspases, caspase-14 displays a variety of unique characteristics. It is expressed in a limited number of tissues and has the shortest amino acid sequence within the caspase protein family. At present, it has been found that caspase-14 is functionally different from the inflammatory reaction group of typical caspase family members. It exerts a certain effect in the promotion of final differentiation of epidermal cells and hydration of stratum corneum so as to maintain the steady state of skin barrier. In recent years, caspase-14 expression has been discovered in neoplastic diseases. Translational medicine integrates experimental research results and clinical guidance into the optimal implementation criteria for promoting the prediction, prevention and treatment of diseases. Via human genomics and molecular biology, translational medicine offers a possibility of screening molecular markers so that it can be used to diagnose the neoplastic diseases. In this article, the biological characteristics and substrates of caspase-14 as well as its expression in embryonic period and neoplastic diseases were reviewed.

Detection of immune complexes in sera of dogs with rheumatic and neoplastic diseases by 125I-Clq binding test

International Nuclear Information System (INIS)

Terman, D.S.; Moore, D.; Collins, J.; Johnston, B.; Person, D.; Templeton, J.; Poser, R.; Quinby, F.

1979-01-01

Some canine rheumatic and neoplastic diseases bear a striking clinical and serological resemblance to their counterparts in man. In the present study, human 125 I-Clq was employed in a radioimmunoassay for detection of immune complexes in sera of normal dogs and those with rheumatic and neoplastic diseases. Human 125 I-Clq showed binding of 16.7 +- 5.73% in a group of normal dog sera with binding of 32.5 +- 17.3% and 43.0 +- 16.0% in sera of dogs with rheumatic and neoplastic diseases. respectively. Human 125 I-Clq bound similar quantities of heat-aggregated canine and human gamma-globulin over a broad range of concentrations and human 125 I-Clq binding in canine sera was effectively inhibited by similar quantities of heat aggregated canine and human gamma-globulin. Seven of 12 dogs with elevated levels of Clq binding had active clinical and serological rheumatic disease (SLE or rheumatoid arthritis), while none of 7 dogs with values within the normal range had active clinical disease. All 5 dogs with widespread osteogenic sarcoma and all 4 dogs with high grade adenocarcinoma of the mammary gland had elevated Clq binding values while 2 animals with low grade malignancies without evident metastases did not. Thus, it appears that human 125 I-Clq may be employed to assay immune complexes in canine sera and may be a valuable technique for the study of dogs with various rheumatic and neoplastic diseases. (author)

Gastroesophageal reflux disease and its association with bronchiolitis obliterans syndrome in allogeneic hematopoietic stem cell transplant recipients.

Science.gov (United States)

Khalid, Mohammed; Aljurf, Mahmoud; Saleemi, Sarfraz; Khan, Mohammed Qaseem; Khan, Basha; Ahmed, Shad; Ibrahim, Khalid El Tayeb; Mobeireek, Abdullah; Al Mohareb, Fahad; Chaudhri, Naeem

2013-06-01

Bronchiolitis obliterans syndrome is a significant postallogeneic hematopoietic stem cell transplant problem. Recent data in lung transplant patients suggest an association with gastroesophageal reflux disease and bronchiolitis obliterans syndrome. We studied posthematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome for gastroesophageal reflux disease and its response to a proton pump inhibitor. Seven postallogeneic hematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome were studied. Gastroesophageal reflux disease was assessed by 24-hour pH monitoring with a Bravo catheter-free radio pH capsule. Patients with positive gastroesophageal reflux disease were started on omeprazole. Pretreatment and posttreatment pulmonary function tests were done at 3-month intervals. Of 7 patients, 5 had positive results for gastroesophageal reflux disease (71%). Omeprazole had a disease-stabilizing effect on the patients' pulmonary function tests. Our study shows a significant association between bronchiolitis obliterans syndrome and gastroesophageal reflux disease in postallogeneic hematopoietic stem cell transplant patients. Use of omeprazole may have a disease-stabilizing effect in short-term follow-up.

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

NARCIS (Netherlands)

Haycock, P.C.; Burgess, S.; Nounu, A.; Zheng, J.; Okoli, G.N.; Bowden, J.; Wade, K.H.; Timpson, N.J.; Evans, D.M.; Willeit, P.; Aviv, A.; Gaunt, T.R.; Hemani, G.; Mangino, M.; Ellis, H.P.; Kurian, K.M.; Pooley, K.A.; Eeles, R.A.; Lee, J.E.; Fang, S.; Chen, W.V.; Law, M.H.; Bowdler, L.M.; Iles, M.M.; Yang, Q.; Worrall, B.B.; Markus, H.S.; Hung, R.J.; Amos, C.I.; Spurdle, A.B.; Thompson, D.J.; O'Mara, T.A.; Wolpin, B.; Amundadottir, L.; Stolzenberg-Solomon, R.; Trichopoulou, A.; Onland-Moret, N.C.; Lund, E.; Duell, E.J.; Canzian, F.; Severi, G.; Overvad, K.; Gunter, M.J.; Tumino, R.; Svenson, U.; Rij, A. van; Baas, A.F.; Bown, M.J.; Samani, N.J.; t'Hof, F.N.G. van; Tromp, G.; Jones, G.T.; Kuivaniemi, H.; Elmore, J.R.; Johansson, M.; McKay, J.; Scelo, G.; Carreras-Torres, R.; Gaborieau, V.; Brennan, P.; Bracci, P.M.; Neale, R.E.; Olson, S.H.; Gallinger, S.; Li, D.; Petersen, G.M.; Risch, H.A.; Klein, A.P.; Han, J.; Abnet, C.C.; Freedman, N.D.; Taylor, P.R.; Maris, J.M.; Aben, K.K.H.; Kiemeney, L.A.; Vermeulen, S.H.; Wiencke, J.K.; Walsh, K.M.; Wrensch, M.; Rice, T.; Turnbull, C.; Litchfield, K.; Paternoster, L.; Standl, M.; Abecasis, G.R.; SanGiovanni, J.P.; Li, Y.; Mijatovic, V.; Sapkota, Y.; Low, S.K.; Zondervan, K.T.; Montgomery, G.W.; Nyholt, D.R.; Heel, D.A. van; Hunt, K.; Arking, D.E.; Ashar, F.N.; Sotoodehnia, N.; Woo, D.; et al.,

2017-01-01

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study,

Perfusion abnormalities in congenital and neoplastic pulmonary disease: comparison of MR perfusion and multislice CT imaging

International Nuclear Information System (INIS)

Boll, Daniel T.; Lewin, Jonathan S.; Young, Philip; Gilkeson, Robert C.; Siwik, Ernest S.

2005-01-01

The aim of this work was to assess magnetic resonance (MR) perfusion patterns of chronic, nonembolic pulmonary diseases of congenital and neoplastic origin and to compare the findings with results obtained with pulmonary, contrast-enhanced multislice computed tomography (CT) imaging to prove that congenital and neoplastic pulmonary conditions require MR imaging over the pulmonary perfusion cycle to successfully and directly detect changes in lung perfusion patterns. Twenty-five patients underwent concurrent CT and MR evaluation of chronic pulmonary diseases of congenital (n=15) or neoplastic (n=10) origin. Analysis of MR perfusion and contrast-enhanced CT datasets was realized by defining pulmonary and vascular regions of interest in corresponding positions. MR perfusion calculated time-to-peak enhancement, maximal enhancement and the area under the perfusion curve. CT datasets provided pulmonary signal-to-noise ratio measurements. Vessel centerlines of bronchial arteries were determined. Underlying perfusion type, such as pulmonary arterial or systemic arterial supply, as well as regions with significant variations in perfusion were determined statistically. Analysis of the pulmonary perfusion pattern detected pulmonary arterial supply in 19 patients; six patients showed systemic arterial supply. In pulmonary arterial perfusion, MR and multislice CT imaging consistently detected the perfusion type and regions with altered perfusion patterns. In bronchial arterial supply, MR perfusion and CT imaging showed significant perfusion differences. Patients with bronchial arterial supply had bronchial arteries ranging from 2.0 to 3.6 mm compared with submillimeter diameters in pulmonary arterial perfusion. Dynamic MR imaging of congenital and neoplastic pulmonary conditions allowed characterization of the pulmonary perfusion type. CT imaging suggested the presence of systemic arterial perfusion by visualizing hypertrophied bronchial arteries. (orig.)

Collaborating with the Enemy: Function of Macrophages in the Development of Neoplastic Disease

OpenAIRE

Andrzej Eljaszewicz; Małgorzata Wiese; Anna Helmin-Basa; Michal Jankowski; Lidia Gackowska; Izabela Kubiszewska; Wojciech Kaszewski; Jacek Michalkiewicz; Wojciech Zegarski

2013-01-01

Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages...

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing's syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing's syndrome).

Science.gov (United States)

Findling, James W; Raff, Hershel

2017-05-01

Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/non-neoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome). © 2017 European Society of Endocrinology.

Age and Spatial Peculiarities of Non-neoplastic Diseases of the Skin and Subcutaneous Tissue in Kazakhstan, 2003-2015.

Science.gov (United States)

Igissinov, Nurbek; Kulmirzayeva, Dariyana; Bilyalova, Zarina; Akpolatova, Gulnur; Mamyrbayeva, Marzya; Zhumagaliyeva, Galina

2017-11-01

Arrangement of effective management aimed at improving dermatological services and consistent care of patients with skin diseases depends on understanding the epidemiological situation. This retrospective study presents an epidemiological assessment of non-neoplastic skin and subcutaneous tissue diseases in Kazakhstan registered in 2003-2015. The yearly incidence rate of the diseases among the whole population was in average 3,341.8±121.1 per 100000 population. This represents 4835.0±156.1 for children, 5503.2±141.8 for adolescents and 2646.6±106.7 for adults per 100000 inhabitants. Space and time incidence rate was evaluated according to the administrative division. The overall trend decreased to 3.5% in children to 2.8% in adolescents to 1.9%, and in adults to 3.9%. Considerable variation in rates was seen across the country, with highest rates in East Kazakhstan, Mangystau and Aktobe regions, the lowest - in Atyrau and South-Kazakhstan regions. Non-neoplastic diseases of skin and subcutaneous tissue continue to be an urgent public health problem, especially among children in many regions of Kazakhstan.

Hematopoietic stem cell transplantation monitoring in childhood. Hematological diseases in Serbia: STR-PCR techniques

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Krstić Aleksandra D.

2007-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is a very successful method of treatment for children with different aquired or inborn diseases. The main goal of post-transplantation chimerism monitoring in HSCT is to predict negative events (such as disease relapse and graft rejection, in order to intervene with appropriate therapy and improve the probability of long-term DFS (disease free survival. In this context, by quantifying the relative amounts of donor and recipient cells present in the peripheral blood sample, it can be determined if engraftment has taken place at all, or if full or mixed chimerism exists. In a group of patients who underwent hematopoietic stem cell transplantation at the Mother and Child Health Care Institute, we decided to use standard human identfication tests based on multiplex PCR analyses of short tandem repeats (STRs, as they are highly informative, sensitive, and fast and therefore represent an optimal methodological approach to engraftment analysis.

Age and Spatial Peculiarities of Non-neoplastic Diseases of the Skin and Subcutaneous Tissue in Kazakhstan, 2003–2015

OpenAIRE

IGISSINOV, Nurbek; KULMIRZAYEVA, Dariyana; BILYALOVA, Zarina; AKPOLATOVA, Gulnur; MAMYRBAYEVA, Marzya; ZHUMAGALIYEVA, Galina

2017-01-01

Background: Arrangement of effective management aimed at improving dermatological services and consistent care of patients with skin diseases depends on understanding the epidemiological situation. Methods: This retrospective study presents an epidemiological assessment of non-neoplastic skin and subcutaneous tissue diseases in Kazakhstan registered in 2003–2015. Results: The yearly incidence rate of the diseases among the whole population was in average 3,341.8±121.1 per 100000 population. T...

Quality of life of patients with graft-versus-host disease (GvHD post-hematopoietic stem cell transplantation

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Sibéli de Fátima Ferraz Simão Proença

Full Text Available Abstract OBJECTIVE Assessing the quality of life of adult patients with hematological cancer in the 100 days after transplantation of hematopoietic stem cells and verifying whether the variable graft-versus-host disease (GvHD is predictive of worse results. METHOD An observational correlational and quantitative study with 36 adult participants diagnosed with hematologic cancer who underwent hematopoietic stem cell transplantation from September 2013 to June 2015. RESULT The mean age was 37 years, 52.78% were female, and 61.11% were diagnosed with leukemia. Quality of life scores showed a significant impact between pre-transplantation and pre-hospital discharge, and also within the 100 days post-transplantation. The statistical analysis between the scores for the groups with and without GvHD showed a significant difference between the presence of the complication and worse results. CONCLUSION Quality of life is altered as a result of hematopoietic stem cells transplantation, especially in patients who have graft-versus-host disease.

Osteogenic tumour in Australopithecus sediba: Earliest hominin evidence for neoplastic disease

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Patrick S. Randolph-Quinney

2016-07-01

Full Text Available We describe the earliest evidence for neoplastic disease in the hominin lineage. This is reported from the type specimen of the extinct hominin Australopithecus sediba from Malapa, South Africa, dated to 1.98 million years ago. The affected individual was male and developmentally equivalent to a human child of 12 to 13 years of age. A penetrating lytic lesion affected the sixth thoracic vertebra. The lesion was macroscopically evaluated and internally imaged through phase-contrast X-ray synchrotron microtomography. A comprehensive differential diagnosis was undertaken based on gross- and micro-morphology of the lesion, leading to a probable diagnosis of osteoid osteoma. These neoplasms are solitary, benign, osteoid and bone-forming tumours, formed from well-vascularised connective tissue within which there is active production of osteoid and woven bone. Tumours of any kind are rare in archaeological populations, and are all but unknown in the hominin record, highlighting the importance of this discovery. The presence of this disease at Malapa predates the earliest evidence of malignant neoplasia in the hominin fossil record by perhaps 200 000 years.

The analysis of health condition and the assessment of the risk of neoplastic diseases among residents of villages

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Anna Lewandowska

2017-06-01

Full Text Available Introduction: Neoplastic diseases have been classified as civilization diseases and are a big problem for modern medicine. According to the data from the International Agency for Research of Cancer, about 10 million people suffer from cancer and a number of deaths due to this disease has exceeded 6 million; until 2020 those numbers may double. In Poland, cancer survivors of five years concern 22% of men and 35% of women suffering from tumours, while in northern and western Europe there is a cure rate of 40% for men and 50% for women. The main reason for the adverse situation in Poland is a low percentage of early diagnosis of cancer. On the one hand this results from insufficient preparation of both family doctors and physicians of other specialties, but on the other, from insufficient dissemination of early diagnosis methods. Objective: The objective of the study is to analyze the health condition and to assess the risk of a neoplastic disease among residents of villages. Material and methods: The research involved 1000 residents of villages in Podkarpackie Voivodeship. The age of the researched ranges from 18 to 30 years, with mean age 26.96±0.84 (range [18;30], median 25.95%CI [18,9;29,01]. The researched group is represented in 43,8% by women in 56,2% by men. In order to obtain the research material, a standardized questionnaire has been applied including interview and physical examination, enabling assessment of symptoms reported during the interview and analysis of symptoms indicating a disease, including cancer. Results: According to the data analysis, during last few months the respondents have suffered from such ailments as cough (8.22% W, 7.12% M, dyspnea (3.2% W, 1.78% M, abdominal pain (13.7% W, 4.27% M, pain (5.48% W, 2.14% M and weakness (14.61% W, 4.98% M. During observations, one female respondent was diagnosed with symptoms of melanoma (0.46%, which has been confirmed in later dermatological test. Conclusions: No changes in

Radioresistant canine hematopoietic cells

International Nuclear Information System (INIS)

Kawakami, T.G.; Shimizu, J.; Rosenblatt, L.S.; Goldman, M.

1987-01-01

Survival of dogs that are continuously exposed to a moderate dose-rate of gamma radiation (10 cGy/day) is dependent on the age of the dog at the time of exposure. Most dogs exposed postpartum to gamma radiation suffered from suppressed hematopoiesis and died of aplasia. On the other hand, none of the in utero-exposed dogs suffered from suppressed hematopoiesis and most became long-term survivors, tolerating 10-fold greater total dose, but dying of myeloproliferative disease (MPD). Using acute gamma irradiation of hematopoietic cells and colony forming unit cell assay (CFU), they observed that a canine hematopoietic cell line established from a myeloid leukemic dog that was a long-term survivor of continuous irradiation was approximately 4-fold more radioresistant than a hematopoietic cell line established from a dog with nonradiation-induced myeloid leukemia or hematopoietic cells from normal canine bone marrow. In utero dogs that are long-term survivors of continuous irradiation have radioresistant hematopoietic cells, and radioresistance that is a constitutive property of the cells

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease].

Science.gov (United States)

Hladun, R; Elorza, I; Olivé, T; Dapena, J L; Llort, A; Sánchez de Toledo, J; Díaz de Heredia, C

2013-08-01

The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival

The biochemistry of hematopoietic stem cell development

NARCIS (Netherlands)

P. Kaimakis (Polynikis); M. Crisan (Mihaela); E.A. Dzierzak (Elaine)

2013-01-01

textabstractBackground: The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short

PARASITIC INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

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Isidro Jarque

2016-07-01

Full Text Available Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients.

Hematopoietic stem cell transplantation in Niemann-Pick disease type B monitored by chitotriosidase activity.

Science.gov (United States)

Quarello, Paola; Spada, Marco; Porta, Francesco; Vassallo, Elena; Timeus, Fabio; Fagioli, Franca

2018-02-01

Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness. © 2017 Wiley Periodicals, Inc.

Imaging of demyelinating and neoplastic diseases of the spinal cord; Bildgebung bei demyelinisierenden und tumoroesen Erkrankungen des Rueckenmarks

Energy Technology Data Exchange (ETDEWEB)

Mueller-Mang, C. [Institut fuer CT und MRT Gaenserndorf, Gaenserndorf (Austria)

2010-12-15

The clinical symptoms of myelopathy are variable and non-specific. Demyelinating as well as neoplastic spinal cord diseases can cause paresthesia, progressive sensomotoric deficits and bowel and bladder dysfunction. Imaging of the spine, especially with magnetic resonance imaging (MRI), is an essential component in the diagnostic assessment of myelopathy and makes a substantial contribution to achieving the correct diagnosis. Although intramedullary neoplasms are far less common than demyelinating spinal cord diseases, radiologists should be familiar with the three most common entities, astrocytoma, ependymoma and hemangioblastoma, which represent over 70% of all spinal cord neoplasms. An early diagnosis and therapy is essential with neoplastic and demyelinating spinal cord diseases to hold residual neurological deficits as low as possible. (orig.) [German] Die klinische Symptomatik von Myelopathien ist aeusserst variabel und unspezifisch. Sowohl demyelinisierende als auch tumoroese Rueckenmarkerkrankungen koennen Paraesthesien, progrediente sensomotorische Ausfaelle und eine Sphinkterdysfunktion hervorrufen. Bildgebende Untersuchungen, und hier allen voran die MRT, sind ein unerlaesslicher Bestandteil zur Abklaerung von Myelopathien und tragen wesentlich zur korrekten Diagnose bei. Intramedullaere Tumoren sind zwar weitaus seltener als demyelinisierende Rueckenmarkerkrankungen, dennoch sollte der Radiologe mit den Bildmerkmalen der 3 haeufigsten Tumorarten, dem Astrozytom, Ependymom und Haemangioblastom vertraut sein, die ueber 70% aller Rueckenmarktumoren verursachen. Eine moeglichst fruehe Diagnostik und Therapie sind bei tumoroesen und demyelinisierenden Rueckenmarkerkrankungen essenziell, um bleibende neurologische Defizite moeglichst gering zu halten. (orig.)

Non-neoplastic gliotic cerebellar cysts

International Nuclear Information System (INIS)

Weisberg, L.A.

1982-01-01

The clinical and CT findings in 3 patients with non-neoplastic gliotic cerebellar cyst are described. CT does not permit accurate preoperative differentiation of these lesions from neoplastic disorders. (orig.)

Changing patterns of radiosensitivity of hematopoietic progenitors from chronically irradiated dogs prone either to aplastic anemia or to myeloproliferative disease

International Nuclear Information System (INIS)

Seed, T.M.; Kaspar, L.V.

1990-01-01

Hematopoietic patterns have been assessed in chronic 60 Co gamma irradiated dogs during preclinical phases of evolving aplastic anemia (AA) or myeloproliferative disease (MPD), principally myeloid leukemia. The results support the concept that acquired radioresistance of vital granulocyte/monocyte lineage-committed hematopoietic progenitors is temporally, perhaps causally, linked to the processes mediating hematopoietic recovery and accommodation under chronic irradiation, and in turn to preclinical events of evolving MPD. In addition, the marked differential responses of progenitors to gamma and neutron irradiation in vitro might suggest differences in the nature of cellular lesions elicited by chronic gamma irradiation, in vivo. (author)

Changing patterns of radiosensitivity of hematopoietic progenitors from chronically irradiated dogs prone either to aplastic anemia or to myeloproliferative disease

Energy Technology Data Exchange (ETDEWEB)

Seed, T.M.; Kaspar, L.V. (Oak Ridge National Lab., TN (USA))

1990-01-01

Hematopoietic patterns have been assessed in chronic {sup 60}Co gamma irradiated dogs during preclinical phases of evolving aplastic anemia (AA) or myeloproliferative disease (MPD), principally myeloid leukemia. The results support the concept that acquired radioresistance of vital granulocyte/monocyte lineage-committed hematopoietic progenitors is temporally, perhaps causally, linked to the processes mediating hematopoietic recovery and accommodation under chronic irradiation, and in turn to preclinical events of evolving MPD. In addition, the marked differential responses of progenitors to gamma and neutron irradiation in vitro might suggest differences in the nature of cellular lesions elicited by chronic gamma irradiation, in vivo. (author).

Neoplastic and proliferative disorders of the perinephric space

International Nuclear Information System (INIS)

Heller, M.T.; Haarer, K.A.; Thomas, E.; Thaete, F.L.

2012-01-01

The perinephric space is a well-marginated central compartment of the retroperitoneum, located between the anterior and posterior pararenal spaces. Various neoplastic and proliferative disorders can affect the perinephric space, and there is a wide array of imaging findings. Although many perinephric lesions may extend directly from the kidney and adrenal gland, other lesions occur in the perinephric space due to haematogenous spread, as part of a systemic disease, or by extension from an adjacent retroperitoneal compartment. Imaging plays a pivotal role in the diagnosis of perinephric diseases, as many of the disease processes affecting this space will not result in clinical signs or symptoms until the disease is at an advanced stage. Despite the often shared non-specific clinical and imaging findings among these disease processes, application of a categorical differential diagnosis based on the imaging characteristics will serve to narrow the differential diagnosis and direct further evaluation and treatment. In this article, the lesions have been categorized as soft-tissue rind [nephroblastomatosis, fibrosis, Erdheim–Chester disease (ECD), extramedullary haematopoiesis, lymphoma, infiltrating metastases], focal solid lesions (extension of renal or adrenal malignancies, melanoma metastases, treated lymphoma), fat-containing lesions (angiomyolipoma, liposarcoma, myelolipoma), and cystic lesions (lymphangiomas, abscesses). The aim of this article is to demonstrate and describe the key imaging features of several neoplastic and proliferative disorders that affect the perinephric space.

A HISTOPATHOLOGICAL STUDY OF NON-NEOPLASTIC AND NEOPLASTIC LESIONS OF KIDNEY FOR A PERIOD OF TWO YEARS

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Jagadeeswari Suvvari

2018-01-01

Full Text Available BACKGROUND Nephrectomy is a common procedure in surgical practice. There are many indications for nephrectomy, non-neoplastic and neoplastic conditions. The common conditions being chronic pyelonephritis and renal tumours. A detailed and meticulous histopathological examination is essential to establish the diagnosis of lesions of kidney. MATERIALS AND METHODS It is a retrospective study for a period of two years from January 2015 to December 2016 at a tertiary care centre. 34 cases of nephrectomy specimens were analysed and data recorded. RESULTS Non-neoplastic lesions were constituting 47.05% (16 of cases and 52.94% (18 cases were neoplastic lesions. Lesions were more common in females with male:female ratio of 1:1.4. Both the lesions were common in age group of 41-50 years. CONCLUSION The prevalence of neoplastic lesions was more common than non-neoplastic lesions. The commonest indication for nephrectomy was chronic pyelonephritis followed by renal tumours. Histopathological examination in correlation with clinical and radiological features plays a great role in subcategorisation of lesions accurately to ensure better therapy.

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

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Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

2017-01-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

Science.gov (United States)

Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

2017-09-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine.

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Ogino, Shuji; Nishihara, Reiko; VanderWeele, Tyler J; Wang, Molin; Nishi, Akihiro; Lochhead, Paul; Qian, Zhi Rong; Zhang, Xuehong; Wu, Kana; Nan, Hongmei; Yoshida, Kazuki; Milner, Danny A; Chan, Andrew T; Field, Alison E; Camargo, Carlos A; Williams, Michelle A; Giovannucci, Edward L

2016-07-01

Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public

Corneal Structural Changes in Nonneoplastic and Neoplastic Monoclonal Gammopathies.

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Aragona, Pasquale; Allegra, Alessandro; Postorino, Elisa Imelde; Rania, Laura; Innao, Vanessa; Wylegala, Edward; Nowinska, Anna; Ieni, Antonio; Pisani, Antonina; Musolino, Caterina; Puzzolo, Domenico; Micali, Antonio

2016-05-01

To investigate corneal confocal microscopic changes in nonneoplastic and neoplastic monoclonal gammopathies. Three groups of subjects were considered: group 1, twenty normal subjects; group 2, fifteen patients with monoclonal gammopathy of undetermined significance (MGUS); group 3, eight patients with smoldering multiple myeloma and eight patients with untreated multiple myeloma. After hematologic diagnosis, patients underwent ophthalmologic exam and in vivo confocal microscopic study. The statistical analysis was performed using ANOVA and Student-Newman-Keuls tests and receiver operating characteristic (ROC) curve analysis. Epithelial cells of gammopathic patients showed significantly higher reflectivity than controls, demonstrated by optical density (P < 0.001). Subbasal nerve density, branching, and beading were significantly altered in gammopathic patients (P = 0.01, P = 0.02, P = 0.02, respectively). The number of keratocytes was significantly reduced in neoplastic patients (P < 0.001 versus both normal and MGUS) in the anterior, medium, and posterior stroma. The ROC curve analysis showed good sensitivity and specificity for this parameter. Group 2 and 3 keratocytes showed higher nuclear and cytoplasmatic reflectivity in the medium and posterior stroma. Endothelial cells were not affected. Patients with neoplastic gammopathies showed peculiar alterations of the keratocyte number, which appeared significantly reduced. A follow-up with corneal confocal microscopy of patients with MGUS is suggested as a useful tool to identify peripheral tissue alterations linked to possible neoplastic disease development.

Neural Crossroads in the Hematopoietic Stem Cell Niche.

Science.gov (United States)

Agarwala, Sobhika; Tamplin, Owen J

2018-05-29

The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

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Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

2011-01-01

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

Science.gov (United States)

Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

2014-04-01

The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.

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Chen, Tong; Wang, Fen; Wu, Mengyao; Wang, Zack Z

2015-07-01

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non-hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. © 2015 Wiley Periodicals, Inc.

Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease

International Nuclear Information System (INIS)

Fink, J.K.; Correll, P.H.; Perry, L.K.; Brady, R.O.; Karlsson, S.

1990-01-01

Retroviral gene transfer has been used successfully to correct the glucocerebrosidase (GCase) deficiency in primary hematopoietic cells from patients with Gaucher disease. For this model of somatic gene therapy, the authors developed a high-titer, amphotropic retroviral vector designated NTG in which the human GCase gene was driven by the mutant polyoma virus enhancer/herpesvirus thymidine kinase gene (tk) promoter (Py + /Htk). NTG normalized GCase activity in transduced Gaucher fibroblasts and efficiently infected human monocytic and erythroleukemic cell lines. RNA blot-hybridization (Northern blot) analysis of these hemaptopoietic cell lines showed unexpectedly high-level expression from the Moloney murine leukemia virus long terminal repeat (Mo-MLV LTR) and levels of Py + /Htk enhancer/promoter-initiated human GCase RNA that approximated endogenous GCase RNA levels. Furthermore, NTG efficiently infected human hematopoietic progenitor cells. Detection of the provirus in approximately one-third of NTG-infected progenitor colonies that had not been selected in G418-containing medium indicates that relative resistance to G418 underestimated the actual gene transfer efficiency. Northern blot analysis of NTG-infected, progenitor-derived cells showed expression from both the Mo-MLV LTR and the Py + /Htk enhancer/promoter. NTG-transduced hematopoietic progenitor cells from patients with Gaucher disease generated progeny in which GCase activity has been normalized

Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease

Energy Technology Data Exchange (ETDEWEB)

Fink, J.K.; Correll, P.H.; Perry, L.K.; Brady, R.O.; Karlsson, S. (National Institutes of Health, Bethesda, MD (USA))

1990-03-01

Retroviral gene transfer has been used successfully to correct the glucocerebrosidase (GCase) deficiency in primary hematopoietic cells from patients with Gaucher disease. For this model of somatic gene therapy, the authors developed a high-titer, amphotropic retroviral vector designated NTG in which the human GCase gene was driven by the mutant polyoma virus enhancer/herpesvirus thymidine kinase gene (tk) promoter (Py{sup +}/Htk). NTG normalized GCase activity in transduced Gaucher fibroblasts and efficiently infected human monocytic and erythroleukemic cell lines. RNA blot-hybridization (Northern blot) analysis of these hemaptopoietic cell lines showed unexpectedly high-level expression from the Moloney murine leukemia virus long terminal repeat (Mo-MLV LTR) and levels of Py{sup +}/Htk enhancer/promoter-initiated human GCase RNA that approximated endogenous GCase RNA levels. Furthermore, NTG efficiently infected human hematopoietic progenitor cells. Detection of the provirus in approximately one-third of NTG-infected progenitor colonies that had not been selected in G418-containing medium indicates that relative resistance to G418 underestimated the actual gene transfer efficiency. Northern blot analysis of NTG-infected, progenitor-derived cells showed expression from both the Mo-MLV LTR and the Py{sup +}/Htk enhancer/promoter. NTG-transduced hematopoietic progenitor cells from patients with Gaucher disease generated progeny in which GCase activity has been normalized.

Management of neoplastic meningitis.

Science.gov (United States)

Roth, Patrick; Weller, Michael

2015-06-01

Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.

Capsule endoscopy in neoplastic diseases

Science.gov (United States)

Pennazio, Marco; Rondonotti, Emanuele; de Franchis, Roberto

2008-01-01

Until recently, diagnosis and management of small-bowel tumors were delayed by the difficulty of access to the small bowel and the poor diagnostic capabilities of the available diagnostic techniques. An array of new methods has recently been developed, increasing the possibility of detecting these tumors at an earlier stage. Capsule endoscopy (CE) appears to be an ideal tool to recognize the presence of neoplastic lesions along this organ, since it is non-invasive and enables the entire small bowel to be visualized. High-quality images of the small-bowel mucosa may be captured and small and flat lesions recognized, without exposure to radiation. Recent studies on a large population of patients undergoing CE have reported small-bowel tumor frequency only slightly above that reported in previous surgical series (range, 1.6%-2.4%) and have also confirmed that the main clinical indication to CE in patients with small-bowel tumors is obscure gastrointestinal (GI) bleeding. The majority of tumors identified by CE are malignant; many were unsuspected and not found by other methods. However, it remains difficult to identify pathology and tumor type based on the lesion’s endoscopic appearance. Despite its limitations, CE provides crucial information leading in most cases to changes in subsequent patient management. Whether the use of CE in combination with other new diagnostic (MRI or multidetector CT enterography) and therapeutic (Push-and-pull enteroscopy) techniques will lead to earlier diagnosis and treatment of these neoplasms, ultimately resulting in a survival advantage and in cost savings, remains to be determined through carefully-designed studies. PMID:18785274

Gauchers disease--a reappraisal of hematopoietic stem cell transplantation.

Science.gov (United States)

Ito, Sawa; Barrett, A John

2013-03-01

Hematopoietic stem cell transplantation (HSCT), first performed in 1984, was the first treatment approach for Gaucher's disease (GD) which had curative intent. The early successes in HSCT were soon eclipsed by the introduction of a highly effective enzyme replacement therapy (ERT), which has remained the single most widely used treatment. Experience with HSCT is limited to about 50 reported cases, mainly performed in the last century, with an overall survival around 85%. HSCT typically achieves complete correction of visceral and bony changes and can fully stabilize neurological features in otherwise progressive type II and III GD. ERT, in contrast, is completely safe and effective, but is limited by cost, incomplete resolution of visceral, hematological, and bony features in some patients, and lack of neurological correction in type II and III disease. In this review, we summarize and compare HSCT and ERT. With 20 years of experience of ERT, its limitations as well as its advantages are now well delineated. Meanwhile progress in HSCT over the last decade suggests that transplantation would today represent a very safe curative approach for GD offering one time complete correction of the disease, contrasting with the lifelong need for ERT with its associated expense and dependence on sophisticated drug manufacture. Additionally, unlike ERT, HSCT can be beneficial for neurological forms of GD. We conclude that the time has come to re-evaluate HSCT in selected patients with GD where ERT is less likely to fully eradicate symptoms of the disease.

Matrix Metalloproteinases in Non-Neoplastic Disorders

Science.gov (United States)

Tokito, Akinori; Jougasaki, Michihisa

2016-01-01

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. PMID:27455234

Hematopoietic cytokines as therapeutic players in early stages Parkinson’s disease

Directory of Open Access Journals (Sweden)

Kyle eFarmer

2015-07-01

Full Text Available Parkinson's disease (PD is a devastating age related neurodegenerative disease that is believed to have a lengthy prodromal state. It is critical to find methods of interfering with the progression of this early degenerative stage by inducing compensatory recovery processes to slow or prevent the eventual clinical symptoms. The current perspective article argues that immune system signalling molecules represent such a promising therapeutic approach. Two cytokines of interest are granulocyte macrophage-colony stimulating factor (GM-CSF and erythropoietin (EPO. These hematopoietic cytokines have been protective in models of stroke, neuronal injury, and more recently PD. It is our belief that these trophic cytokines can be used not only for cell protection but also regeneration. However, success is likely dependent on early intervention. This paper will outline our perspective on the development of novel trophic recovery treatments for PD. In particular, we present new data from our lab suggesting that EPO and GM-CSF can foster neural re-innervation in a mild or partial lesion PD model that could be envisioned as reflecting the early stages of the disease.

Biology and flow cytometry of proangiogenic hematopoietic progenitors cells.

Science.gov (United States)

Rose, Jonathan A; Erzurum, Serpil; Asosingh, Kewal

2015-01-01

During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM. © 2014 International Society for Advancement of Cytometry.

Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations

Directory of Open Access Journals (Sweden)

Bhatia M

2015-07-01

Full Text Available Monica Bhatia,1 Sujit Sheth21Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, 2Division of Pediatric Hematology and Oncology, Weill Cornell Medical College, New York, NY, USAAbstract: Hematopoietic stem cell transplantation remains the only curative treatment currently in use for patients with sickle cell disease (SCD. The first successful hematopoietic stem cell transplantation was performed in 1984. To date, approximately 1,200 transplants have been reported. Given the high prevalence of this disorder in Africa, and its emergence in the developed world through immigration, this number is relatively small. There are many reasons for this; primary among them are the availability of a donor, the risks associated with this complex procedure, and the cost and availability of resources in the developing world. Of these, it is fair to say that the risks associated with the procedure have steadily decreased to the point where, if currently performed in a center with experience using a matched sibling donor, overall survival is close to 100% and event-free survival is over 90%. While there is little controversy around offering hematopoietic stem cell transplantation to symptomatic SCD patients with a matched sibling donor, there is much debate surrounding the use of this modality in “less severe” patients. An overview of the current state of our understanding of the pathology and treatment of SCD is important to show that our current strategy is not having the desired impact on survival of homozygous SCD patients, and should be changed to significantly impact the small proportion of these patients who have matched siblings and could be cured, especially those without overt clinical manifestations. Both patient families and providers must be made to understand the progressive nature of SCD, and should be encouraged to screen full siblings of patients with homozygous SCD for their potential to

Morphological spectrum of non‑neoplastic lesions of the uterine ...

African Journals Online (AJOL)

Background: The uterine cervix is a gateway to several non‑neoplastic and neoplastic gynecological lesions. Most of these non‑neoplastic lesions are commonly found in women of reproductive age. These lesions constitute a source of morbidity and mortality in women worldwide hence the need to analyze them to provide ...

Células-tronco de origem hematopoéticas: expansão e perspectivas de uso terapêutico Hematopoietic stem cells: expansion and perspectives for therapeutic use

Directory of Open Access Journals (Sweden)

Eliana S. F. W. Abdelhay

2009-05-01

Full Text Available A célula-tronco hematopoética (CTH tem um enorme potencial para reconstituir o sistema hematopoético, o que permitiu o desenvolvimento de estratégias de terapias celulares para doenças neoplásicas ou não. Em paralelo com os avanços clínicos, estudos sobre os mecanismos moleculares que levam as células-tronco hematopoéticas a decidir pela autorrenovação, diferenciação ou apoptose têm contribuído para o conhecimento de como controlar a cinética da CTH. Esta revisão tenta descrever como estes novos avanços podem ser utilizados no desenvolvimento de estratégias de expansão das CTHs para uso terapêutico.Hematopoietic stem cells (HSCs have the potential for reconstituting the hematopoietic system a characteristic that has enabled the development of cell based therapies for neoplastic and non-malignant diseases. In parallel with these clinical advances, elucidation of molecular mechanisms controlling self-renewal, differentiation or apoptosis have contributed to our understanding of the molecular events that control HSC kinetics. This review focuses on how these advances can be translated in new strategies for HSC expansion and their use in therapies.

Acquisition and Cure of Autoimmune Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

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Hsin-An Hou

2007-09-01

Full Text Available Hematopoietic stem cell transplantation (HSCT can either cause or eliminate autoimmune disease. Here, we report two cases. One was a 33-year-old woman with myelodysplastic syndrome (refractory anemia who received bone marrow transplantation from her human leukocyte antigen (HLA-identical sister who had a history of Graves' disease. Antithyroid antibodies, including antimicrosomal antibody and antithy-roglobulin antibody, appeared 4 months after transplantation. Clinical hyperthyroidism appeared 7 months after transplantation, and a hypothyroid state was noted 2 months later. The other case was a 50-year-old woman with Sjögren's syndrome and hypothyroidism who was diagnosed with peripheral T cell non-Hodgkin's lymphoma. She received allogeneic peripheral blood stem cell transplantation (PBSCT from her histocompatible sister owing to only partial response to traditional chemotherapy. Cure of lymphoma and remission of Sjögren's syndrome was noted 4 years after PBSCT. These two illustrative cases, one of acquisition of hyperthyroidism and the other of remission of Sjögren's syndrome after transplantation, highlights that HSCT can induce adoptive autoimmune disease or cure coincidental autoimmune disease. Donor selection and attentive monitoring is required in such circumstances.

A HISTOPATHOLOGICAL STUDY OF NEOPLASTIC LESIONS OF UTERINE CERVIX OF PERI AND POSTMENOPAUSAL WOMEN

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Jogesh Kakati

2017-03-01

Full Text Available BACKGROUND Neoplastic lesions of uterine cervix is one of the most common malignant neoplasms in women. The tremendous success in giving a confirmed diagnosis of the disease by doing histopathological examination is of prime importance in giving the most appropriate treatment and to understand the prognosis. The aim of the study is to study the incidence and age-wise distribution of the neoplastic lesions of the uterine cervix in peri and postmenopausal women by doing histopathological examination of neoplastic lesions and by doing correlation of clinical findings with histopathological examination. MATERIALS AND METHODS The study included 803 cases of total cervical specimens, out of which 180 cases of neoplastic cervical lesions were found, out of which 150 cases were found in the peri and postmenopausal age groups, i.e. above 40 years of age. The study was done in Gauhati Medical College and Hospital, Guwahati, from the period 1 st June, 2013, to 1 st June, 2014. The specimens that were included in the study were punch biopsies, hysterectomies and polypectomies and cervical specimens were studied by doing histopathological examinations. RESULTS Out of the 150 cases of neoplastic lesions in the peri and postmenopausal women, the most common neoplastic lesion was cervical intraepithelial neoplasia, i.e. CIN (8.3% of the cervix, followed by malignant (5.6% and benign (4.7% lesions of the cervix in this study group of patients. CONCLUSION Histopathological examination of the cervix is an effective method of giving a confirmed diagnosis of all the noncancerous, precancerous and cancerous lesions of uterine cervix, which helps in giving the most appropriate treatment and also helps in understanding the prognosis.

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

DEFF Research Database (Denmark)

Wong, Yan Fung; Micklem, Chris N; Taguchi, Masataka

2014-01-01

Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease...... regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population...... is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS...

Hematopoietic tissue repair under chronic low daily dose irradiation

International Nuclear Information System (INIS)

Seed, T.M.

1994-01-01

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d -1 ). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 ampersand 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity

Imaging of limbic para-neoplastic encephalitis

International Nuclear Information System (INIS)

Rimmelin, A.; Sellat, F.; Morand, G.; Quoix, E.; Clouet, P.L.; Dietemann, J.L.

1997-01-01

Para-neoplastic limbic encephalitis is a rare syndrome mostly associated with small cell lung cancer. We present the case of a 69-year-old man with selective amnesia suggesting limbic encephalitis. A neuroendocrine cell lung cancer was found, confirming the diagnostics of para-neoplastic limbic encephalitis. Contrast-enhanced cerebral CT was normal whether magnetic resonance imaging showed signal abnormalities of the medial part of temporal lobes and hippocampal regions. Because neurologic improvement may follow treatment of the primary tumor, early diagnosis is important. (authors)

Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant.

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Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E

2014-11-01

Epstein-Barr virus (EBV) reactivation can cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant. Delays in reconstitution of EBV-specific T lymphocyte activity can lead to life-threatening EBV lymphoproliferative disease (EBV-PTLD). This review highlights recent advances in the understanding of pathophysiology, risk factors, diagnosis, and management of EBV viremia and PTLD. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load, have helped identify high-risk patients and diagnose early lymphoproliferation. The most significant advances have come in the form of innovative treatment options, including manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response, and targeting infected B cells with monoclonal antibodies, chemotherapy, unmanipulated donor lymphocytes, and donor or more recently third-party EBV cytotoxic T lymphocytes. Defining criteria for preemptive therapy remains a challenge. EBV reactivation is a significant complication after stem cell transplant. Continued improvements in risk stratification and treatment options are required to improve the morbidity and mortality caused by EBV-associated diseases. Current approaches use rituximab to deplete B cells or adoptive transfer of EBV cytotoxic T lymphocyte to reconstitute immunity. The availability of rapid EBV-specific T cell products offers the possibility of improved outcomes.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

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Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

In Utero Hematopoietic Cell Transplantation for Hemoglobinopathies

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Tippi C. Mackenzie

2015-01-01

Full Text Available In utero hematopoietic cell transplantation (IUHCTx is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.

Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

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Enblad, Malin; Birgisson, Helgi; Wanders, Alkwin; Sköldberg, Filip; Ghanipour, Lana; Graf, Wilhelm

2016-04-01

The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.

Herpes zoster-associated voiding dysfunction in hematopoietic malignancy patients.

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Imafuku, Shinichi; Takahara, Masakazu; Uenotsuchi, Takeshi; Iwato, Koji; Furue, Masutaka

2008-01-01

Voiding dysfunction is a rare but important complication of lumbo-sacral herpes zoster. Although the symptoms are transient, the clinical impact on immunocompromised patients cannot be overlooked. To clarify the time course of voiding dysfunction in herpes zoster, 13 herpes zoster patients with voiding dysfunction were retrospectively analyzed. Of 13 patients, 12 had background disease, and six of these were hematopoietic malignancies; four of these patients were hematopoietic stem cell transplant (HSCT) recipients. Ten patients had sacral lesions, two had lumbar, and one had thoracic lesions. Interestingly, patients with severe rash, or with hematopoietic malignancy had later onset of urinary retention than did patients with mild skin symptoms (Mann-Whitney U analysis, P = 0.053) or with other background disease (P = 0.0082). Patients with severe skin rash also had longer durations (P = 0.035). In one case, acute urinary retention occurred as late as 19 days after the onset of skin rash. In immune compromised subjects, attention should be paid to patients with herpes zoster in the lumbo-sacral area for late onset of acute urinary retention even after the resolution of skin symptoms.

Low antigenicity of hematopoietic progenitor cells derived from human ES cells

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Eun-Mi Kim

2010-02-01

Full Text Available Eun-Mi Kim1, Nicholas Zavazava1,21Department of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa, USA; 2Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USAAbstract: Human embryonic stem (hES cells are essential for improved understanding of diseases and our ability to probe new therapies for use in humans. Currently, bone marrow cells and cord blood cells are used for transplantation into patients with hematopoietic malignancies, immunodeficiencies and in some cases for the treatment of autoimmune diseases. However, due to the high immunogenicity of these hematopoietic cells, toxic regimens of drugs are required for preconditioning and prevention of rejection. Here, we investigated the efficiency of deriving hematopoietic progenitor cells (HPCs from the hES cell line H13, after co-culturing with the murine stromal cell line OP9. We show that HPCs derived from the H13 ES cells poorly express major histocompatibility complex (MHC class I and no detectable class II antigens (HLA-DR. These characteristics make hES cell-derived hematopoietic cells (HPCs ideal candidates for transplantation across MHC barriers under minimal immunosuppression.Keywords: human embryonic stem cells, H13, hematopoiesis, OP9 stromal cells, immunogenicity

Prevalence of human papillomavirus types in women with pre-neoplastic and neoplastic cervical lesions in the Federal District of Brazil

OpenAIRE

Camara, Geni NL; Cerqueira, Daniela M; Oliveira, Ana PG; Silva, Evandro O; Carvalho, Luciano GS; Martins, Cláudia RF

2003-01-01

As a contribution to the public health authorities in planning prophylactic and therapeutic vaccine strategies, we describe the prevalence of human papillomavirus (HPV) types in women presenting abnormal cytological results in Pap smear screening tests in the Federal District, Central Brazil. We studied 129 cervical scraping samples from women whose cytological tests showed either pre-neoplastic or neoplastic lesions. Amplification of HPV DNA was performed by polymerase chain reaction using c...

Potential Therapeutic Effects of Curcumin, the Anti-inflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases

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Aggarwal, Bharat B.; Harikumar, Kuzhuvelil B.

2009-01-01

Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that the this activity of turmeric is due to curcumin, a diferuloylmethane. This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various pro-inflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further. PMID:18662800

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey

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Alişan Yıldıran

2017-12-01

Full Text Available Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11, Chediak-Higashi syndrome (n=2, leukocyte adhesion deficiency (n=2, MHC class 2 deficiency (n=2, chronic granulomatous syndrome (n=2, hemophagocytic lymphohistiocytosis (n=1, Wiskott-Aldrich syndrome (n=1, and Omenn syndrome (n=1. Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey.

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Yıldıran, Alişan; Çeliksoy, Mehmet Halil; Borte, Stephan; Güner, Şükrü Nail; Elli, Murat; Fışgın, Tunç; Özyürek, Emel; Sancak, Recep; Oğur, Gönül

2017-12-01

Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class 2 deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

NEOPLASTIC LESIONS OF THE APPENDIX

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Piotr Bryk

2013-11-01

Full Text Available The aim of the research was to present the clinical observations of neoplastic lesions of the appendix (one carcinoid and two mucous cysts and to discuss various manners of treatment and prognosis. Material and methods: The authors of the following paper present a description of three cases of appendix tumours, two patients with a mucous cyst and a patient with carcinoid, against the background of all the appendectomies performed at the Clinical Department of General, Endocrine and Oncological Surgery of the Provincial Polyclinical Hospital in Kielce in the years 2005–2011. Results : Within the 7-year period, a total of 11 719 surgical operations have been performed, where 834 (7.1% were that of appendectomy. Among all of the removed vermiform appendixes, neoplastic lesions occurred in three cases constituting a mere 0.3% of all of the appendectomies performed within that period. In two of the cases there was a suspicion of mucous cysts before the surgical operation. In none of the above-mentioned cases was is possible to ultimately establish the diagnosis before the operation. The patients were subjected to a simple appendectomy. The patients are in good clinical health, with no signs of relapse. Conclusions : The presented cases of patients with appendix tumours illustrate the difficulty of preoperative detection of a neoplastic lesion. This is mainly due to a scantily symptomatic course or symptoms typical of appendicitis. In light of this, histopathological examination of each appendix should be treated as obligatory.

Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

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Michael M. B. Green

2016-08-01

Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

Computed tomography in neoplastic diseases of the skull base and adjacent areas using EMI scanner CT-1000

International Nuclear Information System (INIS)

Ono, Yoshimi; Ohtake, Eiji; Asakura, Koichi; Tanohata, Kazunori; Ito, Otomasa

1980-01-01

CT-findings of 145 patients with and without neoplastic diseases of the skull base were evaluated using EMI CT-1000. Analysis of 64 patients without any lesion at the skull base showed more artifacts compared with that of higher slices, so that good or fair images were obtained only in 64% of this groups of patients. The most important factor in producing artifacts are considered to be caused by patient's movement. We also evaluated the tumor extension to the skull base in 81 patients. They were 24 brain tumors, 21 pituitary adenomas, and 36 nasopharyngeal and paranasal cancers. Four out of 24 brain tumors showed extracranial extension, 12 pituitary adenomas infiltrating outside of the sella turcica, and 10 cases of nasopharyngeal cancers showed intracranial extension. It was concluded that CT presented an excellent information in evaluating the degree of extension of neoplasms which invading to the skull base. (author)

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism.

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Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

2017-05-23

Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma

DEFF Research Database (Denmark)

Braendstrup, P; Langkilde, Annika; Schreiber, K

2012-01-01

Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases.......Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases....

X-ray-induced in vitro neoplastic transformation of human diploid cells

International Nuclear Information System (INIS)

Borek, C.

1980-01-01

Techniques have recently been developed to identify and score quantitatively neoplastic transformation caused by x-rays in cultured cells derived from rodents. The present report describes for the first time the neoplastic transformation in vitro of human diploid cells by x-ray irradiation into cells which can progress in vitro into advanced stages of neoplastic development, namely, to form colonies in agar and give rise to tumors when injected into nude mice

Pathophysiology of infectious hematopoietic necrosis virus disease in rainbow trout: hematological and blood chemical changes in moribund fish

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Amend, D.F.; Smith, L.

1975-01-01

Infectious hematopoietic necrosis (IHN) is a rhabdoviral disease of rainbow trout (Salmo gairdneri). Trout were injected with IHNV, and various hematological and biochemical measurements of clinically ill fish were compared to uninfected controls. Infected fish had reduced corpuscular counts, hemoglobin, and packed cell volume, but normal mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. The percentage of immature erythrocytes was increased, but the percentage of leukocytes was unchanged. Differential leukocyte counts showed a significant decrease in neutrophils, increase in lymphocytes, but no change in monocytes. Unidentifiable necrobiotic cells were prevelant in blood smears and hematopoietic tissue imprints. Plasma bicarbonate, chloride, calcium, phosphorus, bilirubin, and osmolality were significantly reduced, but plasma glucose and anterior kidney ascorbate were unchanged. Plasma pH increased and the alpha fractions of the serum proteins were altered. No change was found in plasma enzymes, except that a LDH isozyme was significantly increased. The alkali reserve was diminished and alterations in acid-base and fluid balance occurred. Death probably resulted from a severe electrolyte and fluid imbalance caused by renal failure.

Lessons Learned from Talking with Parents about the Role of Hematopoietic Stem Cell Transplantation in the Treatment of Children with Sickle Cell Disease

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Friedrich, Paola; Steinfield, Elizabeth; Kim, Francis; Hays, Mary Margaret; Lehmann, Leslie; Sprinz, Philippa

2015-01-01

Background: Hematopoietic stem cell transplantation (HSCT) is currently the only cure for sickle cell disease (SCD), but only a fraction of eligible children proceed to transplantation. We aimed to understand parental awareness and perceptions as a contributor. Purpose: To discuss HSCT with parents of children with SCD and assess their awareness…

Probiotics against neoplastic transformation of gastric mucosa: effects on cell proliferation and polyamine metabolism.

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Russo, Francesco; Linsalata, Michele; Orlando, Antonella

2014-10-07

Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism.

The biochemistry of hematopoietic stem cell development.

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Kaimakis, P; Crisan, M; Dzierzak, E

2013-02-01

The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult. HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC

Symptoms after hospital discharge following hematopoietic stem cell transplantation

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Gamze Oguz

2014-01-01

Full Text Available Aims: The purposes of this study were to assess the symptoms of hematopoietic stem cell transplant patients after hospital discharge, and to determine the needs of transplant patients for symptom management. Materials and Methods: The study adopted a descriptive design. The study sample comprised of 66 hematopoietic stem cell transplant patients. The study was conducted in Istanbul. Data were collected using Patient Information Form and Memorial Symptom Assessment Scale (MSAS. Results: The frequency of psychological symptoms in hematopoietic stem cell transplant patients after discharge period (PSYCH subscale score 2.11 (standard deviation (SD = 0.69, range: 0.93-3.80 was higher in hematopoietic stem cell transplant patients than frequency of physical symptoms (PHYS subscale score: 1.59 (SD = 0.49, range: 1.00-3.38. Symptom distress caused by psychological and physical symptoms were at moderate level (Mean = 1.91, SD = 0.60, range: 0.95-3.63 and most distressing symptoms were problems with sexual interest or activity, difficulty sleeping, and diarrhea. Patients who did not have an additional chronic disease obtained higher MSAS scores. University graduates obtained higher Global Distress Index (GDI subscale and total MSAS scores with comparison to primary school graduates. Total MSAS, MSAS-PHYS subscale, and MSAS-PSYCH subscale scores were higher in patients with low level of income (P < 0.05. The patients (98.5% reported to receive education about symptom management after hospital discharge. Conclusions: Hematopoietic stem cell transplant patients continue to experience many distressing physical or psychological symptoms after discharge and need to be supported and educated for the symptom management.

The Meaning of Disease and Spiritual Responses to Stressors in Adults With Acute Leukemia Undergoing Hematopoietic Stem Cell Transplantation.

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Farsi, Zahra

2015-12-01

Some studies have shown that patients with cancer may experience significant spiritual distress as well as spiritual growth, that there is a positive association between spirituality and coping, and that positive religious coping predicts enhanced health outcomes. This study was designed to help explain how the meaning of disease and spiritual responses to threatening stressors influence the final experiential outcomes of adults with leukemia undergoing hematopoietic stem cell transplantation in Iran. This grounded theory study conducted in-depth interviews between 2009 and 2011 on 10 adults in Iran with leukemia undergoing hematopoietic stem cell transplantation. Recorded audio interviews were transcribed verbatim in Persian and coded and analyzed using Corbin and Strauss (2008)'s approach. Main categories that emerged from data included "experiencing the meaning of cancer"; "changing perceptions of death, life and health"; and "moving toward perfection and sublimity." "Finding meaning" was the main concept that defined the final outcome of the experience of participants. Understanding the meaning to patients of disease and treatments may help healthcare providers better appreciate the patients' perspective and improve the physician-patient relationship. Nurses are well positioned to play a decisive role in helping patients cope effectively with their treatment process and in helping ensure positive outcomes for treatments through their helping patients find the unique meaning of their experience.

Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.

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Xuan, Li; Jiang, Xinmiao; Sun, Jing; Zhang, Yu; Huang, Fen; Fan, Zhiping; Guo, Xutao; Dai, Min; Liu, Can; Yu, Guopan; Zhang, Xian; Wu, Meiqing; Huang, Xiaojun; Liu, Qifa

2013-09-01

Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 263 recipients undergoing allo-HSCT were prospectively enrolled. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction. The 3-year cumulative incidence of total EBV-associated diseases, posttransplantation lymphoproliferative diseases (PTLD), EBV fever, and EBV end-organ diseases (pneumonia, encephalitis/myelitis, and hepatitis) were 15.6%±2.5%, 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2% (2.2%±1.0%, 1.6%±0.8%, and 0.9%±0.6%), respectively. Fever was the most common symptom of EBV-associated diseases. Patients with PTLD had better response rate to rituximab-based treatments compared with those with EBV end-organ diseases (including PTLD accompanied by EBV end-organ diseases) (P=0.014). The 3-year overall survival was 37.3%±13.7%, 100.0%, and 0.0%±0.0% in patients with PTLD, EBV fever, and EBV end-organ diseases (P=0.001). EBV-associated diseases other than PTLD are not rare in the recipients of allo-HSCT. The clinical manifestations of EBV end-organ diseases are similar to PTLD. EBV end-organ diseases had poorer response to rituximab-based therapy compared with PTLD.

Explanation of application standards of hematopoietic stimulating factors in the treatment of acute radiation sickness

International Nuclear Information System (INIS)

Xing Zhiwei; Jiang Enhai; Wang Guilin; Luo Qingliang

2012-01-01

Occupational standard of the Ministry of health-Application Standards of Hematopoietic Stimulating Factors in the Treatment of Acute Radiation Sickness has been completed as a draft standard. Based on the wide study and analysis of related animal experimental literature about hematopoietic stimulating factor in the treatment of acute radiation sickness and domestic and foreign clinical reports about application of hematopoietic stimulating factor in radiation accidents in the past decade, the standard was enacted according to the suggestions of International Atomic Energy Agency and the United States Strategic National Stockpile Radiation Working Group and European countries about the application of hematopoietic stimulating factor. It is mainly used for nuclear accident emergency and the treatment of the bone marrow form of acute radiation sickness caused by radiation accidents. It also applies to other hematopoietic failure diseases. In order to implement this standard correctly, the relevant contents of the standard were interpreted in this article. (authors)

Hematopoietic and mesenchymal stem cells for the treatment of chronic respiratory diseases: role of plasticity and heterogeneity.

Science.gov (United States)

Conese, Massimo; Piro, Donatella; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

2014-01-01

Chronic lung diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal (stem) cells (MSCs), encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases.

Regulatory Systems in Bone Marrow for Hematopoietic Stem/Progenitor Cells Mobilization and Homing

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P. Alvarez

2013-01-01

Full Text Available Regulation of hematopoietic stem cell release, migration, and homing from the bone marrow (BM and of the mobilization pathway involves a complex interaction among adhesion molecules, cytokines, proteolytic enzymes, stromal cells, and hematopoietic cells. The identification of new mechanisms that regulate the trafficking of hematopoietic stem/progenitor cells (HSPCs cells has important implications, not only for hematopoietic transplantation but also for cell therapies in regenerative medicine for patients with acute myocardial infarction, spinal cord injury, and stroke, among others. This paper reviews the regulation mechanisms underlying the homing and mobilization of BM hematopoietic stem/progenitor cells, investigating the following issues: (a the role of different factors, such as stromal cell derived factor-1 (SDF-1, granulocyte colony-stimulating factor (G-CSF, and vascular cell adhesion molecule-1 (VCAM-1, among other ligands; (b the stem cell count in peripheral blood and BM and influential factors; (c the therapeutic utilization of this phenomenon in lesions in different tissues, examining the agents involved in HSPCs mobilization, such as the different forms of G-CSF, plerixafor, and natalizumab; and (d the effects of this mobilization on BM-derived stem/progenitor cells in clinical trials of patients with different diseases.

Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

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Akunuru, Shailaja; Geiger, Hartmut

2016-01-01

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

Epidemiological characteristics of infectious hematopoietic necrosis virus (IHNV): a review.

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Dixon, Peter; Paley, Richard; Alegria-Moran, Raul; Oidtmann, Birgit

2016-06-10

Infectious hematopoietic necrosis virus (IHNV, Rhabdoviridae), is the causative agent of infectious hematopoietic necrosis (IHN), a disease notifiable to the World Organisation for Animal Health, and various countries and trading areas (including the European Union). IHNV is an economically important pathogen causing clinical disease and mortalities in a wide variety of salmonid species, including the main salmonid species produced in aquaculture, Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). We reviewed the scientific literature on IHNV on a range of topics, including geographic distribution; host range; conditions required for infection and clinical disease; minimum infectious dose; subclinical infection; shedding of virus by infected fish; transmission via eggs; diagnostic tests; pathogen load and survival of IHNV in host tissues. This information is required for a range of purposes including import risk assessments; parameterisation of disease models; for surveillance planning; and evaluation of the chances of eradication of the pathogen to name just a few. The review focuses on issues that are of relevance for the European context, but many of the data summarised have relevance to IHN globally. Examples for application of the information is presented and data gaps highlighted.

Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease.

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Elske T Massolt

Full Text Available Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects.We studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs. We measured serum levels of brain-derived neurotrophic factor (BDNF, Stem Cell Factor (SCF, Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2, Epidermal Growth Factor (EGF and IL-7 at baseline.BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001, while EGF (506.9 vs 307.6 pg/ml, P = 0.003 and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028 were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017. In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion.Relatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A

Oral changes in individuals undergoing hematopoietic stem cell transplantation

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Regina Haddad Barrach

2015-04-01

Full Text Available INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression.OBJECTIVE: To report an oral disease management protocol before and after hematopoietic stem cell transplantation.METHODS: A prospective study was carried out with 65 patients aged > 18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients; B (autologous transplant, 31 patients. A total of three dental status assessments were performed: in the pre-transplantation period (moment 1, one week after stem cell infusion (moment 2, and 100 days after transplantation (moment 3. In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks.RESULTS: The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression.CONCLUSION: Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications.

Potential role of immunoablation and hematopoietic cell transplantation in the treatment of early diabetes type 1.

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Snarski, Emilian; Milczarczyk, Alicja; Franek, Edward; Jedrzejczak, Wieslaw

2010-01-01

Immunoablation with autologous hematopoietic cell transplantation has shown some effectiveness in the treatment of autoimmune diseases as diverse as aplastic anemia, systemic lupus erythematosus, multiple sclerosis and Crohn's disease. It has been recently shown that this treatment might prevent or delay development of diabetes type 1. The majority of more than 30 patients with early diabetes type 1 who underwent immunoablation and hematopoietic cell transplantation in various centers in the world achieved durable remission of diabetes and independence of exogenous insulin. This review summarizes advantages and risks of this treatment of early diabetes type 1.

Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

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Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

2017-07-01

Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

Cognitive ability in children with chronic granulomatous disease: a comparison of those managed conservatively with those who have undergone hematopoietic stem cell transplant.

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Cole, Theresa S; McKendrick, Fiona; Cant, Andrew J; Pearce, Mark S; Cale, Catherine M; Goldblatt, David R; Gennery, Andrew R; Titman, Penny

2013-08-01

Chronic granulomatous disease (CGD) is a primary immunodeficiency managed conservatively or with hematopoietic stem cell transplant. Studies have shown people with CGD and those transplanted for primary immunodeficiencies have lower than average cognitive ability. In this study, IQ in children with CGD and those transplanted for it was within the normal range. Georg Thieme Verlag KG Stuttgart · New York.

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

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Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas

2014-02-01

Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (PEpstein-Barr virus mismatch recipient-/donor+ (Pdisease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (Pdisease after transplantation in need of pre-emptive measures.

Umbilical Cord-Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation

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Yu-Hua Chao

2012-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted.

X-ray-induced in vitro neoplastic transformation of human diploid cells

International Nuclear Information System (INIS)

Borek, C.

1980-01-01

The neoplastic transformation, in vitro, of human diploid cells by x-ray irradiation into cells which can progress, in vitro, into advanced stages of neoplastic development is described. The cells are shown to form colonies in agar and to give rise to tumours when injected into nude mice. (U.K.)

The spectrum of non- neoplastic skin lesions in Ibadan, Nigeria: a ...

African Journals Online (AJOL)

The other common specific skin lesions were lichen planus/lichenoid dermatitis 27(12.9% of 209 cases), verruca vulgaris 25 (12% of 209 cases). Conclusion: The number of histologically diagnosed non-neoplastic skin lesions is relatively small. There is a very wide spectrum of non-neoplastic skin lesions diagnosed within ...

Neoplastic Meningitis from Solid Tumors: A Prospective Clinical Study in Lombardia and a Literature Review on Therapeutic Approaches

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A. Silvani

2013-01-01

Full Text Available Neoplastic dissemination to the leptomeninges is an increasingly common occurrence in patients with both haematological and solid tumors arising outside the central nervous system. Both refinement of diagnostic techniques (Magnetic resonance imaging and increased survival in patients treated with targeted therapies for systemic tumors account for this increased frequency. Cerebrospinal fluid cytological analysis and MRI confirm clinical diagnosis based on multifocal central nervous system signs/symptoms in a patient with known malignancy. Overall survival in patients with leptomeningeal neoplastic dissemination from solid tumors is short, rarely exceeding 3-4 months. However, selected patients may benefit from aggressive therapies, Apart from symptomatic treatment, intrathecal chemotherapy is used, with both free (methotrexate, Thiotepa, AraC and liposomal antitumor agents (liposomal AraC. Palliative radiotherapy is indicated only in cases of symptomatic bulky disease, surgery is limited to positioning of Ommaya recervoirs or C5F shunting. We report clinical data on a cohort of 26 prospectively followed patients with neoplastic leptomeningitis followed in Lombardia, Italy, in 2011. Prognostic factors and pattern of care are reported.

Uptake of iodine-123-α-methyl tyrosine by gliomas and non-neoplastic brain lesions

International Nuclear Information System (INIS)

Kuwert, T.; Morgenroth, C.; Woesler, B.; Matheja, P.; Palkovic, S.; Vollet, B.; Samnick, S.; Maasjosthusmann, U.; Lerch, H.; Gildehaus, F.J.; Wassmann, H.; Schober, O.

1996-01-01

Using single-photon emission tomography (SPET), the radiopharmaceutical L-3-iodine-123-α-methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating higc-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours. (orig.)

Bone marrow transplantations to study gene function in hematopoietic cells

NARCIS (Netherlands)

de Winther, Menno P. J.; Heeringa, Peter

2011-01-01

Immune cells are derived from hematopoietic stem cells in the bone marrow. Experimental replacement of bone marrow offers the unique possibility to replace immune cells, to study gene function in mouse models of disease. Over the past decades, this technique has been used extensively to study, for

Knowledge of nursing students about the care provided to people with neoplastic wounds

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Roseane Ferreira Gomes

2017-05-01

Full Text Available Objective: To investigate the knowledge of nursing students about the care provided to patients with neoplastic wound. Method: This is an exploratory research of a qualitative nature, which was attended by 15 students of the Bachelor's Degree in Nursing from the Center of Education and Health of the Federal University of Campina Grande, campus Cuité - PB, in the period from October to November 2015. For data collection, we used a form for an interview. The data were analyzed through the Technique of Thematic Analysis of Minayo. Results: From the analysis of the empirical material emerged the following thematic categories: Category 1 - Defining neoplastic wounds; Category 2 - Knowledge incipient on ‘neoplastic wounds’ for academic and professional practice; Category 3 - Envisioning the theme "neoplastic wound" in the Academy; Category 4 - Knowledge about methods of evaluation of neoplastic wounds and Category 5 - Knowledge of therapeutic modalities of neoplastic wounds. Conclusions: The academics know the evaluative method of a patient with neoplastic wound as integralizadora unit of care process; recognize palliative care as the best therapeutic modality for these customers, especially when they are in completion and indicate the products contraindicated in the treatment of these lesions; however, do not mention the covers and recommended substances for the control of the signs and symptoms of these injuries. In this context, it is believed that the creation of academic projects of extension, with the aim of creating opportunities for integration between theory and practice, is one of the ways to improve the knowledge.   Keywords: Knowledge; Students of Nursing; Skin Neoplasms.

AF10 plays a key role in the survival of uncommitted hematopoietic cells.

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Raquel Chamorro-Garcia

Full Text Available Hematopoiesis is a complex process regulated by both cell intrinsic and cell extrinsic factors. Alterations in the expression of critical genes during hematopoiesis can modify the balance between stem cell differentiation and proliferation, and may ultimately give rise to leukemia and other diseases. AF10 is a transcription factor that has been implicated in the development of leukemia following chromosomal rearrangements between the AF10 gene and one of at least two other genes, MLL and CALM. The link between AF10 and leukemia, together with the known interactions between AF10 and hematopoietic regulators, suggests that AF10 may be important in hematopoiesis and in leukemic transformation. Here we show that AF10 is important for proper hematopoietic differentiation. The induction of hematopoietic differentiation in both human hematopoietic cell lines and murine total bone marrow cells triggers a decrease of AF10 mRNA and protein levels, particularly in stem cells and multipotent progenitors. Gain- and loss-of-function studies demonstrate that over- or under-expression of AF10 leads to apoptotic cell death in stem cells and multipotent progenitors. We conclude that AF10 plays a key role in the maintenance of multipotent hematopoietic cells.

Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model.

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Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; Mora-García, María de Lourdes

2015-09-25

BACKGROUND Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. MATERIAL AND METHODS Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. RESULTS We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (psodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings.

Hematopoietic and Mesenchymal Stem Cells for the Treatment of Chronic Respiratory Diseases: Role of Plasticity and Heterogeneity

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Massimo Conese

2014-01-01

Full Text Available Chronic lung diseases, such as cystic fibrosis (CF, asthma, and chronic obstructive pulmonary disease (COPD are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs and mesenchymal stromal (stem cells (MSCs, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases.

Protracted radiation-induced alterations in hematopoietic repair and recovery

International Nuclear Information System (INIS)

Seed, T.M.; Fritz, T.E.

1997-01-01

Pathologic predisposition of beagle dogs under chronic, low daily dose (7.5 cGy day -1 ) whole-body gamma irradiation has been studied relative to molecular repair and hematopoietic competency. Molecular repair, assessed by a microscopy-based unscheduled DNA synthesis (UDS) response, was measured within proliferative and nonproliferative marrow myeloid elements of dogs with markedly different hematopoietic capacities (low capacity, aplasia-prone [AA + ] versus high capacity, myeloproliferative disease-prone [MPD + ]) under protracted radiation stress. Results indicated that protracted exposure elicited a net increase in UDS-repair capacity that was largely independent of exposure duration. This enhanced capacity resulted from the increased strength of the UDS signal together with an expanded number of positively responding cells. The combined response was strong in primitive blasts and weak in more differentiated myelocytic cells. The UDS repair response of the MPD + dogs was significantly greater than that of the AA + animals and was clearly modified relative to the controls. These results suggest that both resiliency and pathologic potential of the hematopoietic system under protracted radiation stress is, in part, associated with an augmentable DNA repair within the more primitive myeloid marrow elements. (author)

Cell cycle regulation of hematopoietic stem or progenitor cells.

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Hao, Sha; Chen, Chen; Cheng, Tao

2016-05-01

The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

Umbilical cord bloods hematopoietic stem cells ex vivo expansion (the literature review

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T. V. Shamanskaya

2012-01-01

Full Text Available Umbilical cord blood (CB is now an attractive source of hematopoietic stem cells (HSCs for transplantation in pediatric and adult patients with various malignant and non-malignant diseases. However, its clinical application is limited by low cells numbers in graft, which correlates with delayed engraftment, an extension of time to platelets and neutrophils recovery and increasing risk of infectious complications. Several strategies have been suggested to overcome this limitation, one of which is obtaining a sufficient number of hematopoietic progenitor cells by ex vivo expansion. Literature review about CB HSCs expansion in given article is presented.

Orthopaedic management of Hurler's disease after hematopoietic stem cell transplantation : A systematic review

NARCIS (Netherlands)

van der Linden, Marleen H.; Kruyt, Moyo C.; Sakkers, Ralph J. B.; de Koning, Tom J.; Oner, F. Cumhur; Castelein, Rene M.

The introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the

Trasplante de células progenitoras hematopoyéticas en enfermedades autoinmunes Hematopoietic stem cell transplantation in autoimmune diseases

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Flavio Albarracín

2008-04-01

Full Text Available El trasplante de células progenitoras hematopoyéticas, células con capacidad de autorrenovación y reconstitución de todos los tipos de células sanguíneas, se utiliza en el tratamiento de numerosas enfermedades potencialmente letales incluyendo leucemias y linfomas. Hoy en día es posible además aplicarlo en el tratamiento de enfermedades autoinmunes graves, como esclerosis múltiple, lupus eritematoso sistémico o esclerosis sistémica, resistentes a la terapia convencional. Estudios en modelos animales nos demuestran que la transferencia de células progenitoras hematopoyéticas podría revertir el proceso de autoinmunidad, un fenómeno que puede explicarse mediante diferentes mecanismos. El resultado de los estudios clínicos que se están llevando a cabo, así como también estudios en pacientes y modelos animales, ayudarán a determinar el rol que el transplante de células progenitoras hematopoyéticas puede jugar en el tratamiento de enfermedades autoinmunes.Transplantation of hematopoietic stem cells, which are capable of self renewal and reconstitution of all types of blood cells, can be a treatment for numerous potential lethal diseases, including leukemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant multiple sclerosis, lupus and systemic sclerosis. Studies in animal models show that the transfer of hematopoietic stem cells can reverse autoimmunity. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

Correlation between standardized uptake value and apparent diffusion coefficient of neoplastic lesions evaluated with whole-body simultaneous hybrid PET/MRI.

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Rakheja, Rajan; Chandarana, Hersh; DeMello, Linda; Jackson, Kimberly; Geppert, Christian; Faul, David; Glielmi, Christopher; Friedman, Kent P

2013-11-01

The purpose of this study was to assess the correlation between standardized uptake value (SUV) and apparent diffusion coefficient (ADC) of neoplastic lesions in the use of a simultaneous PET/MRI hybrid system. Twenty-four patients with known primary malignancies underwent FDG PET/CT. They then underwent whole-body PET/MRI. Diffusion-weighted imaging was performed with free breathing and a single-shot spin-echo echo-planar imaging sequence with b values of 0, 350, and 750 s/mm(2). Regions of interest were manually drawn along the contours of neoplastic lesions larger than 1 cm, which were clearly identified on PET and diffusion-weighted images. Maximum SUV (SUVmax) on PET/MRI and PET/CT images, mean SUV (SUVmean), minimum ADC (ADCmin), and mean ADC (ADCmean) were recorded on PET/MR images for each FDG-avid neoplastic soft-tissue lesion with a maximum of three lesions per patient. Pearson correlation coefficient was used to asses the following relations: SUVmax versus ADCmin on PET/MR and PET/CT images, SUVmean versus ADCmean, and ratio of SUVmax to mean liver SUV (SUV ratio) versus ADCmin. A subanalysis of patients with progressive disease versus partial treatment response was performed with the ratio of SUVmax to ADCmin for the most metabolically active lesion. Sixty-nine neoplastic lesions (52 nonosseous lesions, 17 bone metastatic lesions) were evaluated. The mean SUVmax from PET/MRI was 7.0 ± 6.0; SUVmean, 5.6 ± 4.6; mean ADCmin, 1.10 ± 0.58; and mean ADCmean, 1.48 ± 0.72. A significant inverse Pearson correlation coefficient was found between PET/MRI SUVmax and ADCmin (r = -0.21, p = 0.04), between SUVmean and ADCmean (r = -0.18, p = 0.07), and between SUV ratio and ADCmin (r = -0.27, p = 0.01). A similar inverse Pearson correlation coefficient was found between the PET/CT SUVmax and ADCmin. Twenty of 24 patients had previously undergone PET/CT; five patients had a partial treatment response, and six had progressive disease according to Response Evaluation

Pathophysiology of MDS: genomic aberrations.

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Ichikawa, Motoshi

2016-01-01

Myelodysplastic syndromes (MDS) are characterized by clonal proliferation of hematopoietic stem/progenitor cells and their apoptosis, and show a propensity to progress to acute myelogenous leukemia (AML). Although MDS are recognized as neoplastic diseases caused by genomic aberrations of hematopoietic cells, the details of the genetic abnormalities underlying disease development have not as yet been fully elucidated due to difficulties in analyzing chromosomal abnormalities. Recent advances in comprehensive analyses of disease genomes including whole-genome sequencing technologies have revealed the genomic abnormalities in MDS. Surprisingly, gene mutations were found in approximately 80-90% of cases with MDS, and the novel mutations discovered with these technologies included previously unknown, MDS-specific, mutations such as those of the genes in the RNA-splicing machinery. It is anticipated that these recent studies will shed new light on the pathophysiology of MDS due to genomic aberrations.

Pitfalls of improperly procured adjacent non-neoplastic tissue for somatic mutation analysis using next-generation sequencing

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Lei Wei

2016-10-01

Full Text Available Abstract Background The rapid adoption of next-generation sequencing provides an efficient system for detecting somatic alterations in neoplasms. The detection of such alterations requires a matched non-neoplastic sample for adequate filtering of non-somatic events such as germline polymorphisms. Non-neoplastic tissue adjacent to the excised neoplasm is often used for this purpose as it is simultaneously collected and generally contains the same tissue type as the neoplasm. Following NGS analysis, we and others have frequently observed low-level somatic mutations in these non-neoplastic tissues, which may impose additional challenges to somatic mutation detection as it complicates germline variant filtering. Methods We hypothesized that the low-level somatic mutation observed in non-neoplastic tissues may be entirely or partially caused by inadvertent contamination by neoplastic cells during the surgical pathology gross assessment or tissue procurement process. To test this hypothesis, we applied a systematic protocol designed to collect multiple grossly non-neoplastic tissues using different methods surrounding each single neoplasm. The procedure was applied in two breast cancer lumpectomy specimens. In each case, all samples were first sequenced by whole-exome sequencing to identify somatic mutations in the neoplasm and determine their presence in the adjacent non-neoplastic tissues. We then generated ultra-deep coverage using targeted sequencing to assess the levels of contamination in non-neoplastic tissue samples collected under different conditions. Results Contamination levels in non-neoplastic tissues ranged up to 3.5 and 20.9 % respectively in the two cases tested, with consistent pattern correlated with the manner of grossing and procurement. By carefully controlling the conditions of various steps during this process, we were able to eliminate any detectable contamination in both patients. Conclusion The results demonstrated that the

Para neoplastic syndromes: Usefulness of 18F-fluoro-deoxy-glucose (F.D.G.) positron emission tomography (PET)

International Nuclear Information System (INIS)

Banayan, S.; Janier, M.; Guillerma-Zucchi, N.; Billotey, C.; Ninet, J.; Delmas, P.; Thivolet, C.; Pellet, O.

2008-01-01

Background We evaluated the performance of 18 F-fluorodeoxyglucose ( 18 F.D.G.) positron emission tomography (PET) in the diagnosis of underlying malignancy in cases of suspected para neoplastic syndrome (P.S.). Methods 18 F.D.G.-PET was performed in 31 patients, clinically suspected to have P.S.. The P.S. were 34, among which 12 neurological diseases, eight endocrine, seven rheumatological, one dermatological and six vascular. We compared computed tomography (CT), iodine-enhanced most of the time, and 18 F.D.G.-PET reports to clinicians definitive conclusion at the end of the work-up and a follow-up period of, at least, two months. Results We obtained a histological diagnosis of cancer for ten patients, but could only identify the primary site of malignancy for nine of them. 18 F.D.G.-PET showed six primary sites among which three were not seen on CT. CT disclosed four primary sites, among which one was not seen on 18 F.D.G.-PET. In one case, 18 F.D.G.-PET disclosed regional lymph node metastases whereas these were not identified by CT. Eleven non-neoplastic causes were evidenced, among which 18 F.D.G.-PET played a major role in three cases. Ten causes were still undetermined at the end of the study. Conclusion Whole-body 18 F.D.G.-PET study plays an important role in the identification of underlying malignancy in clinically suspected para neoplastic syndromes; either by identifying the primary tumor or by directing biopsy of metastases. Furthermore, it can identify non-neoplastic causes. (authors)

Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system.

Science.gov (United States)

Song, Bing; Fan, Yong; He, Wenyin; Zhu, Detu; Niu, Xiaohua; Wang, Ding; Ou, Zhanhui; Luo, Min; Sun, Xiaofang

2015-05-01

The generation of beta-thalassemia (β-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the β-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected β-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected β-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of β-Thal iPSC-derived HSCs in transplantation.

Exogenous endothelial cells as accelerators of hematopoietic reconstitution

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Mizer J

2012-11-01

Full Text Available Abstract Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a ability to regulate secretion of cytokines based on biological need; b long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.

The human and murine hematopoietic stem cell niches: are they comparable?

Science.gov (United States)

van Pel, Melissa; Fibbe, Willem E; Schepers, Koen

2016-04-01

Hematopoietic stem cells (HSCs) reside in specific niches that provide various instructive cues that regulate HSC self-renewal and their development into all mature cells of the peripheral blood. Progress in this research field has largely been guided by mouse studies. However, parallel studies with human subjects, tissues, and cells, in combination with xenotransplantation experiments in immunodeficient mice, have contributed to our increased understanding of the human HSC niche. Here, we summarize our current knowledge of the various specialized subsets of both stromal and hematopoietic cells that support HSCs through cell-cell interactions and secreted factors, and the many parallels between the murine and human HSC niches. Furthermore, we discuss recent technological advances that are likely to improve our understanding of the human HSC niche, a better understanding of which may allow further identification of unique molecular and cellular pathways in the HSC niche. This information may help to further improve the outcome of HSC transplantation and refine the treatment of hematopoietic diseases. © 2015 New York Academy of Sciences.

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation.

Science.gov (United States)

Corbacioglu, Selim; Richardson, Paul G

2017-10-01

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease. Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar. Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.

Superficial inflammatory and primary neoplastic lymphadenopathy: diagnostic accuracy of power-doppler sonography

International Nuclear Information System (INIS)

Magarelli, N.; Guglielmi, G.; Savastano, M.; Toro, V.; Sborgia, M.; Fioritoni, G.; Mattei, P.A.; Steinbach, L.; Bonomo, L.

2004-01-01

Objective: To evaluate the sensitivity, specificity and diagnostic accuracy of a cut-off of the resistive index of 0.5 for the differentiation between inflammatory and neoplastic primary lymphadenopathies. Subjects and methods: We measured the resistive index of superficial enlarged lymph nodes in a total of 50 patients (29 males and 21 females; age range 12-72 years, mean age 41.6 year) using an ATL 5000 HDI. A resistive index greater than or equal to 0.5 indicated an inflammatory lymph node and a resistive index <0.5 was consistent with neoplastic primary lymphadenopathies. The gold standard was either surgical biopsy or lymph-node reduction seen with ultrasound examination after antibiotic therapy. Results: The sensitivity of the resistive index for distinguishing inflammatory from neoplastic lymphadenopathy was 84.6%, the specificity 100% and the diagnostic accuracy 95.7% (P<0.001, statistically significant). Conclusion: The results of this study indicate that power-Doppler using a resistive index cut-off of 0.5 was a valid technique for distinguising between inflammatory and primary neoplastic lymph nodes in patients with superficial lymphadenopathies

Age-related mutations associated with clonal hematopoietic expansion and malignancies.

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Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D; Johnson, Kimberly J; Wendl, Michael C; McMichael, Joshua F; Schmidt, Heather K; Yellapantula, Venkata; Miller, Christopher A; Ozenberger, Bradley A; Welch, John S; Link, Daniel C; Walter, Matthew J; Mardis, Elaine R; Dipersio, John F; Chen, Feng; Wilson, Richard K; Ley, Timothy J; Ding, Li

2014-12-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Neoplastic lesions of the temporomandibular joint (TMJ): diagnosis, differential diagnosis and intervention

International Nuclear Information System (INIS)

Vogl, T.J.; Abolmaali, N.; Schedel, H.; Bergh, B.

2001-01-01

Purpose. To evaluate the effectiveness of diagnostic and interventional radiological techniques for neoplastic lesions of the temporomandibular joint (TMJ). Material and methods. Modern diagnosis of the TMJ is based on the clinical use of conventional X-ray techniques, computed tomography (CT), magnetic resonance imaging (MRI) and interventional techniques like biopsies, vascular occlusion and ablation. Results. Conventional X-ray still forms the basic diagnostic procedure applied in open and closed mouth position. CT improves the diagnostic information and serves as the standard diagnostical instrument for cartaliganeous or osseous neoplastic lesions. MRI evaluates soft tissue infiltration in multiplanar techniques and high spatial resolution. Interventional vascular and ablative techniques improve the treatment of neoplastic disorders. (orig.) [de

Treatment of non-neoplastic renal hemorrhage with segmental embolization of renal artery

International Nuclear Information System (INIS)

Zhu Bing

2007-01-01

Objective: To explore the value of segmental embolization of renal artery in dealing with non- neoplastic renal hemorrhage. Methods: Four cases of non-neoplastic hemorrhage, including 2 with bleeding after renal acupuncture biopsy, 2 with bleeding after nephrolithotomy and 1 with congenital renal arteriovenous malformation, were treated with superselective segmental embolization of renal artery. 2 were embolized with coil, 1 with alcohol plus coil and 1 with PVA parcels. Results: Hematuria disappeared in 1-3 days. There was no recurrence in 7-45 months follow up and no complications induced by embolization. Conclusion: It is a safe and reliable therapy to treat non-neoplastic renal hemorrhage with segmental embolization of renal artery. (authors)

Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation

DEFF Research Database (Denmark)

Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E

2013-01-01

We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the pures...

Deregulation of vital mitotic kinase-phosphatase signaling in hematopoietic stem/progenitor compartment leads to cellular catastrophe in experimental aplastic anemia.

Science.gov (United States)

Chatterjee, Ritam; Chattopadhyay, Sukalpa; Law, Sujata

2016-11-01

Aplastic anemia, the paradigm of bone marrow failure, is characterized by pancytopenic peripheral blood and hypoplastic bone marrow. Among various etiologies, inappropriate use of DNA alkylating drugs like cyclophosphamide and busulfan often causes the manifestation of the dreadful disease. Cell cycle impairment in marrow hematopoietic stem/progenitor compartment together with cellular apoptosis has been recognized as culpable factors behind aplastic pathophysiologies. However, the intricate molecular mechanisms remain unrevealed till date. In the present study, we have dealt with the mechanistic intervention of the disease by peripheral blood hemogram, bone marrow histopathology, cytopathology, hematopoietic kinetic study, scanning electron microscopy, DNA damage assessment and flowcytometric analysis of cellular proliferation and apoptosis in hematopoietic stem/progenitor cell (HSPC) rich marrow compartment using busulfan and cyclophosphamidemediated mouse model. To unveil the molecular mechanisms behind aplastic pathophysiology, we further investigated the role of some crucial mitotic and apoptotic regulators like Protein kinase-B (PKB), Gsk-3β, Cyclin-D1, PP2A, Cdc25c, Plk-1, Aurora kinase-A, Chk-1 regarding the hematopoietic catastrophe. Our observations revealed that the alteration of PKB-GSK-3β axis, Plk-1, and Aurora kinase-A expressions in HSPC compartment due to DNA damage response was associated with the proliferative impairment and apoptosis during aplastic anemia. The study established the correlation between the accumulation of DNA damage and alteration of the mentioned molecules in aplastic HSPCs that lead to the hematopoietic catastrophe. We anticipate that our findings will be beneficial for developing better therapeutic strategies for the dreadful disease concerned.

Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

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Sidinh Luc

2016-09-01

Full Text Available B cell CLL/lymphoma 11A (BCL11A is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6, and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.

Diffusion tensor imaging in inflammatory and neoplastic intramedullary spinal cord lesions: Focusing on fiber tracking

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Kim, Hyo Jin; Lee, Joon Woo; Lee, Eugene; Kim, Sung Gon; Kang, Yu Suhn; Ahn, Joong Mo; Kang, Heung Sik [Dept. of Radiology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

2017-02-15

Inflammatory and neoplastic intramedullary spinal cord lesions have overlapping clinical features, and it is occasionally difficult to distinguish one from the other on conventional magnetic resonance imaging. We aimed to compare diffusion tensor imaging findings between inflammatory and neoplastic intramedullary spinal cord lesions, with a specific focus on patterns of fiber tracking. Diffusion tensor imaging was performed in patients with either inflammatory or neoplastic intramedullary spinal cord lesions. The fiber tracking patterns (categorized as “intact,” “displaced,” or “interrupted”) were compared between these two groups. Eight patients were included in the study: 5 patients with pathologically or clinically confirmed inflammatory lesions and 3 patients with pathologically or clinically confirmed neoplastic lesions. Among the 5 patients with inflammatory lesions, 2 patients exhibited the displaced pattern and 3 patients exhibited the intact pattern. Among the 3 patients with neoplastic lesions, 1 patient exhibited the intact pattern, 1 patient exhibited the displaced pattern, and 1 patient exhibited the interrupted pattern. In this study, inflammatory and neoplastic intramedullary spinal cord lesions were not clearly differentiated by fiber tracking; both conditions can present with overlapping features such as displaced fibers. The exclusion of inflammatory conditions based on the presence of displaced fibers in fiber tracking images should be avoided.

Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience

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Juliana Folloni Fernandes

2011-06-01

Full Text Available Objective: To report the experience of a tertiary care hospital withallogeneic hematopoietic stem cell transplantation in children withprimary immunodeficiencies. Methods: Seven patients with primaryimmunodeficiencies (severe combined immunodeficiency: n = 2;combined immunodeficiency: n = 1; chronic granulomatous disease:n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1who underwent eight hematopoietic stem cell transplants (HSCTin a single center, from 2007 to 2010, were studied. Results: Twopatients received transplants from HLA-identical siblings; the othersix transplants were done with unrelated donors (bone marrow: n= 1; cord blood: n = 5. All patients had pre-existing infectionsbefore hematopoietic stem cell transplants. One patient receivedonly anti-thymocyte globulin prior to transplant, three transplantswere done with reduced intensity conditioning regimens and fourtransplants were done after myeloablative therapy. Two patientswere not evaluable for engraftment due to early death. Three patientsengrafted, two had primary graft failure and one received a secondtransplant with posterior engraftment. Two patients died of regimenrelated toxicity (hepatic sinusoidal obstruction syndrome; one patient died of progressive respiratory failure due to Parainfluenza infection diagnosed prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Conclusion: Patients’ status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

KRAS Mutation and Epithelial-Macrophage Interplay in Pancreatic Neoplastic Transformation.

Science.gov (United States)

Bishehsari, Faraz; Zhang, Lijuan; Barlass, Usman; Preite, Nailliw; Turturro, Sanja; Najor, Matthew S; Shetuni, Brandon B; Zayas, Janet P; Mahdavinia, Mahboobeh; Abukhdeir, Abde M; Keshavarzian, Ali

2018-05-14

Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased i) ductal to acinar gene expression ratios, ii) epithelial cells proliferation, and iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a pro-tumorigenic phenotype in macrophages. Altered macrophages decreased epithelial Pigment Epithelial Derived Factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) as well as in our human PDA specimens. Epithelium-macrophage cross talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a pro-tumorigenic phenotype in macrophages, in turn augmenting neoplastic growth. This article is protected by copyright. All rights reserved. © 2018 UICC.

Rearrangements and amplification of the ABL1 gene as an example of kinase activation in T-cell acute lymphoblastic

OpenAIRE

Graux, Carlos

2008-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder that develops from a single hematopoietic T-cell precursor that acquired oncogenic anomalies. T-ALL is a heterogeneous disease comprising several clinico-biological entities characterized by distinct underlying genetic defects. In the first part of this work, we attempted to correlate those numerous anomalies with the role of the corresponding non mutated genes or pathways in normal T-cell development. Mutations targeting se...

Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation

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Matthias J. Reddehase

2016-08-01

Full Text Available Hematopoietic cell transplantation (HCT is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a ‘window of opportunity’ for latent cytomegalovirus (CMV by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A ‘window of opportunity’ for the virus represents a ‘window of risk’ for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8+ T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP representing the most severe clinical manifestation. Here I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a pre-emptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing ‘proof of concept’ for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8+ T cells bridging the critical interim. CMV, however, is not a ‘passive antigen’ but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected bone marrow stroma and impaired colony growth and lineage differentiation can lead to ‘graft failure’. In consequence

Castleman disease (literature review

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A. L. Melikyan

2016-01-01

Full Text Available Castleman disease (angiofollicular hyperplasia of lymph nodes – a rare benign lymphoproliferative disease with prolonged asymptomatic course, associated with a wide variety of autoimmune and oncological diseases and the risk of non-Hodgkin’s lymphoma. The rare occurrence of this disease and a variety of clinical course did not allow for a complete and consistent research on the etiology and pathogenesis and the standard therapies development. In recent years, the number of patients with Castleman disease in the Russian Federation has increased, which requires its recognition among non-neoplastic and neoplastic lymphadenopathy. The article provides an overview about clinical and histological variants of Castleman’s disease, its pathogenesis concepts, classification and treatment.

Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

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Afonso José Pereira Cortez

2011-02-01

Full Text Available BACKGROUND: Hodgkin's lymphoma has high rates of cure, but in 15% to 20% of general patients and between 35% and 40% of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. OBJECTIVES: To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. METHODS: A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. RESULTS: The overall survival rates of this population at five and ten years were 86% and 70%, respectively. The disease-free survival was approximately 60% at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. CONCLUSION: Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not

Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture.

Science.gov (United States)

Buddingh, Emilie P; Ruslan, S Eriaty N; Reijnders, Christianne M A; Szuhai, Karoly; Kuijjer, Marieke L; Roelofs, Helene; Hogendoorn, Pancras C W; Maarten Egeler, R; Cleton-Jansen, Anne-Marie; Lankester, Arjan C

2015-01-01

In vitro expanded mesenchymal stromal cells (MSCs) are increasingly used as experimental cellular therapy. However, there have been concerns regarding the safety of their use, particularly with regard to possible oncogenic transformation. MSCs are the hypothesized precursor cells of high-grade osteosarcoma, a tumor with often complex karyotypes occurring mainly in adolescents and young adults. To determine if MSCs from osteosarcoma patients could be predisposed to malignant transformation we cultured MSCs of nine osteosarcoma patients and five healthy donors for an average of 649 days (range 601-679 days). Also, we compared MSCs derived from osteosarcoma patients at diagnosis and from healthy donors using genome wide gene expression profiling. Upon increasing passage, increasing frequencies of binucleate cells were detected, but no increase in proliferation suggestive of malignant transformation occurred in MSCs from either patients or donors. Hematopoietic cell specific Lyn substrate 1 (HLCS1) was differentially expressed (fold change 0.25, P value 0.0005) between MSCs of osteosarcoma patients (n = 14) and healthy donors (n = 9). This study shows that although HCLS1 expression was downregulated in MSCs of osteosarcoma patients and binucleate cells were present in both patient and donor derived MSCs, there was no evidence of neoplastic changes to occur during long-term culture.

Hematopoietic stem cells transplant in patients with common variable immunodeficiency. Is a therapeutic option?

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Julio César Cambray-Gutiérrez

2017-02-01

Full Text Available Background: Patients with common variable immunodeficiency show higher incidence of sinopulmonary and gastrointestinal infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin. Hematopoietic stem cell transplantation is a non-conventional therapeutic modality. Clinical case: Twenty-six-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum antimicrobials and macrolides. At 22 years of age, she underwent hematopoietic stem cell transplantation owing to continued severe infections. At 4 months, post-transplantation she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud’s disease and upper respiratory tract persistent infections. At the moment of this report she is being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol. Conclusions: Given the high rate of morbidity and mortality associated and immune reconstitution failure, hematopoietic stem cell transplantation should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders.

Immunohistochemistry expression of TCF4 protein on carcinoma, adenoma and non neoplastic colorectal mucosa

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Leonardo Huber Tauil

2014-01-01

Full Text Available Purpose: To detect and quantify the immunoreactivity of TCF4 protein in colorectal carci- noma, colorectal adenoma and non-neoplasic colorectal epithelium. Methods: We studied 129 individuals: 40 with colorectal cancer, 52 with colorectal ad- enoma and 37 with non-neoplastic colorectal epithelium. The colorectal adenoma and carcinoma samples were obtained from patients who underwent surgical procedures, and colonoscopies and samples of non-neoplastic colorectal epithelium were taken from patients who died from cardiovascular diseases, without diseases of the large intestine. Samples of different tissues were included in paraffin blocks, and the immunohistochem- ical expression of protein TCF4 was analyzed using the technique of tissue microarray (TMA with polyclonal antibody TCF4. The immunoreactivity was analyzed and classified as positive and negative. Results: The immunohistochemical expression of TCF4 protein was significantly higher (p < 0.01 in colorectal carcinoma than in the non-neoplastic colorectal epithelium and adenoma. There was no difference (p = 0.76 between TCF4 protein immunohistochemical expression in colorectal adenoma and non-neoplastic colorectal tissue. Conclusions: TCF4 protein showed a more intense expression in colorectal carcinoma than in non-neoplastic colorectal epithelium and adenoma, indicating that this protein is in- volved in colorectal carcinogenesis. Resumo: Objetivos: Detectar e quantificar a imunoexpressão da proteína TCF4 no carcinoma e no adenoma colorretal e no epitélio colorretal não neoplásico. Método: Foram estudados 129 indivíduos: 40 com carcinoma colorretal, 52 com adenoma colorretal e 37 com epitélio colorretal não neoplásico. Os tecidos de adenoma e carcinoma colorretais foram representados por amostras da lesão retirada de doentes submetidos a procedimentos cirúrgicos e colonoscópicos, e as amostras de epitélio colorretal não neo- plásico foram retiradas de doentes falecidos por

Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

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Mila Elich

2018-05-01

Full Text Available One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5trisphosphate (PIP3 by class I phosphoinositide 3 kinases (PI3K. Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function. Recent studies have shown that beyond “canonical” turnover by the PIP3 phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2, PIP3 function in hematopoietic cells can also be dampened through antagonism with the soluble PIP3 analogs inositol(1,3,4,5tetrakisphosphate (IP4 and inositol-heptakisphosphate (IP7. Other evidence suggests that IP4 can promote PIP3 function in thymocytes. Moreover, IP4 or the kinases producing it limit store-operated Ca2+ entry through Orai channels in B cells, T cells, and neutrophils to control cell survival and function. We discuss current models for how soluble inositol phosphates can have such diverse functions and can govern as distinct processes as hematopoietic stem cell homeostasis, neutrophil macrophage and NK cell function, and development and function of B cells and T cells. Finally, we will review the pathological consequences of dysregulated IP4 activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.

Glycomics expression analysis of sulfated glycosaminoglycans of human colorectal cancer tissues and non-neoplastic mucosa by electrospray ionization mass spectrometry.

Science.gov (United States)

Marolla, Ana Paula Cleto; Waisberg, Jaques; Saba, Gabriela Tognini; Waisberg, Daniel Reis; Margeotto, Fernando Beani; Pinhal, Maria Aparecida da Silva

2015-01-01

To determine the presence of glycosaminoglycans in the extracellular matrix of connective tissue from neoplastic and non-neoplastic colorectal tissues, since it has a central role in tumor development and progression. Tissue samples from neoplastic and non-neoplastic colorectal tissues were obtained from 64 operated patients who had colorectal carcinoma with no distant metastases. Expressions of heparan sulphate, chondroitin sulphate, dermatan sulphate and their fragments were analyzed by electrospray ionization mass spectrometry, with the technique for extraction and quantification of glycosaminoglycans after proteolysis and electrophoresis. The statistical analysis included mean, standard deviation, and Student'st test. The glycosaminoglycans extracted from colorectal tissue showed three electrophoretic bands in agarose gel. Electrospray ionization mass spectrometry showed characteristic disaccharide fragments from glycosaminoglycans, indicating their structural characterization in the tissues analyzed. Some peaks in the electrospray ionization mass spectrometry were not characterized as fragments of sugars, indicating the presence of fragments of the protein structure of proteoglycans generated during the glycosaminoglycan purification. The average amount of chondroitin and dermatan increased in the neoplastic tissue compared to normal tissue (p=0.01). On the other hand, the average amount of heparan decreased in the neoplastic tissue compared to normal tissue (p= 0.03). The method allowed the determination of the glycosaminoglycans structural profile in colorectal tissue from neoplastic and non-neoplastic colorectal tissue. Neoplastic tissues showed greater amounts of chondroitin sulphate and dermatan sulphate compared to non-neoplastic tissues, while heparan sulphate was decreased in neoplastic tissues.

Glycomics expression analysis of sulfated glycosaminoglycans of human colorectal cancer tissues and non-neoplastic mucosa by electrospray ionization mass spectrometry

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Marolla, Ana Paula Cleto [Universidade Federal de São Paulo, São Paulo, SP (Brazil); Waisberg, Jaques [Hospital do Servidor Público Estadual, São Paulo, SP (Brazil); Faculdade de Medicina do ABC, Santo André, SP (Brazil); Saba, Gabriela Tognini [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Waisberg, Daniel Reis [Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP (Brazil); Margeotto, Fernando Beani; Pinhal, Maria Aparecida da Silva [Faculdade de Medicina do ABC, Santo André, SP (Brazil)

2015-07-01

To determine the presence of glycosaminoglycans in the extracellular matrix of connective tissue from neoplastic and non-neoplastic colorectal tissues, since it has a central role in tumor development and progression. Tissue samples from neoplastic and non-neoplastic colorectal tissues were obtained from 64 operated patients who had colorectal carcinoma with no distant metastases. Expressions of heparan sulphate, chondroitin sulphate, dermatan sulphate and their fragments were analyzed by electrospray ionization mass spectrometry, with the technique for extraction and quantification of glycosaminoglycans after proteolysis and electrophoresis. The statistical analysis included mean, standard deviation, and Student’s t test. The glycosaminoglycans extracted from colorectal tissue showed three electrophoretic bands in agarose gel. Electrospray ionization mass spectrometry showed characteristic disaccharide fragments from glycosaminoglycans, indicating their structural characterization in the tissues analyzed. Some peaks in the electrospray ionization mass spectrometry were not characterized as fragments of sugars, indicating the presence of fragments of the protein structure of proteoglycans generated during the glycosaminoglycan purification. The average amount of chondroitin and dermatan increased in the neoplastic tissue compared to normal tissue (p=0.01). On the other hand, the average amount of heparan decreased in the neoplastic tissue compared to normal tissue (p= 0.03). The method allowed the determination of the glycosaminoglycans structural profile in colorectal tissue from neoplastic and non-neoplastic colorectal tissue. Neoplastic tissues showed greater amounts of chondroitin sulphate and dermatan sulphate compared to non-neoplastic tissues, while heparan sulphate was decreased in neoplastic tissues.

Glycomics expression analysis of sulfated glycosaminoglycans of human colorectal cancer tissues and non-neoplastic mucosa by electrospray ionization mass spectrometry

International Nuclear Information System (INIS)

Marolla, Ana Paula Cleto; Waisberg, Jaques; Saba, Gabriela Tognini; Waisberg, Daniel Reis; Margeotto, Fernando Beani; Pinhal, Maria Aparecida da Silva

2015-01-01

To determine the presence of glycosaminoglycans in the extracellular matrix of connective tissue from neoplastic and non-neoplastic colorectal tissues, since it has a central role in tumor development and progression. Tissue samples from neoplastic and non-neoplastic colorectal tissues were obtained from 64 operated patients who had colorectal carcinoma with no distant metastases. Expressions of heparan sulphate, chondroitin sulphate, dermatan sulphate and their fragments were analyzed by electrospray ionization mass spectrometry, with the technique for extraction and quantification of glycosaminoglycans after proteolysis and electrophoresis. The statistical analysis included mean, standard deviation, and Student’s t test. The glycosaminoglycans extracted from colorectal tissue showed three electrophoretic bands in agarose gel. Electrospray ionization mass spectrometry showed characteristic disaccharide fragments from glycosaminoglycans, indicating their structural characterization in the tissues analyzed. Some peaks in the electrospray ionization mass spectrometry were not characterized as fragments of sugars, indicating the presence of fragments of the protein structure of proteoglycans generated during the glycosaminoglycan purification. The average amount of chondroitin and dermatan increased in the neoplastic tissue compared to normal tissue (p=0.01). On the other hand, the average amount of heparan decreased in the neoplastic tissue compared to normal tissue (p= 0.03). The method allowed the determination of the glycosaminoglycans structural profile in colorectal tissue from neoplastic and non-neoplastic colorectal tissue. Neoplastic tissues showed greater amounts of chondroitin sulphate and dermatan sulphate compared to non-neoplastic tissues, while heparan sulphate was decreased in neoplastic tissues

Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

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Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

2016-10-01

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.

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Faraci, Maura; Zecca, Marco; Pillon, Marta; Rovelli, Attilio; Menconi, Maria Cristina; Ripaldi, Mimmo; Fagioli, Franca; Rabusin, Marco; Ziino, Ottavio; Lanino, Edoardo; Locatelli, Franco; Daikeler, Thomas; Prete, Arcangelo

2014-02-01

Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Hematopoietic stem cell expansion : challenges and opportunities

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Walasek, Marta A.; van Os, Ronald; de Haan, Gerald; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

2012-01-01

Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell

Body composition of Fanconi anemia patients after hematopoietic stem cell transplantation

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Priscilla Peixoto Policarpo da Silva

Full Text Available Abstract Introduction: Fanconi anemia is a rare genetic disease linked to bone marrow failure; a possible treatment is hematopoietic stem cell transplantation. Changes in the nutritional status of Fanconi anemia patients are not very well known. This study aimed to characterize body composition of adult, children and adolescent patients with Fanconi anemia who were submitted to hematopoietic stem cell transplantation or not. Methods: This cross-sectional study enrolled 63 patients (29 adults and 34 children and adolescents. Body composition was assessed based on diverse methods, including triceps skin fold, arm circumference, arm muscle area and bioelectrical impedance analysis, as there is no established consensus for this population. Body mass index was also considered as reference according to age. Results: Almost half (48.3% of the transplanted adult patients were underweight considering body mass index whereas eutrophic status was observed in 66.7% of the children and adolescents submitted to hematopoietic stem cell transplantation and in 80% of those who were not. At least 50% of all groups displayed muscle mass depletion. Half of the transplanted children and adolescents presented short/very short stature for age. Conclusion: All patients presented low muscle stores, underweight was common in adults, and short stature was common in children and adolescents. More studies are needed to detect whether muscle mass loss measured at the early stages of treatment results in higher risk of mortality, considering the importance of muscle mass as an essential body component to prevent mortality related to infectious and non-infectious diseases and the malnutrition inherent to Fanconi anemia.

Hodgkin's disease as unusual presentation of post-transplant lymphoproliferative disorder after autologous hematopoietic cell transplantation for malignant glioma

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Scelsi Mario

2005-08-01

Full Text Available Abstract Background Post-transplant lymphoproliferative disorder (PTLD is a complication of solid organ and allogeneic hematopoietic stem cell transplantation (HSCT; following autologous HSCT only rare cases of PTLD have been reported. Here, a case of Hodgkin's disease (HD, as unusual presentation of PTLD after autologous HSCT for malignant glioma is described. Case presentation 60-years old man affected by cerebral anaplastic astrocytoma underwent subtotal neurosurgical excision and subsequent high-dose chemotherapy followed by autologous HSCT. During the post HSCT course, cranial irradiation and corticosteroids were administered as completion of therapeutic program. At day +105 after HSCT, the patient developed HD, nodular sclerosis type, with polymorphic HD-like skin infiltration. Conclusion The clinical and pathological findings were consistent with the diagnosis of PTLD.

Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

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Choi, S.W.; Gatza, E.; Hou, G.; Sun, Y; Whitfield, J.; Song, Y.; Oravecz-Wilson, K.; Tawara, I.; Dinarello, C.A.; Reddy, P.

2015-01-01

We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from

Hematopoietic stem cell fate through metabolic control.

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Ito, Kyoko; Ito, Keisuke

2018-05-25

Hematopoietic stem cells (HSCs) maintain a quiescent state in the bone marrow to preserve their self-renewal capacity, but also undergo cell divisions as required. Organelles such as the mitochondria sustain cumulative damage during these cell divisions, and this damage may eventually compromise the cells' self-renewal capacity. HSC divisions result in either self-renewal or differentiation, with the balance between the two directly impacting hematopoietic homeostasis; but the heterogeneity of available HSC-enriched fractions, together with the technical challenges of observing HSC behavior, has long hindered the analysis of individual HSCs, and prevented the elucidation of this process. However, recent advances in genetic models, metabolomics analyses and single-cell approaches have revealed the contributions made to HSC self-renewal by metabolic cues, mitochondrial biogenesis, and autophagy/mitophagy, which have highlighted mitochondrial quality as a key control factor in the equilibrium of HSCs. A deeper understanding of precisely how specific modes of metabolism control HSC fate at the single cell level is therefore not only of great biological interest, but will have clear clinical implications for the development of therapies for hematological disease. Copyright © 2018. Published by Elsevier Inc.

Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience.

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Fernandes, Juliana Folloni; Kerbauy, Fabio Rodrigues; Ribeiro, Andreza Alice Feitosa; Kutner, Jose Mauro; Camargo, Luis Fernando Aranha; Stape, Adalberto; Troster, Eduardo Juan; Zamperlini-Netto, Gabriele; Azambuja, Alessandra Milani Prandini de; Carvalho, Bruna; Dorna, Mayra de Barros; Vilela, Marluce Dos Santos; Jacob, Cristina Miuki Abe; Costa-Carvalho, Beatriz Tavares; Cunha, Jose Marcos; Carneiro-Sampaio, Magda Maria; Hamerschlak, Nelson

2011-06-01

To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies. Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied. Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Patients' status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage.

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Tulpule, Asmin; Lensch, M William; Miller, Justine D; Austin, Karyn; D'Andrea, Alan; Schlaeger, Thorsten M; Shimamura, Akiko; Daley, George Q

2010-04-29

Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. The effect of FA gene deficiency on hematopoietic development in utero remains poorly described as mouse models of FA do not develop hematopoietic failure and such studies cannot be performed on patients. We have created a human-specific in vitro system to study early hematopoietic development in FA using a lentiviral RNA interference (RNAi) strategy in human embryonic stem cells (hESCs). We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hematopoietic fates and progenitor numbers that can be rescued by FA gene complementation. Our data indicate that hematopoiesis is impaired in FA from the earliest stages of development, suggesting that deficiencies in embryonic hematopoiesis may underlie the progression to bone marrow failure in FA. This work illustrates how hESCs can provide unique insights into human development and further our understanding of genetic disease.

Tritium contamination of hematopoietic stem cells alters long-term hematopoietic reconstitution

International Nuclear Information System (INIS)

Di Giacomo, F.; Barroca, V.; Laurent, D.; Lewandowski, D.; Saintigny, Y.; Romeo, P.H.; Granotier, Ch.; Boussin, F.D.

2011-01-01

Purpose: In vivo effects of tritium contamination are poorly documented. Here, we study the effects of tritiated Thymidine ([ 3 H] Thymidine) or tritiated water (HTO) contamination on the biological properties of hematopoietic stem cells (HSC). Materials and methods: Mouse HSC were contaminated with concentrations of [ 3 H] Thymidine ranging from 0.37-37.03 kBq/ml or of HTO ranging from 5-50 kBq/ml. The biological properties of contaminated HSC were studied in vitro after HTO contamination and in vitro and in vivo after [ 3 H] Thymidine contamination. Results: Proliferation, viability and double-strand breaks were dependent on [ 3 H] Thymidine or HTO concentrations used for contamination but in vitro myeloid differentiation of HSC was not affected by [ 3 H] Thymidine contamination. [ 3 H] Thymidine contaminated HSC showed a compromised long-term capacity of hematopoietic reconstitution and competition experiments showed an up to two-fold decreased capacity of contaminated HSC to reconstitute hematopoiesis. These defects were not due to impaired homing in bone marrow but to an initial decreased proliferation rate of HSC. Conclusion: These results indicate that contaminations of HSC with doses of tritium that do not result in cell death, induce short-term effects on proliferation and cell cycle and long-term effects on hematopoietic reconstitution capacity of contaminated HSC. (authors)

Fanconi anemia genes are highly expressed in primitive CD34+ hematopoietic cells

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Brodeur Isabelle

2003-06-01

Full Text Available Abstract Background Fanconi anemia (FA is a complex recessive genetic disease characterized by progressive bone marrow failure (BM and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. Methods Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. Results We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34- stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. Conclusions These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34+ cells correlates with a role at the CD34+ differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism.

Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases.

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Snowden, John A; Badoglio, Manuela; Labopin, Myriam; Giebel, Sebastian; McGrath, Eoin; Marjanovic, Zora; Burman, Joachim; Moore, John; Rovira, Montserrat; Wulffraat, Nico M; Kazmi, Majid; Greco, Raffaella; Snarski, Emilian; Kozak, Tomas; Kirgizov, Kirill; Alexander, Tobias; Bader, Peter; Saccardi, Riccardo; Farge, Dominique

2017-12-26

Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index ( P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10 -5 ), relapse/progression ( P < 10 -5 ), and nonrelapse mortality ( P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status ( P = .02). Despite improved survival over time ( P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.

Rabbit Oncology : Diseases, Diagnostics, and Therapeutics

NARCIS (Netherlands)

van Zeeland, Yvonne

Neoplasia has long been reported as a rare finding in rabbits, but over the past decades the number of reports on neoplastic disease in rabbits has risen considerably. Similar to other animals, neoplastic changes may occur in any organ system, but the rate in which the organ systems are affected

Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases.

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Bueren, Juan A; Guenechea, Guillermo; Casado, José A; Lamana, María Luisa; Segovia, José C

2003-01-01

Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous stem cells. On the other hand, severe side effects in a few patients treated with gene therapy have also been reported, indicating the usefulness of further improving the vectors currently used in gene therapy clinical trials. In the field of stem cell biology, evidence showing the plastic potential of adult hematopoietic stem cells and data indicating the multipotency of adult mesenchymal precursor cells have been presented. Also, the generation of embryonic stem cells by means of nuclear transfer techniques has appeared as a new methodology with direct implications in gene therapy.

RESULTS OF HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC LEUKEMIA

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A. Mousavi

2008-05-01

Full Text Available Hematopoietic cell transplantation (HCT is an accepted treatment for acute myeloid leukemia (AML in first remission, the treatment of choice for chronic myeloid leukemia (CML and high risk groups of ALL who relapse with conventional chemotherapy. We assessed results of HCT for pediatric leukemia in our center. A total of 92 children, 63 with diagnose of AML, 23 with ALL and 6 with CML received allogeneic transplantation from HLA full matched siblings (57.6% and autologous transplantation (42.4%. Source of hematopoietic cells were peripheral blood 83.7%, bone marrow 15.2% and cord blood 1.6%. The median transplanted nucleated cells were 6.4 ± 4.7 ×108 /Kg (body weight of patients and mononuclear cells were 5.5 ± 2.9×108/Kg. The most common conditioning regimens were cyclophosphamide + busulfan. Prophylaxis regimen for GVHD was cyclosporin ± methotrexate. GVHD occurred in 50 (54.3% patients. Eighty five of children had engraftment, 26 (28.6% relapsed and 57 (62% are alive. The most common cause of death was relapse (68.6%. Five years overall survival of patients with AML and ALL were 49% and 44% respectively and disease free survival of them were 52% and 49%. One year overall survival and disease free survival of CML was 57%. Overall survival increased with increasing age of patients at transplantation time (P = 0.06. Longer survival significantly related to earlier WBC and platelet recovery (P < 0.0001 and P = 0.006 respectively. Considering acceptable overall and disease free survival of patients after HCT, we concluded that is a good modality in treatment of leukemia of children.

Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

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Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

2017-08-01

Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 10 8 /kg and 4.3 × 10 6 /kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

International Nuclear Information System (INIS)

Diez Cabezas, B.

2015-01-01

Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

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Diez Cabezas, B.

2015-07-01

Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives

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Israel Henig

2014-10-01

Full Text Available Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

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Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

2010-01-01

BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocyto...

Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls.

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Tian, Xinghui; Kaufman, Dan S

2008-07-01

Hematopoietic development from embryonic stem cells has been one of the most productive areas of stem cell biology. Recent studies have progressed from work with mouse to human embryonic stem cells. Strategies to produce defined blood cell populations can be used to better understand normal and abnormal hematopoiesis, as well as potentially improve the generation of hematopoietic cells with therapeutic potential. Molecular profiling, phenotypic and functional analyses have all been utilized to demonstrate that hematopoietic cells derived from embryonic stem cells most closely represent a stage of hematopoiesis that occurs at embryonic/fetal developmental stages. Generation of hematopoietic stem/progenitor cells comparable to hematopoietic stem cells found in the adult sources, such as bone marrow and cord blood, still remains challenging. However, genetic manipulation of intrinsic factors during hematopoietic differentiation has proven a suitable approach to induce adult definitive hematopoiesis from embryonic stem cells. Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.

Non-neoplastic cystic and cystic-like lesions of the pancreas: may mimic pancreatic cystic neoplasms.

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Goh, Brian K P; Tan, Yu-Meng; Chung, Yaw-Fui A; Chow, Pierce K H; Ong, Hock-Soo; Lim, Dennis T H; Wong, Wai-Keong; Ooi, London L P J

2006-05-01

epithelial (congenital) cyst (n = 3), retention cyst (n = 1) and mucinous non-neoplastic cyst (n = 1). At a median follow up of 20 months (range, 3-34 months), none of the patients had any evidence of recurrent disease. Non-neoplastic cystic and cystic-like lesions of the pancreas are rare causes of pancreatic cystic lesions that are generally benign and do not require surgery when asymptomatic. However, despite advances in diagnostic investigations such as endoscopic ultrasound with fluid aspirate and magnetic resonance imaging, the preoperative diagnosis remains unreliable. Hence, the challenge for all clinicians is to recognize these lesions preoperatively and to avoid 'unnecessary' surgery.

Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

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Anja Geiselhart

2012-01-01

Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice.

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Scott G Kitchen

Full Text Available There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR. Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control.

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: review and update on the use of defibrotide.

Science.gov (United States)

Ho, Vincent T; Linden, Erica; Revta, Carolyn; Richardson, Paul G

2007-06-01

Veno-occlusive disease (VOD) of the liver remains one of the most feared complications associated with high-dose chemotherapy and hematopoietic stem cell transplantation (SCT). As a clinical syndrome characterized by fluid retention, hyperbilirubinemia, and painful hepatomegaly, VOD incidence varies widely, but it is universally recognized that severe cases of VOD have an extremely poor prognosis, with mortality at day 100 after SCT in excess of 80%. Systemic anticoagulant and thrombolytic therapies have been tested extensively in this disease, but are largely ineffective and are associated with significant bleeding complications. In recent years, defibrotide (DF; a polydisperse oligonucleotide derived from porcine intestinal mucosa with antithrombotic and protective properties on the microvasculature but minimal hemorrhagic risk) has emerged as a promising therapy for VOD. In large, multicenter, international phase I/II trials targeting patients with severe VOD, DF has been associated with complete response rates between 36 and 60%, survival past transplant day 100 in the range of 32 to 50%, and few significant attributable side effects. On the basis of these encouraging results, a pivotal, prospective, multinational, phase III trial of DF is underway in patients with severe VOD, and should provide validation of this agent as a therapy for established disease with a high risk of mortality. This article reviews our current understanding of hepatic VOD after SCT and provides a summary of the data to date on the use of DF as both therapy and prophylaxis for this disease.

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα.

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Hasan, Salma; Lacout, Catherine; Marty, Caroline; Cuingnet, Marie; Solary, Eric; Vainchenker, William; Villeval, Jean-Luc

2013-08-22

The acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2(V617F)) is the main mutation involved in BCR/ABL-negative myeloproliferative neoplasms (MPNs), but its effect on hematopoietic stem cells as a driver of disease emergence has been questioned. Therefore, we reinvestigated the role of endogenous expression of JAK2(V617F) on early steps of hematopoiesis as well as the effect of interferon-α (IFNα), which may target the JAK2(V617F) clone in humans by using knock-in mice with conditional expression of JAK2(V617F) in hematopoietic cells. These mice develop a MPN mimicking polycythemia vera with large amplification of myeloid mature and precursor cells, displaying erythroid endogenous growth and progressing to myelofibrosis. Interestingly, early hematopoietic compartments [Lin-, LSK, and SLAM (LSK/CD48-/CD150+)] increased with the age. Competitive repopulation assays demonstrated disease appearance and progressive overgrowth of myeloid, Lin-, LSK, and SLAM cells, but not lymphocytes, from a low number of engrafted JAK2(V617F) SLAM cells. Finally, IFNα treatment prevented disease development by specifically inhibiting JAK2(V617F) cells at an early stage of differentiation and eradicating disease-initiating cells. This study shows that JAK2(V617F) in mice amplifies not only late but also early hematopoietic cells, giving them a proliferative advantage through high cell cycling and low apoptosis that may sustain MPN emergence but is lost upon IFNα treatment.

Allogeneic Hematopoietic Cell Transplantation for Older Patients: Prognosis Determined by Disease Risk Index.

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He, Fiona; Cao, Qing; Lazaryan, Aleksandr; Brunstein, Claudio; Holtan, Shernan; Warlick, Erica; Ustun, Celalettin; McClune, Brian; Arora, Mukta; Rashidi, Armin; Eckfeldt, Craig; Weisdorf, Daniel J; Bejanyan, Nelli

2017-09-01

The treatment of elderly patients with advanced hematological malignancies has expanded to include reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT) as a potentially curative option. We studied the association between Disease Risk Index (DRI) and clinical outcomes of 196 elderly patients (median age, 64.8; range, 60 to 75 years) with hematological malignancies receiving RIC alloHCT (2000 to 2014). Donors were related and unrelated adults (n = 100, 51.1%) or umbilical cord blood (n = 96, 48.9%). DRI classified 12 patients (6.1%) as low risk (LR), 146 patients (74.5%) as intermediate risk (IR), and 38 patients (19.4%) as high risk (HR). Two-year overall survival (OS) was 47% (52% for LR/IR versus 29% for HR, P risk of relapse (hazard ratio, 2.07; 95% confidence interval [CI], 1.34 to 3.33; P = .02) and treatment failure (hazard ratio, 2.07; 95% CI, 1.35 to 3.18; P risk of relapse leading to poor survival in HR DRI, participation in clinical trials offering relapse prevention strategies after RIC alloHCT should be encouraged when available. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Cord Blood-Derived Hematopoietic Stem/Progenitor Cells: Current Challenges in Engraftment, Infection, and Ex Vivo Expansion

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Katsuhiro Kita

2011-01-01

Full Text Available Umbilical cord blood has served as an alternative to bone marrow for hematopoietic transplantation since the late 1980s. Numerous clinical studies have proven the efficacy of umbilical cord blood. Moreover, the possible immaturity of cells in umbilical cord blood gives more options to recipients with HLA mismatch and allows for the use of umbilical cord blood from unrelated donors. However, morbidity and mortality rates associated with hematopoietic malignancies still remain relatively high, even after cord blood transplantation. Infections and relapse are the major causes of death after cord blood transplantation in patients with hematopoietic diseases. Recently, new strategies have been introduced to improve these major problems. Establishing better protocols for simple isolation of primitive cells and ex vivo expansion will also be very important. In this short review, we discuss several recent promising findings related to the technical improvement of cord blood transplantation.

Imaging of limbic para-neoplastic encephalitis; Imagerie de l`encephalite limbique paraneoplastique

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Rimmelin, A.; Sellat, F.; Morand, G.; Quoix, E.; Clouet, P.L.; Dietemann, J.L. [Centre Hospitalier Universitaire, 67 - Strasbourg (France)

1997-09-01

Para-neoplastic limbic encephalitis is a rare syndrome mostly associated with small cell lung cancer. We present the case of a 69-year-old man with selective amnesia suggesting limbic encephalitis. A neuroendocrine cell lung cancer was found, confirming the diagnostics of para-neoplastic limbic encephalitis. Contrast-enhanced cerebral CT was normal whether magnetic resonance imaging showed signal abnormalities of the medial part of temporal lobes and hippocampal regions. Because neurologic improvement may follow treatment of the primary tumor, early diagnosis is important. (authors). 10 refs.

Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction

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Lécluse Yann

2007-07-01

Full Text Available Abstract Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC, precursors formed earlier in the yolk sac (YS display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors or early somite (hematopoietic precursors stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

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Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

Age-related cancer mutations associated with clonal hematopoietic expansion

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Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.; Wendl, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Chen, Feng; Wilson, Richard K.; Ley, Timothy J.; Ding, Li

2015-01-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion. PMID:25326804

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies.

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Ho, V T; Revta, C; Richardson, P G

2008-02-01

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), remains one of the most serious and common complications after myeloablative hematopoietic stem cell transplantation (HSCT). Clinical diagnosis of hepatic VOD is based on the clinical triad of (1) painful hepatomegaly, (2) hyperbilirubinemia and (3) unexplained fluid retention. While milder cases usually resolve spontaneously, severe VOD is associated with a grim prognosis. Defibrotide (DF), a polydisperse mixture of single-stranded oligonucleotide with antithrombotic and fibrinolytic effects on microvascular endothelium, has emerged as an effective and safe therapy for patients with severe VOD. Multiple studies, including a recent large international multicenter phase II clinical trial, have demonstrated 30-60% complete remission rates with DF, even among patients with severe VOD and multiorgan failure. This article will review our current understanding of hepatic VOD, and update the clinical trial experience with DF and other potential therapies for this feared transplant complication.

Evaluation of Calretinin expression in Ameloblastoma and Non-Neoplastic Odontogenic Cysts - An immunohistochemical study.

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D'Silva, Shaloom; Sumathi, M K; Balaji, N; Shetty, Nisha K N; Pramod, K M; Cheeramelil, Jacob

2013-12-01

Calretinin a 29-kDa calcium binding protein is expressed widely in normal human tissue and tumours including amelobastoma. The objective of this study was to determine calretinin expression in heamatoxylin and eosin diagnosed cases of ameloblastoma and non-neoplastic odontogenic cysts. The lining epithelium in 3 cases of radicular cysts, 5 cases of odontogenic keratocysts, 5 cases of dentigerous cysts and 11 cases of ameloblastomas were examined for expression of calretinin. No positive epithelial staining was observed in radicular and dentigerous cysts. In comparison, however 100% of cases of ameloblastomas and 40% of cases of odontogenic karatocysts showed positive calretinin expression. Calretinin may be a specific immunohistochemical marker for ameloblastoma. If there is any possible relation between calretinin expression and neural origin of the odontogenic epithelium and its neoplastic transformation and if calretinin could be used as an early marker to predict the tendency of neoplastic change of odontogenic epithelium could be answered through further researches. How to cite this article: D'Silva S, Sumathi MK, Balaji N, Shetty NK, Pramod KM, Cheeramelil J. Evaluation of Calretinin expression in Ameloblastoma and Non-Neoplastic Odontogenic Cysts - An immunohistochemical study. J Int Oral Health 2013; 5(6):42-8 .

Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

Science.gov (United States)

Sasazuki, Takehiko; Inoko, Hidetoshi; Morishima, Satoko; Morishima, Yasuo

2016-01-01

The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure. © 2016 Elsevier Inc. All rights reserved.

Hematopoietic (stem) cell development — how divergent are the roads taken?

NARCIS (Netherlands)

M.-L. Kauts (Mari-Liis); C.S. Vink (Chris); E.A. Dzierzak (Elaine)

2016-01-01

textabstractThe development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Hematopoietic stem cells (HSC), the most potent and self-renewing cells of this system, are produced in the final ‘definitive’ wave of hematopoietic cell

Glycaemic adverse drug reactions from anti-neoplastics used in ...

African Journals Online (AJOL)

235625 records ... Glycaemic adverse drug reactions from anti-neoplastics used in treating pancreatic cancer. ... Based on the emphasized nine antineoplastic drugs with high hyperglycemic ADR incidence, we found: fluorouracil, sorafenib and pemetrexed with high ADR record of metabolism and nutrition disorders; ...

Value of the biological data in the sonographic diagnosis of neoplastic biliary obstruction

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Ferrari, F; Fagioli Zucchi, A; Rappuoli, G; Guercia, M; Terrosi Vagnoli, P

1988-01-01

The authors' purpose is to demonstrate the possibility of improving US reliability in the diagnosis of neoplastic obstructions of the bile ducts, basing their study on the hematic alkaline phosphates level (AP), wich is an earlier sign of obstruction than bilirubine values. All 368 patients observed had AP levels above the threshold of 270 IU/l. The 34 patients with neoplastic obstruction (including 13 without jaundice) had more than twice the normal level of AP, and presented with at least one dilated bile duct in the biliary tree. Coronal scans of the main bile duct are fundamental in the diagnosis of the level of obstruction. It seems thus possible to affirm that US diagnosis of the biliary obstruction, together with high AP values (more than twice the normal), provides with reliable information as to the neoplastic nature of the biliary obstruction, even if jaundice is not present.

Value of the biological data in the sonographic diagnosis of neoplastic biliary obstruction

International Nuclear Information System (INIS)

Ferrari, F.; Fagioli Zucchi, A.; Rappuoli, G.; Guercia, M.; Terrosi Vagnoli, P.

1988-01-01

The authors' purpose is to demonstrate the possibility of improving US reliability in the diagnosis of neoplastic obstructions of the bile ducts, basing their study on the hematic alkaline phosphates level (AP), wich is an earlier sign of obstruction than bilirubine values. All 368 patients observed had AP levels above the threshold of 270 IU/l. The 34 patients with neoplastic obstruction (including 13 without jaundice) had more than twice the normal level of AP, and presented with at least one dilated bile duct in the biliary tree. Coronal scans of the main bile duct are fundamental in the diagnosis of the level of obstruction. It seems thus possible to affirm that US diagnosis of the biliary obstruction, together with high AP values (more than twice the normal), provides with reliable information as to the neoplastic nature of the biliary obstruction, even if jaundice is not present

Hematopoietic defects in response to reduced Arhgap21

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Juliana Xavier-Ferrucio

2018-01-01

Full Text Available Arhgap21 is a member of the Rho GTPase activating protein (RhoGAP family, which function as negative regulators of Rho GTPases. Arhgap21 has been implicated in adhesion and migration of cancer cells. However, the role of Arhgap21 has never been investigated in hematopoietic cells. Herein, we evaluated functional aspects of hematopoietic stem and progenitor cells (HSPC using a haploinsufficient (Arhgap21+/− mouse. Our results show that Arhgap21+/− mice have an increased frequency of phenotypic HSC, impaired ability to form progenitor colonies in vitro and decreased hematopoietic engraftment in vivo, along with a decrease in LSK cell frequency during serial bone marrow transplantation. Arhgap21+/− hematopoietic progenitor cells have impaired adhesion and enhanced mobilization of immature LSK and myeloid progenitors. Arhgap21+/− mice also exhibit reduced erythroid commitment and differentiation, which was recapitulated in human primary cells, in which knockdown of ARHGAP21 in CMP and MEP resulted in decreased erythroid commitment. Finally, we observed enhanced RhoC activity in the bone marrow cells of Arhgap21+/− mice, indicating that Arhgap21 functions in hematopoiesis may be at least partially mediated by RhoC inactivation. Keywords: Arhgap21, Hematopoiesis, Erythroid cells, Hematopoietic stem and progenitor cells, Fate decision

FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders

International Nuclear Information System (INIS)

Chiappetta, Gennaro; Pierantoni, Giovanna Maria; Fusco, Alfredo; Ferraro, Angelo; Botti, Gerardo; Monaco, Mario; Pasquinelli, Rosa; Vuttariello, Emilia; Arnaldi, Liliane; Di Bonito, Maurizio; D'Aiuto, Giuseppe

2007-01-01

Fos-related antigen 1 (FRA-1) is an immediate early gene encoding a member of AP-1 family of transcription factors involved in cell proliferation, differentiation, apoptosis, and other biological processes. fra-1 gene overexpression has an important role in the process of cellular transformation, and our previous studies suggest FRA-1 protein detection as a useful tool for the diagnosis of thyroid neoplasias. Here we investigate the expression of the FRA-1 protein in benign and malignant breast tissues by immunohistochemistry, Western blot, RT-PCR and qPCR analysis, to evaluate its possible help in the diagnosis and prognosis of breast neoplastic diseases. We investigate the expression of the FRA-1 protein in 70 breast carcinomas and 30 benign breast diseases by immunohistochemistry, Western blot, RT-PCR and qPCR analysis. FRA-1 protein was present in all of the carcinoma samples with an intense staining in the nucleus. Positive staining was also found in most of fibroadenomas, but in this case the staining was present both in the nucleus and cytoplasm, and the number of positive cells was lower than in carcinomas. Similar results were obtained from the analysis of breast hyperplasias, with no differences in FRA-1 expression level between typical and atypical breast lesions; however the FRA-1 protein localization is mainly nuclear in the atypical hyperplasias. In situ breast carcinomas showed a pattern of FRA-1 protein expression very similar to that observed in atypical hyperplasias. Conversely, no FRA-1 protein was detectable in 6 normal breast tissue samples used as controls. RT-PCR and qPCR analysis confirmed these results. Similar results were obtained analysing FRA-1 expression in fine needle aspiration biopsy (FNAB) samples. The data shown here suggest that FRA-1 expression, including its intracellular localization, may be considered a useful marker for hyperplastic and neoplastic proliferative breast disorders

Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients.

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Diez, Begoña; Genovese, Pietro; Roman-Rodriguez, Francisco J; Alvarez, Lara; Schiroli, Giulia; Ugalde, Laura; Rodriguez-Perales, Sandra; Sevilla, Julian; Diaz de Heredia, Cristina; Holmes, Michael C; Lombardo, Angelo; Naldini, Luigi; Bueren, Juan Antonio; Rio, Paula

2017-11-01

Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34 + cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34 + cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Complications of allogeneic hematopoietic stem cell transplantation.

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Arnaout, Karim; Patel, Nihar; Jain, Maneesh; El-Amm, Joelle; Amro, Farah; Tabbara, Imad A

2014-08-01

Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.

Fetal liver stromal cells promote hematopoietic cell expansion

International Nuclear Information System (INIS)

Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

2009-01-01

Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction

Science.gov (United States)

Tulpule, Asmin; Kelley, James M.; Lensch, M. William; McPherson, Jade; Park, In Hyun; Hartung, Odelya; Nakamura, Tomoka; Schlaeger, Thorsten M.; Shimamura, Akiko; Daley, George Q.

2013-01-01

Summary Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS by knock-down of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two SDS patients. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated auto-digestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease. PMID:23602541

In utero hematopoietic stem cell transfer: current status and future strategies.

Science.gov (United States)

Surbek, D V; Gratwohl, A; Holzgreve, W

1999-07-01

Successful prenatal treatment of severe immunodeficiencies by allogeneic hematopoietic stem cell transplantation in utero has been reported. Though other diseases like hemoglobinopathies or storage diseases are potentially amenable to this novel therapeutic approach, no success has yet been achieved in recipients without severe immunodeficiency. Graft rejection by the developing fetus and/or lack of selective, competitive advantage of donor versus host stem cells preventing stable engraftment seem to be the major obstacles. Several strategies to overcome these hurdles are being explored in preclinical settings, including timing and repeated dosing of stem cell administration to the fetus, ex vivo modification of the transplant, using different fetal compartments as targets for early stem cell transfer, or inducing microchimerism for postnatal transplantation from the same donor. In addition, the exact definition of the basic concept of early fetal immunologic naivete and the understanding of the molecular basics of migration and homing in fetal hematopoiesis system seem mandatory for a successful approach. Gene therapy using ex vivo transduced autologous cord blood cells or direct gene targeting in utero are other potential means to correct hematopoietic and immunologic single gene disorders in utero, though this approach is still away from the stage of clinical trials.

Stem cell therapy for inflammatory bowel disease

NARCIS (Netherlands)

Duijvestein, Marjolijn

2012-01-01

Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal

[Non-neoplastic enlargement of salivary glands: clinico-histologic analysis].

Science.gov (United States)

González Guevara, Martha Beatriz; Torres Tejero, Marco Antonio; Martínez Mata, Guillermo

2005-01-01

We carried out a retrospective study on non-neoplastic enlargement of the salivary glands at the Oral Histopathology Diagnostic Center of the Autonomous Metropolitan University at Xochimilco (UAM-Xochimilco) in Mexico during a period of 24 years (1979-2003). From 5,625 biopsies received and analyzed, a total of 461 (8.2%) were non-neoplastic enlargement of the salivary glands; for each case, we registered demographic data as well as clinic characteristics. These lesions were characterized as a heterogeneous group of pathologic entities among which we included local, obstructive, infectious, and immunopathologic lesions. The most frequent lesion was the extravasation cyst in 341 (74%) cases, followed by chronic sialoadenitis and Sjögren's syndrome with 54 (11.7%) and 41 (8.8%) cases, respectively, and at a lesser percentage mucous retention cyst, sialosis, benign lymphoepithelial lesions and those related with sialolytes. Females were affected more frequently; mean age was second to third life decades. These lesions were most frequently localized on inferior labial mucosa.

Umbilical cord blood banking in the worldwide hematopoietic stem cell transplantation system: perspectives for Ukraine.

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Kalynychenko, T O

2017-09-01

Significant progress in the promotion of procedural technologies associated with the transplantation of hematopoietic stem cells caused a rapid increase in activity. The exchange of hematopoietic stem cells for unrelated donor transplantations is now much easier due to the relevant international professional structures and organizations established to support cooperation and standard setting, as well as rules for the functioning of both national donor registries and cord blood banks. These processes are increasing every year and are contributing to the outpacing rates of development in this area. Products within their country should be regulated by the competent government authorities. This study analyzes the work of international and national levels of support for transplantation activity in the field of unrelated hematopoietic stem cell transplantation, the standardization order of technologies, as well as data that justify the need to create a network of donated umbilical cord blood banks in Ukraine as a factor in the development of allogeneic transplantation. This will promote the accessibility of international standards for the treatment of serious diseases for Ukrainian citizens.

Hematopoietic Sphingosine 1-Phosphate Lyase Deficiency Decreases Atherosclerotic Lesion Development in LDL-Receptor Deficient Mice

NARCIS (Netherlands)

Bot, Martine; Van Veldhoven, Paul P.; de Jager, Saskia C. A.; Johnson, Jason; Nijstad, Niels; Van Santbrink, Peter J.; Westra, Marijke M.; Van Der Hoeven, Gerd; Gijbels, Marion J.; Mueller-Tidow, Carsten; Varga, Georg; Tietge, Uwe J. F.; Kuiper, Johan; Van Berkel, Theo J. C.; Nofer, Jerzy-Roch; Bot, Ilze; Biessen, Erik A. L.

2013-01-01

Aims: Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets

Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice

NARCIS (Netherlands)

Bot, Martine; van Veldhoven, Paul P.; de Jager, Saskia C. A.; Johnson, Jason; Nijstad, Niels; van Santbrink, Peter J.; Westra, Marijke M.; van der Hoeven, Gerd; Gijbels, Marion J.; Müller-Tidow, Carsten; Varga, Georg; Tietge, Uwe J. F.; Kuiper, Johan; van Berkel, Theo J. C.; Nofer, Jerzy-Roch; Bot, Ilze; Biessen, Erik A. L.

2013-01-01

Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets relevant to

Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches

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Hira, Vashendriya V. V.; van Noorden, Cornelis J. F.; Carraway, Hetty E.; Maciejewski, Jaroslaw P.; Molenaar, Remco J.

2017-01-01

Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are

The Role of Toll Like Receptors in Hematopoietic Malignancies

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Darlene Monlish

2016-09-01

Full Text Available Toll-like receptors (TLRs are a family of pattern recognition receptors (PRRs that shape the innate immune system by identifying pathogen-associated molecular patterns (PAMPS and host-derived damage associated molecular patterns (DAMPS. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of pro-inflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed.

Cerebellar hemangioblastomas: A study of the immunoprofile of neoplastic stromal component

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Tasić Desanka

2004-01-01

Full Text Available Background. Central nervous system hemangioblastomas (HBs are uncommon highly vascularized tumors that are predominantly found in the cerebellum. They occur sporadically or in association with von Hippel-Lindau (VHL disease. HBs are of unknown histogenesis, and the origin of stromal cells is still a subject of debate. The aim of this study was to investigate the immunoprofile of neoplastic stromal component, and to determine whether the profile of the expression of immunomarkers used can contribute to the elucidation of the histogenesis of HBs. Methods. A series of eight cerebellar HBs were histochemically examined for the detection of mast cells and immunohistochemically for the expression of factor VIII-related antigen (FVIII-RAg, CD34, vimentin, factor XIIIa (FXIIIa, S-100 protein, glial fibrillary acidic protein (GFAP, neuron-specific enolase (NSE neurofilaments (NF, synaptophysin, chromogranin, and somatostatin. Results. Mast cells were present in all hemangioblastomas, and were particularly abundant in one tumor. Immunohistochemically, intense reactivity for vimentin and NSE in the stromal cells was constantly seen. Immunoreactivity with S-100 protein and FXIIIa was variable, but generally many HBs stromal cells were negative for these markers. However, stromal cells were uniformly negative for FVIII-RAg in all HBs investigated. They were negative for CD34 GFAP, NF, synaptophysin, chromogranin, as well as somatostatin. GFAP-positivity of the occasional stromal type cells, located only peripherally, was interpreted as "pseudopositivity". Conclusion. The immunoprofile of neoplastic stromal component in this study suggested a possible origin from undifferentiated multipotential mesenchymal cells. High expression of NSE (glycolytic and hypoxia-inducible enzyme in the HBs stromal cells might be related to the loss of the VHL protein function.

Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

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Qin, Xiao-ying; Li, Guo-xuan; Qin, Ya-zhen; Wang, Yu; Wang, Feng-rong; Liu, Dai-hong; Xu, Lan-ping; Chen, Huan; Han, Wei; Wang, Jing-zhi; Zhang, Xiao-hui; Li, Jin-lan; Li, Ling-di; Liu, Kai-yan; Huang, Xiao-jun

2011-08-01

Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

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Balan, A; Lucchini, G; Schmidt, S; Schneider, A; Tramsen, L; Kuçi, S; Meisel, R; Bader, P; Lehrnbecher, T

2014-10-01

Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.

Enteroclysis of non-neoplastic disorders of the small intestine

International Nuclear Information System (INIS)

Nolan, D.J.

2000-01-01

Enteroclysis is now widely used for examining the jejunum and ileum. The technique is ideal for demonstrating the extent and severity of disorders that cause morphological changes to the small intestine. In this review many non-neoplastic small intestinal disorders as demonstrated by enteroclysis are described and illustrated. (orig.)

Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure

NARCIS (Netherlands)

Langereis, Eveline J.; Borgo, Andrea; Crushell, Ellen; Harmatz, Paul R.; van Hasselt, Peter M.; Jones, Simon A.; Kelly, Paula M.; Lampe, Christina; van der Lee, Johanna H.; Odent, Thierry; Sakkers, Ralph; Scarpa, Maurizio; Schafroth, Matthias U.; Struijs, Peter A.; Valayannopoulos, Vassili; White, Klane K.; Wijburg, Frits A.

2013-01-01

Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including

Hematopoiesis and hematopoietic organs in arthropods.

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Grigorian, Melina; Hartenstein, Volker

2013-03-01

Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

An In Vitro Study of Differentiation of Hematopoietic Cells to Endothelial Cells

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Qi Ru Wang

2011-01-01

medium (ECCM. BM-EPCs were characterized in terms of phenotype, lineage potential, and their functional properties. Endothelial cell colonies derived from BM-EPC were cultured with ECCM for 3 months. Cultured EPC colony cells expressed endothelial cell markers and formed the capillary-like network in vitro. EPC colony cells expressed differential proliferative capacity; some of the colonies exhibited a high proliferative potential (HPP capacity up to 20 population doublings. More importantly, these HPP-EPCs expressed hematopoietic marker CD45, exhibited endocytic activities, and preserved some of the myeloid cell activity. In addition, the HPP-EPCs secrete various growth factors including VEGF and GM-CSF into the culture medium. The results demonstrate that these EPCs were primarily derived from hematopoietic origin of early precursor cells and maintained high proliferative potential capacity, a feature with a significant potential in the application of cell therapy in ischemic diseases.

Mobilization of hematopoietic stem and progenitor cells in mice

NARCIS (Netherlands)

Robinson, Simon N; van Os, Ronald P; Bunting, Kevin

2008-01-01

Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components)

Early-enhancing non-neoplastic lesions on gadolinium-enhanced MRI of the liver

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Kanematsu, M. E-mail: masa-gif@umin.ac.jp; Kondo, H.; Semelka, R.C.; Matsuo, M.; Goshima, S.; Hoshi, H.; Moriyama, N.; Itai, Y

2003-10-01

AIM: To assess the frequency, cause, and significance of early-enhancing, non-neoplastic (EN) lesions on gadolinium-enhanced magnetic resonance imaging (MRI) of the liver performed for the detection of malignant hepatic tumours. MATERIALS AND METHODS: From September 1997 to September 2000, we reviewed the images of 125 patients, suspected of having hepatic tumours, in whom (1) gadolinium-enhanced triphasic dynamic gradient-recalled-echo (GRE) imaging in addition to unenhanced T1- and T2-weighted MRI was performed, (2) conventional angiography and combination computed tomography (CT) hepatic arteriography and CT during arterial portography were performed within 2 weeks of the MRI, and (3) definitive surgery within 2 weeks of the MRI or follow-up study by means of intravenously contrast-enhanced CT or MRI in 10 months or more was performed. Angiographic studies were correlated to determine the underlying causes of the EN lesions. RESULTS: We found 78 EN lesions in 36 patients (29%), ranging in size from 4 and 50 mm (mean, 12.2 mm). From the MR reports, our radiologists had prospectively diagnosed EN lesions as probable malignant tumours in eight (10%), possible malignant tumours in 36 (46%), and probable non-neoplastic lesion in 34 (44%). EN lesions were found in 27 of 81 (33%) cirrhotic patients and in nine of 44 (20%) non-cirrhotic patients. Fifty-one EN lesions (65%) were located along the liver edge. The shape was circular in 42 (54%), oval in 14 (18%), irregular in 12 (15%), wedge-shaped in seven (9%), and fan-shaped in three (4%). Twenty EN lesions (26%) appeared slightly hyperintense on T2-weighted images. The causes were non-neoplastic arterio-portal shunting in 48 (62%), cystic venous drainage in four (5%), rib compression in four (5%), aberrant right gastric venous drainage in two (3%), and unknown in 20 (26%). CONCLUSION: Over half the number of EN lesions were caused by non-neoplastic arterio-portal shunting, occasionally showing slight hyperintensity on

ES-cell derived hematopoietic cells induce transplantation tolerance.

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Sabrina Bonde

Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.

Hematopoietic Sphingosine 1-Phosphate Lyase Deficiency Decreases Atherosclerotic Lesion Development in LDL-Receptor Deficient Mice

NARCIS (Netherlands)

Bot, M.; Veldhoven, van P.P.; Jager, de S.C.; Johnson, J.; Nijstad, N.; van, Santbrink P.J.; Westra, M.M.; Hoeven, van der G.; Gijbels, M.J.; Muller-Tidow, C.; Varga, G.; Tietge, U.J.; Kuiper, J.; Berkel, van T.J.; Nofer, J.R.; Bot, I.; Biessen, E.A.

2013-01-01

Abstract Aims Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1−/−) deficiency on leukocyte

DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome.

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Pai, Rish K; Dudley, Beth; Karloski, Eve; Brand, Randall E; O'Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D; Jenkins, Mark A; Thibodeau, Stephen N; French, Amy J; Lindor, Noralane M; Pai, Reetesh K

2018-06-08

Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406).

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Peter, Barbara; Hadzijusufovic, Emir; Blatt, Katharina; Gleixner, Karoline V; Pickl, Winfried F; Thaiwong, Tuddow; Yuzbasiyan-Gurkan, Vilma; Willmann, Michael; Valent, Peter

2010-09-01

Advanced systemic mastocytosis (SM) is characterized by uncontrolled growth of neoplastic mast cells (MC) and drug resistance. The tyrosine kinase receptor KIT is often mutated and activated and thus contributes to malignant growth of MC. Therefore, KIT-targeting drugs are currently tested for their ability to block growth of malignant MC. We determined the effects of the multikinase inhibitor INNO-406 (bafetinib) on primary neoplastic MC, the canine mastocytoma cell line C2, the human MC leukemia cell line HMC-1.1 bearing the KIT mutant V560G, and HMC-1.2 cells harboring KIT V560G and KIT D816V. INNO-406 was found to inhibit proliferation in HMC-1.1 cells (IC(50): 30-40 nM), but not in HMC-1.2 cells or primary neoplastic cells in patients with KIT D816V-positive SM. In canines, growth-inhibitory effects of INNO-406 were seen in C2 cells (IC(50): 50-100 nM) exhibiting a KIT exon 11 internal tandem-duplication and in primary neoplastic MC harboring wild-type exon 11, whereas no effects were seen in MC exhibiting a polymorphism at amino acid 581 in exon 11. INNO-406 was found to block KIT phosphorylation and expression in HMC-1.1 cells and C2 cells, but not in HMC-1.2 cells, whereas Lyn-phosphorylation was blocked by INNO-406 in all types of MC. In neoplastic MC, the major target of INNO-406 appears to be KIT. Drug responses may depend on the presence and type of KIT mutation. In human MC, the KIT D816V mutant introduces resistance, and in canine mastocytomas, an exon 11 polymorphism may be indicative of resistance against INNO-406.

Direct observation of hematopoietic progenitor chimerism in fetal freemartin cattle

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Taponen Juhani

2007-11-01

Full Text Available Abstract Background Cattle twins are well known as blood chimeras. However, chimerism in the actual hematopoietic progenitor compartment has not been directly investigated. Here, we analyzed fetal liver of chimeric freemartin cattle by combining a new anti-bovine CD34 antibody and Y-chromosome specific in situ hybridization. Results Bull-derived CD34+ cells were detected in the liver of the female sibling (freemartin at 60 days gestation. The level of bull-derived CD34+ cells was lower in the freemartin than in its male siblings. Bull (Y+ and cow hematopoietic cells often occurred in separate clusters. Around clusters of Y+CD34+ cells, Y+CD34- cells were typically observed. The thymi were also strongly chimeric at 60 days of gestation. Conclusion The fetal freemartin liver contains clusters of bull-derived hematopoietic progenitors, suggesting clonal expansion and differentiation. Even the roots of the hematopoietic system in cattle twins are thus strongly chimeric from the early stages of fetal development. However, the hematopoietic seeding of fetal liver apparently started already before the onset of functional vascular anastomosis.

Joint approach based on clinical and imaging features to distinguish non-neoplastic from neoplastic pituitary stalk lesions.

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Ji Ye Lee

Full Text Available Distinguishing non-neoplastic pituitary stalk lesions (non-NPSLs from neoplastic pituitary stalk lesions (NPSLs is a major concern in guiding treatment for a thickened pituitary stalk. Our study aimed to aid provide preoperative diagnostic assistance by combining clinical and magnetic resonance imaging (MRI findings to distinguish non-NPSLs from NPSLs.We recruited 158 patients with thickened pituitary stalk lesions visible on MRI. Laboratory findings included hypopituitarism, diabetes insipidus (DI, and hyperprolactinemia. MR images were assessed for anterior-posterior thickness (mm, diffuse pituitary stalk thickening, cystic changes, a high T1 signal, and glandular or extrasellar involvement. A diagnostic model was developed using a recursive partitioning logistic regression analysis. The model was validated in an independent dataset comprising 63 patients, and its diagnostic performance was compared with that of the original radiological reports.A univariate analysis found significant associations of DI (P = 0.006, absence of extrasellar involvement (P = 0.002, and lower stalk thickness (P = 0.031 with non-NPSLs. A diagnostic model was created using the following parameters (in order of priority: 1 lack of extrasellar involvement, 2 stalk thickness < 5.3 mm, and 3 presence of DI. The diagnostic performance (area under the curve; AUC of this model in the independent set was 0.813, representing a significant improvement over the original radiological reports (AUC: 0.713, P = 0.029.The joint diagnostic approach based on clinical and imaging-based factors robustly distinguished non-NPSLs from NPSLs. This approach could guide treatment strategies and prevent unnecessary surgery in patients with non-NPSL.

Prevalence of human papillomavirus types in women with pre-neoplastic and neoplastic cervical lesions in the Federal District of Brazil

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Geni NL Camara

2003-10-01

Full Text Available As a contribution to the public health authorities in planning prophylactic and therapeutic vaccine strategies, we describe the prevalence of human papillomavirus (HPV types in women presenting abnormal cytological results in Pap smear screening tests in the Federal District, Central Brazil. We studied 129 cervical scraping samples from women whose cytological tests showed either pre-neoplastic or neoplastic lesions. Amplification of HPV DNA was performed by polymerase chain reaction using consensus primers MY09 and MY11 followed by identification of isolates by restriction fragment length polymorphism. We detected HPV DNA in 62% of the samples, including HPV-16 in 43.8%, HPV-58 in 12.5%, HPV-31 in 10%, HPV-53 in 6.3%, each of HPV-18 and HPV-33 in 3.8% of the isolates. Other types (HPV-35, -52, -66, -CP8304, -6, -11, and -CP8061 were less frequent (= or < 2.5% each. The prevalence of HPV-58 was relatively higher in this population than in data in South America, but similar to results obtained in other studies in Latin America, Europe, and Eastern Asia. Case-control studies need to be carried out to establish the association between the prevalence of HPV types specially the less frequent high-risk types and cervical cancer.

Early neuroimaging findings of glioblastoma mimicking non-neoplastic cerebral lesion.

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Jung, Tae-Young; Jung, Shin

2007-09-01

A 54-year-old man and a 63-year-old woman presented with glioblastoma manifesting as seizure and headache, respectively. Magnetic resonance imaging of the two patients revealed hypointense area on T(1)-weighted imaging, and hyperintense area on T(2)-weighted and diffusion-weighted imaging, with no enhancement after gadolinium administration. Both patients underwent conservative therapy under diagnoses of non-neoplastic cerebral lesion. Six months later, they suffered aggravated symptoms and new neurological deficits. Follow-up magnetic resonance imaging revealed hypointense area on diffusion-weighted imaging and ring enhancement on T(1)-weighted imaging with gadolinium at the site of the previously detected lesions. The tumors showed growth pattern of superficial origin. The large enhanced masses were totally removed through craniotomy under neuronavigator guidance. The histological diagnoses were glioblastoma. Glioblastoma may mimic non-neoplastic conditions on neuroimaging in the early stages. Close follow up of such patients is essential.

The difficulties of pseudo-Cushing's syndrome (or "non-neoplastic hypercortisolism").

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Chabre, Olivier

2018-06-01

Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH-secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end-stage kidney disease. Glucocorticoid resistance is one differential diagnosis, as are some cases of primary adrenal disease with incompletely suppressed ACTH. Differentiating between NNH and mild-to-moderate Cushing's disease can be a real challenge. Clinical analysis, based on thorough history taking and screening for catabolic signs is essential; useful explorations include midnight serum or salivary cortisol and Dex/CRH and ddAVP stimulation response. Pituitary MRI suffers from limitations regarding both sensitivity and specificity, while bilateral inferior petrosal sinus sampling cannot distinguish between pituitary ACTH secretion by a tumor or by normal cells stimulated by endogenous CRH. Definitive diagnosis of functional etiology requires demonstrating that treatment of the underlying condition restores normal secretion of ACTH and cortisol, but this is not always possible. Lingering diagnostic uncertainty has to be accepted in certain patients, who will have to be followed up for some time before diagnosis can be considered more or less definitive. Copyright © 2018. Published by Elsevier Masson SAS.

Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

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Danilo Santana Alessio Franceschi

2011-01-01

Full Text Available Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein.

DNA measurements on cell nuclei of normal, proliferating and neoplastic thyroid tissues in rats

International Nuclear Information System (INIS)

Christov, K.; Thomas, C.; Sandritter, W.

1975-01-01

Nuclear DNA content was measured in 3 normal, 9 hyperplastic and 16 neoplastic rat thyroid glands. Thyroid hyperplasia and tumor growth were induced after treatment of the animals with X rays and methylthiouracil. In the control animals only diploid thyroid epithelial cells were observed. In stages of diffuse and nodular thyroid hyperplasia, the total DNA content per nucleus indicated that most chromosomes were diploid; only a few cells were hyperdiploid. In thyroid adenomas and carcinomas scattering of the diploid region and an increased number of hyperdiploid cells were found. Among the various types of thyroid tumors neither a difference in the number of hyperdiploid cells, nor the typical pattern of the distribution of these cells in a histogram was found. The increased number of hyperdiploid cells in hyperplastic and neoplastic thyroids only suggested an increase in the proportion of cells entering the cell cycle and not an appearance of a neoplastic strain. (author)

DNA measurements on cell nuclei of normal, proliferating and neoplastic thyroid tissues in rats

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Christov, K [National Center of Oncology, Academy of Medicine, Sofia-56 (Bulgaria); Thomas, C; Sandritter, W [Freiburg Univ. (F.R. Germany). Pathologisches Inst.

1975-01-01

Nuclear DNA content was measured in 3 normal, 9 hyperplastic and 16 neoplastic rat thyroid glands. Thyroid hyperplasia and tumor growth were induced after treatment of the animals with X rays and methylthiouracil. In the control animals only diploid thyroid epithelial cells were observed. In stages of diffuse and nodular thyroid hyperplasia, the total DNA content per nucleus indicated that most chromosomes were diploid; only a few cells were hyperdiploid. In thyroid adenomas and carcinomas scattering of the diploid region and an increased number of hyperdiploid cells were found. Among the various types of thyroid tumors neither a difference in the number of hyperdiploid cells, nor the typical pattern of the distribution of these cells in a histogram was found. The increased number of hyperdiploid cells in hyperplastic and neoplastic thyroids only suggested an increase in the proportion of cells entering the cell cycle and not an appearance of a neoplastic strain.

Instruction of hematopoietic lineage choice by cytokine signaling

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Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

2014-12-10

Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

CRISPR/Cas9 system and its applications in human hematopoietic cells.

Science.gov (United States)

Hu, Xiaotang

2016-11-01

Since 2012, the CRISPR-Cas9 system has been quickly and successfully tested in a broad range of organisms and cells including hematopoietic cells. The application of CRISPR-Cas9 in human hematopoietic cells mainly involves the genes responsible for HIV infection, β-thalassemia and sickle cell disease (SCD). The successful disruption of CCR5 and CXCR4 genes in T cells by CRISPR-Cas9 promotes the prospect of the technology in the functional cure of HIV. More recently, eliminating CCR5 and CXCR4 in induced pluripotent stem cells (iPSCs) derived from patients and targeting the HIV genome have been successfully carried out in several laboratories. The outcome from these approaches bring us closer to the goal of eradicating HIV infection. For hemoglobinopathies the ability to produce iPSC-derived from patients with the correction of hemoglobin (HBB) mutations by CRISPR-Cas9 has been tested in a number of laboratories. These corrected iPSCs also show the potential to differentiate into mature erythrocytes expressing high-level and normal HBB. In light of the initial success of CRESPR-Cas9 in target mutated gene(s) in the iPSCs, a combination of genomic editing and autogenetic stem cell transplantation would be the best strategy for root treatment of the diseases, which could replace traditional allogeneic stem cell transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Duodenum-preserving total pancreatic head resection for benign cystic neoplastic lesions.

Science.gov (United States)

Beger, Hans G; Schwarz, Michael; Poch, Bertram

2012-11-01

Cystic neoplasms of the pancreas are diagnosed frequently due to early use of abdominal imaging techniques. Intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and serous pseudopapillary neoplasia are considered pre-cancerous lesions because of frequent transformation to cancer. Complete surgical resection of the benign lesion is a pancreatic cancer preventive treatment. The application for a limited surgical resection for the benign lesions is increasingly used to reduce the surgical trauma with a short- and long-term benefit compared to major surgical procedures. Duodenum-preserving total pancreatic head resection introduced for inflammatory tumors in the pancreatic head transfers to the patient with a benign cystic lesion located in the pancreatic head, the advantages of a minimalized surgical treatment. Based on the experience of 17 patients treated for cystic neoplastic lesions with duodenum-preserving total pancreatic head resection, the surgical technique of total pancreatic head resection for adenoma, borderline tumors, and carcinoma in situ of cystic neoplasm is presented. A segmental resection of the peripapillary duodenum is recommended in case of suspected tissue ischemia of the peripapillary duodenum. In 305 patients, collected from the literature by PubMed search, in about 40% of the patients a segmental resection of the duodenum and 60% a duodenum and common bile duct-preserving total pancreatic head resection has been performed. Hospital mortality of the 17 patients was 0%. In 305 patients collected, the hospital mortality was 0.65%, 13.2% experienced a delay of gastric emptying and a pancreatic fistula in 18.2%. Recurrence of the disease was 1.5%. Thirty-two of 175 patients had carcinoma in situ. Duodenum-preserving total pancreatic head resection for benign cystic neoplastic lesions is a safe surgical procedure with low post-operative morbidity and mortality.

Diseases of the retroperitoneal space in the dog and cat

International Nuclear Information System (INIS)

Roush, J.K.; Bjorling, D.E.; Lord, P.

1990-01-01

The retroperitoneal space (RPS) is an anatomical area bounded dorsally by the sublumbar musculature and ventrally by the peritoneal surface of the abdomen. The RPS communicates with the pelvic space and mediastinum and is subject to primary diseases of the RPS connective tissue and to extension of disease from organs lying within or adjacent to it. Primary diseases include retroperitonitis, pneumoretroperitoneum, non-neoplastic retroperitoneal space-occupying lesions, and primary neoplasms of the RPS. Primary diseases of kidneys, ureters, adrenal glands or retroperitoneal lymph nodes may extend into the RPS, and the RPS may be the site of metastatic neoplastic disease. Clinical signs suggestive of retroperitoneal disease include lumbar pain, pyrexia, lethargy, and signs referable to organs within the RPS

Non-neoplastic conditions presenting as soft-tissue tumours

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Crundwell, N.; O'Donnell, P.; Saifuddin, A.

2007-01-01

Review of referrals to our unit over the last 7 years showed that of approximately 750 cases referred as soft-tissue tumours, 132 were subsequently diagnosed as non-neoplastic lesions. The imaging characteristics of these lesions are presented to differentiate them from neoplasms. The most common diagnoses were myositis ossificans, ganglion cyst, abscess/infection, bursitis and synovitis. The imaging features of other rarer conditions will also be discussed

Non-neoplastic conditions presenting as soft-tissue tumours

Energy Technology Data Exchange (ETDEWEB)

Crundwell, N. [Royal National Orthopaedic Hospital, Stanmore, Middlesex (United Kingdom); O' Donnell, P. [Royal National Orthopaedic Hospital, Stanmore, Middlesex (United Kingdom); Saifuddin, A. [Royal National Orthopaedic Hospital, Stanmore, Middlesex (United Kingdom)]. E-mail: asif.saifuddin@rnoh.nhs.uk

2007-01-15

Review of referrals to our unit over the last 7 years showed that of approximately 750 cases referred as soft-tissue tumours, 132 were subsequently diagnosed as non-neoplastic lesions. The imaging characteristics of these lesions are presented to differentiate them from neoplasms. The most common diagnoses were myositis ossificans, ganglion cyst, abscess/infection, bursitis and synovitis. The imaging features of other rarer conditions will also be discussed.

The influence of theosophy on Mondrian's neoplastic work

OpenAIRE

Bris Marino, Pablo

2014-01-01

(ENG)The influence of Theosophy in the symbolist painting of Mondrian (1908-1911) has been unanimously recognized. There is not, however, the same consensus with respect to the influence of theosophy in his neoplastic period. There is a relationship between Mondrian’s theoretical writing and his practical work, but no proportionality. Mondrian’s theoretical discourse is not limited to painting and touches on other arts and disciplines (architecture,...

Case of a rare type of non-neoplastic mucinous pancreatic cyst – likely new pathological entity?

International Nuclear Information System (INIS)

Hilendarov, A.; Nedeva, M.; Belovejdov, V.; Aleksieva, D.; Sirakov, N.

2013-01-01

Full text:Introduction: The cystic lesions of the pancreas consists of a range of pathologies which may be broadly divided into neoplastic, non- neoplastic and cysts. Recently a new non-neoplastic cystic lesions, called mucinous non-neoplastic cysts, have been described. Materials and Methods: The imaging methods (ultrasound and CT ) were used as well as invasive imaging methods under image control with a view of the histological verification of the diagnosis. A case of pancreatic cystic lesion is described, accidentally detected by ultrasound and CT scan made for different purpose. Results : The finding was a 28/32 mm cyst in the body of the pancreas, apparently communicating with the pancreatic duct . The Endoscopic Retrograde Cholangiopancreatography and laboratory tests of liver function, serum CEA and carbohydrate antigen C19 -9 were within normal limits. After the distal pancreatectomy and splenectomy the lasting histological specimen showed a simple cyst, lined with mucinous epithelium. Conclusion: The presented case guides the imaging diagnosticians and surgeons towards seeking a thorough preoperative clarification of pancreatic cystic lesions. It is recommended that patients diagnosed with 'benign' mucinous neoplasm are closely monitored due to the inability to completely confirm the benign nature of the lesion

Prostaglandin E2 regulates hematopoietic stem cell

International Nuclear Information System (INIS)

Wang Yingying; Zhou Daohong; Meng Aimin

2013-01-01

Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

Immunity and tolerance to fungi in hematopoietic transplantation: Principles and perspectives

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Agostinho eCarvalho

2012-06-01

Full Text Available Resistance and tolerance are two complementary host defence mechanism that increase fitness in response to low-virulence fungi. Resistance is meant to reduce pathogen burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigate the substantial cost of resistance to host fitness through a multitude of anti-inflammatory mechanisms, including immunological tolerance. In experimental fungal infections, both defense mechanisms are activated through the delicate equilibrium between Th1/Th17 cells, which provide antifungal resistance, and regulatory T cells limiting the consequences of the ensuing inflammatory pathology.Indoleamine 2,3-dioxygenase (IDO, a rate-limiting enzyme in the tryptophan catabolism, plays a key role in induction of tolerance against fungi. Both hematopoietic and nonhematopoietic compartments contribute to the resistance/tolerance balance against Aspergillus fumigatus via the involvement of selected innate receptors converging on IDO. Several genetic polymorphisms in pattern recognition receptors influence resistance and tolerance to fungal infections in human hematopoietic transplantation. Thus, tolerance mechanisms may be exploited for novel diagnostics and therapeutics against fungal infections and diseases.

Hematopoietic Stem Cell Transplant in Adolescent and Young Adults With Fanconi Anemia Is Feasible With Acceptable Toxicity, With Those Surviving 100 Days Posttransplant Having Excellent Outcomes.

Science.gov (United States)

Alhuraiji, Ahmad; Alzahrani, Hazza; Al Mohareb, Fahad; Chaudhri, Naeem; Alsharif, Fahad; Mohamed, Said; Rasheed, Walid; Aldawsari, Ghuzayel; Ahmed, Syed Osman; Aljurf, Mahmoud

2016-12-01

Fanconi anemia is a congenital bone marrow failure syndrome that is associated with congenital anomalies and increased risk of cancer. Hematopoietic stem cell transplant is a potentially curative modality for bone marrow failure in Fanconi anemia patients. Here, we report our center's experience regarding adolescent and young adult patients with Fanconi anemia and hematopoietic stem cell transplant. We conducted a retrospective patient record analyses of patients who presented at our center from 1988 to 2014. We included patients greater than 14 years old with confirmed Fanconi anemia based on positive chromosome breakage study and who underwent hematopoietic stem cell transplant at our institution. Our study group comprised 12 patients with Fanconi anemia who underwent hematopoietic stem cell transplant at our institution. The median age was 20 years (range, 14-31 y) with a female predominance of 83%. Low-dose cyclophosphamide (20-80 mg/kg)-based conditioning regimens were used with different combinations that included fludarabine, antithymocyte globulin, or total body irradiation. All patients had HLA-matched sibling grafts. In all patients, stem cell source was the bone marrow. All patients showed engraftment. Four patients (33%) developed acute graft-versus-host disease. Three patients (25%) died early before day 100 after hematopoietic stem cell transplant due to infectious complications, with 1 patient having steroid refractory acute graft-versus-host disease. Overall survival was 75% at a median follow-up of 43 months. All patients who survived are well and remained transfusion independent without evidence of secondary malignancy. Our findings support the feasibility of reduced intensity conditioning allogeneic hematopoietic stem cell transplant in older and more heavily pretreated patients with Fanconi anemia, especially for those who are engrafted.

The Relationship between Brown Adipose Tissue Activity and Neoplastic Status: an 18F-FDG PET/CT Study in the Tropics

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Huang Yung-Cheng

2011-12-01

Full Text Available Abstract Background Brown adipose tissue (BAT has thermogenic potential. For its activation, cold exposure is considered a critical factor though other determinants have also been reported. The purpose of this study was to assess the relationship between neoplastic status and BAT activity by 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG positron emission tomography/computed tomography (PET/CT in people living in the tropics, where the influence of outdoor temperature was low. Methods 18F-FDG PET/CT scans were reviewed and the total metabolic activity (TMA of identified activated BAT quantified. The distribution and TMA of activated BAT were compared between patients with and without a cancer history. The neoplastic status of patients was scored according to their cancer history and 18F-FDG PET/CT findings. We evaluated the relationships between the TMA of BAT and neoplastic status along with other factors: age, body mass index, fasting blood sugar, gender, and outdoor temperature. Results Thirty of 1740 patients had activated BAT. Those with a cancer history had wider BAT distribution (p = 0.043 and a higher TMA (p = 0.028 than those without. A higher neoplastic status score was associated with a higher average TMA. Multivariate analyses showed that neoplastic status was the only factor significantly associated with the TMA of activated BAT (p = 0.016. Conclusions Neoplastic status is a critical determinant of BAT activity in patients living in the tropics. More active neoplastic status was associated with more vigorous TMA of BAT.

Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience

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Daniela Hespanha Marinho

2015-08-01

Full Text Available OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8% who received bone marrow and 134 (53.2% who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001. Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653. Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007. Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117. Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666.CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

Late effects of selected immunosuppressants on immunocompetence, disease incidence, and mean life-span. III. Disease incidence and life expectancy. [Mice, x radiation

Energy Technology Data Exchange (ETDEWEB)

Peter, C P; Perkins, E H; Peterson, W J; Walburg, H E; Makinodan, T

1975-01-01

The effect of various immunosuppressive treatments on mean life-span and disease incidence have been studied. Significant life shortening was seen only in mice which received X-irradiation early in life and can be ascribed primarily to an increased incidence of certain malignancies. Marginal life shortening was seen in cyclophosphamide-treated animals, however, survival patterns between those and control animals did not differ until 30 months of age and the magnitude of life-shortening never approached that seen in X-irradiated animals. Thymectomy, splenectomy or cortisone treatment did not alter survival. All immunosuppressive treatments enhanced mortality due to non-neoplastic diseases, however, only a small percentage of animals die with these disease entities. With the exception of cortisone all immunosuppressive treatments increased the incidence of neoplastic disease. However, their effects on various neoplastic processes were variable and unpredictable. Four primary patterns in terms of relative immune competence, disease incidence and life expectancy were seen. Thus, immunodepression may or may not correlate with increased disease incidence, which in turn may or may not have a life-shortening effect. These findings are discussed in terms of the marked reduction of both humoral and cell-mediated immunity normally seen in aged mice and the significance of postulated immune surveillance mechanisms to survival.

Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using 111In-DTPA ventriculography

International Nuclear Information System (INIS)

Grossman, S.A.; Trump, D.L.; Chen, D.C.; Thompson, G.; Camargo, E.E.

1982-01-01

Cerebrospinal fluid flow dynamics were evaluated by 111 In-diethylenetriamine pentaacetic acid ( 111 In-DTPA) ventriculography in 27 patients with neoplastic meningitis. Nineteen patients (70 percent) had evidence of cerebrospinal fluid flow disturbances. These occurred as ventricular outlet obstructions, abnormalities of flow in the spinal canal, or flow distrubances over the cortical convexities. Tumor histology, physical examination, cerebrospinal fluid analysis, myelograms, and computerized axial tomographic scans were not sufficient to predict cerebrospinal fluid flow patterns. These data indicate that cerebrospinal fluid flow abnormalities are common in patients with neoplastic meningitis and that 111 In-DTPA cerebrospinal fluid flow imaging is useful in characterizing these abnormalities. This technique provides insight into the distribution of intraventricularly administered chemotherapy and may provide explanations for treatment failure and drug-induced neurotoxicity in patients with neoplastic meningitis

INTESTINAL MICROBIOTA IN DIGESTIVE DISEASES

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Maria do Carmo Friche PASSOS

2017-07-01

Full Text Available ABSTRACT BACKGROUND In recent years, especially after the development of sophisticated metagenomic studies, research on the intestinal microbiota has increased, radically transforming our knowledge about the microbiome and its association with health maintenance and disease development in humans. Increasing evidence has shown that a permanent alteration in microbiota composition or function (dysbiosis can alter immune responses, metabolism, intestinal permeability, and digestive motility, thereby promoting a proinflammatory state. Such alterations can mainly impair the host’s immune and metabolic functions, thus favoring the onset of diseases such as diabetes, obesity, digestive, neurological, autoimmune, and neoplastic diseases. This comprehensive review is a compilation of the available literature on the formation of the complex intestinal ecosystem and its impact on the incidence of diseases such as obesity, non-alcoholic steatohepatitis, irritable bowel syndrome, inflammatory bowel disease, celiac disease, and digestive neoplasms. CONCLUSION: Alterations in the composition and function of the gastrointestinal microbiota (dysbiosis have a direct impact on human health and seem to have an important role in the pathogenesis of several gastrointestinal diseases, whether inflammatory, metabolic, or neoplastic ones.

Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

Science.gov (United States)

Gori, Jennifer L.; Butler, Jason M.; Chan, Yan-Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans-Peter

2015-01-01

Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC–derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina–induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain–null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood–derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence. PMID:25664855

Degree of Predicted Minor Histocompatibility Antigen Mismatch Correlates with Poorer Clinical Outcomes of Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

DEFF Research Database (Denmark)

Larsen, Malene Erup; Kornblit, B; Larsen, Mette Voldby

2010-01-01

In fully HLA-matched allogeneic hematopoietic cell transplantations (HCT), the main mechanism of the beneficial graft-versus-tumor (GVT) effect and of the detrimental graft-versus-host disease (GVHD) is believed to be caused by donor cytotoxic T cells directed against disparate recipient minor hi...

Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.

Science.gov (United States)

Gladstone, Douglas E; Fuchs, Ephraim

2012-03-01

Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity.

The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation

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Ke Zhao

2016-05-01

Full Text Available Abstract Mesenchymal stromal cells (MSCs are multipotent stem cells well known for repairing tissue, supporting hematopoiesis, and modulating immune and inflammation response. These outstanding properties make MSCs as an attractive candidate for cellular therapy in immune-based disorders, especially hematopoietic stem cell transplantation (HSCT. In this review, we outline the progress of MSCs in preventing and treating engraftment failure (EF, graft-versus-host disease (GVHD following HSCT and critically discuss unsolved issues in clinical applications.

Hematopoietic diseases

International Nuclear Information System (INIS)

Dohi, Hiroo

1992-01-01

A-bombing panicked many people with anxiety because they suffered from various symptoms after A-bombing (ie, they generally called them A-bomb disease). In this chapter, major two conditions (ie, leukopenia and anemia), which caused their symptoms, are reviewed based on the early data soon after A-bombing. According to the chronological changes in both white blood cell (WBC) and red blood cell (RBC) counts, both leukopenia and anemia are discussed. The findings can be divided into acute (one week or at least 10 days), subacute (2 weeks to one month), and delayed (thereafter) periods. During an acute period, some exposed even at ≤200 m from the hypocenter showed WBC count of 6,000/mm 3 or more one week after exposure but others exposed at 1,500-2,000 m showed WBC count of less than 3,000/mm 3 , suggesting the influence of shielding on WBC count. WBC count sometimes became the lowest during a subacute period, although it was normal during an acute period. A survey for WBC count during a delayed period (one year later) showed that WBC count of less than 4,000/mm 3 was more frequent in the exposed group (78/523 A-bomb survivors, 14.9%) than the non-exposed group (6/173 persons, 3.5%). In the exposed group, leukopenia was independent of distance and symptoms at the time of exposure. For anemia, there was no data available during an acute period. Anemia frequently occurred during a subacute period. Morphological abnormality of RBC tended to be high in death cases. A delayed survey on anemia 10 years after exposure showed that there was no statistically significant difference in any of the factors, such as hemoglobin, RBC count, hematocrit, mean corpuscular volume and mean corpuscular hemoglobin, between the exposed and non-exposed groups. (N.K.)

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

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Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Li, Zhiguo [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Chao, Nelson J. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Department of Pathology, Duke University Medical Center, Durham, North Carolina (United States); Department of Immunology, Duke University Medical Center, Durham, North Carolina (United States); Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Chen, Benny J., E-mail: chen0032@mc.duke.edu [Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States)

2013-03-15

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

International Nuclear Information System (INIS)

Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S.; Li, Zhiguo; Chao, Nelson J.; Chen, Benny J.

2013-01-01

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells

The fps/fes proto-oncogene regulates hematopoietic lineage output.

Science.gov (United States)

Sangrar, Waheed; Gao, Yan; Zirngibl, Ralph A; Scott, Michelle L; Greer, Peter A

2003-12-01

The fps/fes proto-oncogene is abundantly expressed in myeloid cells, and the Fps/Fes cytoplasmic protein-tyrosine kinase is implicated in signaling downstream from hematopoietic cytokines, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). Studies using leukemic cell lines have previously suggested that Fps/Fes contributes to granulomonocytic differentiation, and that it might play a more selective role in promoting survival and differentiation along the monocytic pathway. In this study we have used a genetic approach to explore the role of Fps/Fes in hematopoiesis. We used transgenic mice that tissue-specifically express a mutant human fps/fes transgene (fps(MF)) that was engineered to encode Fps/Fes kinase that is activated through N-terminal myristoylation (MFps). Hematopoietic function was assessed using lineage analysis, hematopoietic progenitor cell colony-forming assays, and biochemical approaches. fps(MF) transgenic mice displayed a skewed hematopoietic output reflected by increased numbers of circulating granulocytic and monocytic cells and a corresponding decrease in lymphoid cells. Bone marrow colony assays of progenitor cells revealed a significant increase in the number of both granulomonocytic and multi-lineage progenitors. A molecular analysis of signaling in mature monocytic cells showed that MFps promoted GM-CSF-induced STAT3, STAT5, and ERK1/2 activation. These observations support a role for Fps/Fes in signaling pathways that contribute to lineage determination at the level of multi-lineage hematopoietic progenitors as well as the more committed granulomonocytic progenitors.

Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

Science.gov (United States)

Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

2009-01-01

Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

Donor characteristics and hematopoietic stem cell transplantation outcome: experience of a single center in Southern Brazil

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Alessandra Paz

2018-04-01

Full Text Available Background: Hematopoietic stem cell transplantation is a curative treatment for many patients with hematological disorders. Donor–recipient genetic disparity, especially involving the human leukocyte antigen system is a critical factor for transplant outcome. Objective: To evaluate retrospectively donor characteristics and correlations with the occurrence of acute and chronic graft-versus-host disease, disease-free survival and overall survival in a Brazilian population submitted to allogeneic hematopoietic stem cell transplantation between 1994 and 2012 in a single center. Results: Three hundred and forty-seven consecutive transplantations were included. Related transplants (81.2% were significantly more common than unrelated transplants (18.7%; donor and recipient median ages were 34 (range: 1–61 and 33 (range: 3–65 years respectively with donor HLAs being matched for 333 (95.9% patients. Donor gender, cytomegalovirus status and ABO incompatibility did not influence the five-year overall survival. In univariate analyses, overall survival was negatively influenced by the presence of acute graft-versus-host disease (33% vs. 47%, respectively; p-value = 0.04, unrelated transplant (41.5% vs. 50.9%, respectively; p-value = 0.045 and donors aged over 40 years (41% vs. 52%, respectively; p-value = 0.03. Older donors were associated with a higher rate of acute (52% vs. 65.8%; p-value = 0.03 and chronic graft-versus-host disease (60% vs. 43%, respectively; p-value = 0.015. In multivariate analyses, acute graft-versus-host disease [relative risk (RR: 1.8; 95% confidence interval (CI: 1.1–29; p-value = 0.008] and older donors (RR: 1.6; 95% CI 1.11–2.24; p-value = 0.013 were associated with higher transplant-related mortality. Conclusions: In transplant patients, to have a donor older than 40 years of age seems to significantly increase the incidence of acute and chronic graft-versus-host disease and transplant-related mortality

Hematopoietic cell phosphatase is recruited to CD22 following B cell antigen receptor ligation

NARCIS (Netherlands)

Lankester, A. C.; van Schijndel, G. M.; van Lier, R. A.

1995-01-01

Hematopoietic cell phosphatase is a nonreceptor protein tyrosine phosphatase that is preferentially expressed in hematopoietic cell lineages. Motheaten mice, which are devoid of (functional) hematopoietic cell phosphatase, have severe disturbances in the regulation of B cell activation and

TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells

DEFF Research Database (Denmark)

Langlois, Thierry; da Costa Reis Monte Mor, Barbara; Lenglet, Gaëlle

2014-01-01

. Here, we show that TET2 expression is low in human embryonic stem (ES) cell lines and increases during hematopoietic differentiation. ShRNA-mediated TET2 knockdown had no effect on the pluripotency of various ES cells. However, it skewed their differentiation into neuroectoderm at the expense...... profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm...... and hematopoietic differentiation. Stem Cells 2014....

Expression of a fms-related oncogene in carcinogen-induced neoplastic epithelial cells

International Nuclear Information System (INIS)

Walker, C.; Nettesheim, P.; Barrett, J.C.; Gilmer, T.M.

1987-01-01

Following carcinogen exposure in vitro, normal rat tracheal epithelial cells are transformed in a multistage process in which the cultured cells become immortal and ultimately, neoplastic. Five cell lines derived from tumors produced by neoplastically transformed rat tracheal epithelial cells were examined for the expression of 11 cellular oncogenes previously implicated in pulmonary or epithelial carcinogenesis. RNA homologous to fms was expressed at a level 5-19 times higher than normal tracheal epithelial cells in three of five of the tumor-derived lines. All three lines expressing high levels of fms-related RNA gave rise to invasive tumors of epithelial origin when injected into nude mice. Increased expression of the fms-related mRNA was not due to gene amplification, and no gene rearrangement was detected by Southern analyses. RNA blot analysis using a 3' v-fms probe detected a 9.5-kilobase message in the three tumor-derived lines, whereas both normal rat aveolar macrophages and the human choriocarcinoma line BeWo expressed a fms transcript of ≅ 4 kilobases. The authors conclude from these data that the gene expressed as a 9.5-kilobase transcript in these neoplastic epithelial cells is a member of a fms-related gene family but may be distinct from the gene that encodes the macrophage colony-stimulating factor (CSF-1) receptor

Cerebral salt-wasting syndrome after hematopoietic stem cell transplantation in adolescents: 3 case reports

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Yeon Jin Jeon

2015-12-01

Full Text Available Cerebral salt-wasting syndrome (CSWS is a rare disease characterized by a extracellular volume depletion and hyponatremia induced by marked natriuresis. It is mainly reported in patients who experience a central nervous system insult, such as cerebral hemorrhage or encephalitis. The syndrome of inappropriate antidiuretic hormone secretion is a main cause of severe hyponatremia after hematopoietic stem cell transplantation, whereas CSWS is rarely reported. We report 3 patients with childhood acute leukemia who developed CSWS with central nervous system complication after hematopoietic stem cell transplantation. The diagnosis of CSW was made on the basis of severe hyponatremia accompanied by increased urine output with clinical signs of dehydration. All patients showed elevated natriuretic peptide and normal antidiuretic hormone. Aggressive water and sodium replacement treatment was instituted in all 3 patients and 2 of them were effectively recovered, the other one was required to add fludrocortisone administration.

Circulating hematopoietic progenitors and CD34+ cells predicted successful hematopoietic stem cell harvest in myeloma and lymphoma patients: experiences from a single institution

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Yu JT

2016-02-01

Full Text Available Jui-Ting Yu,1,2,* Shao-Bin Cheng,3,* Youngsen Yang,1 Kuang-Hsi Chang,4 Wen-Li Hwang,1 Chieh-Lin Jerry Teng,1,5,6 1Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, 2Division of Hematology/Medical Oncology, Tungs' Taichung MetroHarbor Hospital, 3Division of General Surgery, Department of Surgery, 4Department of Medical Research and Education, Taichung Veterans General Hospital, 5Department of Life Science, Tunghai University, 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China *These authors contributed equally to this work Background: Previous studies have shown that the numbers of both circulating hematopoietic progenitor cell (HPC and CD34+ cell are positively correlated with CD34+ cell harvest yield. However, the minimal numbers of both circulating HPCs and CD34+ cells required for performing an efficient hematopoietic stem cell (HSC harvest in lymphoma and myeloma patients have not been defined in our institution. Patients and methods: Medical records of 50 lymphoma and myeloma patients undergoing peripheral blood HSC harvest in our institution were retrospectively reviewed. The minimal and optimal HSC harvest yield required for the treatment was considered to be ≥2×106 CD34+ cells/kg and ≥5×106 CD34+ cells/kg, respectively. Results: The minimally required or optimal HSC yield obtained was not influenced by age (≥60 years, sex, underlying malignancies, disease status, multiple rounds of chemotherapy, or history of radiotherapy. The numbers of both circulating HPC and CD34+ cell were higher in patients with minimally required HSC yields (P=0.000 for HPC and P=0.000 for CD34+ cell and also in patients with optimal HSC yields (P=0.011 for HPC and P=0.006 for CD34+ cell. The cell count cutoff for obtaining minimally required HSC harvest was determined to be 20/mm3 for HPCs and 10/mm3 for CD34+ cells. Furthermore, the cell count cutoff for obtaining

Neutron and gamma-ray toxicity studies

International Nuclear Information System (INIS)

Ainsworth, E.J.

1975-01-01

Results are reported from studies on the late effects of irradiation on large populations of mice. The effectiveness of neutron and gamma radiation for production of neoplastic and non-neoplastic diseases and life shortening is compared. Basic studies of cellular and functional indices of radiation injury, which provide the opportunity for fundamental new contributions to the understanding of late radiation effects in the vascular, immune, and hematopoietic systems are also reported. Both structural and functional changes in the vasculature have been observed during the second year after irradiation. The structural changes in the pinna include collapse of arteries, arterioles, and some veins along with alterations in the smooth musculature and accumulation of significant fibrosis. Late ultrastructural changes observed in myofibrils involve the endoplasmic reticulum and mitochondria. Cardiac muscle also showed alteration in the size and number of mitochondria, and fibrosis development within 7 days of irradiation. (U.S.)

Bone and bone marrow - nuclear medicine in the diagnosis of disorders of the hematopoetic system

International Nuclear Information System (INIS)

Cremerius, U.

1997-01-01

Significant progress has been achieved during the last years regarding therapy of neoplastic and non-neoplastic diseases of the hematopoietic system by introduction of new therapeutic modalities like highdose chemotherapy, bone marrow and stem cell transplantation, interferon-therapy and others. Diagnosis is still based on biopsy and histopathology of bone marrow. Imaging methods, however, provided by radiology and nuclear medicine, are now increasingly employed to give an additional macroscopic view over morphological and functional changes of the entire bone marrow. Bone marrow scintigraphy either using radiocolloids or immunoscintigraphy against granulocyte-antigenes may be performed as an alternative or an addition to nuclear magnetic resonance imaging. Bone scintigraphy has been successful in the detection of additional bony lesions for more than two decades. Positron emission tomography using 18-fluorine-deoxyglucose has recently been employed as a new and promising tool also for assessment of bone marrow infiltration in malignant lymphomas. (orig.) [de

Imaging of complications from hematopoietic stem cell transplant

International Nuclear Information System (INIS)

Pandey, Tarun; Maximin, Suresh; Bhargava, Puneet

2014-01-01

Stem cell transplant has been the focus of clinical research for a long time given its potential to treat several incurable diseases like hematological malignancies, diabetes mellitus, and neuro-degenerative disorders like Parkinson disease. Hematopoietic stem cell transplantation (HSCT) is the oldest and most widely used technique of stem cell transplant. HSCT has not only been used to treat hematological disorders including hematological malignancies, but has also been found useful in treamtent of genetic, immunological, and solid tumors like neuroblastoma, lymphoma, and germ cell tumors. In spite of the rapid advances in stem cell technology, success rate with this technique has not been universal and many complications have also been seen with this form of therapy. The key to a successful HSCT therapy lies in early diagnosis and effective management of complications associated with this treatment. Our article aims to review the role of imaging in diagnosis and management of stem cell transplant complications associated with HSCT

Psychosocial Changes Associated with Participation in Art Therapy Interventions for Siblings of Pediatric Hematopoietic Stem Cell Transplant Patients

Science.gov (United States)

Wallace, Jo; Packman, Wendy; Huffman, Lynne C.; Horn, Biljana; Cowan, Morton; Amylon, Michael D.; Kahn, Colleen; Cordova, Matt; Moses, Jim

2014-01-01

Hematopoietic stem cell transplantation (HSCT) is an accepted medical treatment for many serious childhood diseases. HSCT is a demanding procedure that creates both physical and emotional challenges for patients and their family members. Research has demonstrated that siblings of children undergoing HSCT are at risk for developing psychosocial…

Depleted uranium induces neoplastic transformation in human lung epithelial cells.

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Xie, Hong; LaCerte, Carolyne; Thompson, W Douglas; Wise, John Pierce

2010-02-15

Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and noncombatants is frequent and widespread. Previous studies have shown that DU has both chemical and radiological toxicity and that the primary route of exposure of DU to humans is through inhalation and ingestion. However, there is limited research information on the potential carcinogenicity of DU in human bronchial cells. Accordingly, we determined the neoplastic transforming ability of particulate DU to human bronchial epithelial cells (BEP2D). We observed the loss of contact inhibition and anchorage independent growth in cells exposed to DU after 24 h. We also characterized these DU-induced transformed cell lines and found that 40% of the cell lines exhibit alterations in plating efficiency and no significant changes in the cytotoxic response to DU. Cytogenetic analyses showed that 53% of the DU-transformed cell lines possess a hypodiploid phenotype. These data indicate that human bronchial cells are transformed by DU and exhibit significant chromosome instability consistent with a neoplastic phenotype.

First evidence of infectious hematopoietic necrosis virus (IHNV) in the Netherlands

DEFF Research Database (Denmark)

Haenen, O L M; Schuetze, H; Cieslak, M

2016-01-01

In spring 2008, infectious hematopoietic necrosis virus (IHNV) was detected for the first time in the Netherlands. The virus was isolated from rainbow trout, Oncorhynchus mykiss (Walbaum), from a put-and-take fishery with angling ponds. IHNV is the causative agent of a serious fish disease...... that these 12 isolates clustered into two different monophyletic groups within the European IHNV genogroup E. One of these two groups indicates a virus-introduction event by a German trout import, whereas the second group indicates that IHNV was already (several years) in the Netherlands before its discovery...

Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs.

Science.gov (United States)

Gao, Shuai; Hou, Xinfeng; Jiang, Yonghua; Xu, Zijian; Cai, Tao; Chen, Jiajie; Chang, Gang

2017-01-23

Transcription factor-mediated reprogramming can reset the epigenetics of somatic cells into a pluripotency compatible state. Recent studies show that induced pluripotent stem cells (iPSCs) always inherit starting cell-specific characteristics, called epigenetic memory, which may be advantageous, as directed differentiation into specific cell types is still challenging; however, it also may be unpredictable when uncontrollable differentiation occurs. In consideration of biosafety in disease modeling and personalized medicine, the availability of high-quality iPSCs which lack a biased differentiation capacity and somatic memory could be indispensable. Herein, we evaluate the hematopoietic differentiation capacity and somatic memory state of hematopoietic progenitor and stem cell (HPC/HSC)-derived-iPSCs (HPC/HSC-iPSCs) using a previously established sequential reprogramming system. We found that HPC/HSCs are amenable to being reprogrammed into iPSCs with unbiased differentiation capacity to hematopoietic progenitors and mature hematopoietic cells. Genome-wide analyses revealed that no global epigenetic memory was detectable in HPC/HSC-iPSCs, but only a minor transcriptional memory of HPC/HSCs existed in a specific tetraploid complementation (4 N)-incompetent HPC/HSC-iPSC line. However, the observed minor transcriptional memory had no influence on the hematopoietic differentiation capacity, indicating the reprogramming of the HPC/HSCs was nearly complete. Further analysis revealed the correlation of minor transcriptional memory with the aberrant distribution of H3K27me3. This work provides a comprehensive framework for obtaining high-quality iPSCs from HPC/HSCs with unbiased hematopoietic differentiation capacity and minor transcriptional memory.

Atypical focal non-neoplastic brain changes in neurofibromatosis type 1: mass effect and contrast enhancement

International Nuclear Information System (INIS)

Raininko, R.; Thelin, L.; Eeg-Olofsson, O.

2001-01-01

Abstract Children and young adults with neurofibromatosis type 1 often have small high-signal foci on T2-weighted images of the brain. We describe follow-up of two patients in whom one of the foci had atypical features, commonly regarded as signs of a neoplasm. In the first, one lesion showed temporary contrast enhancement and decreasing mass effect. The second developed an expanding lesion that increased minimally in size over 4.5 year's follow-up. The borderline between neoplastic and non-neoplastic lesions seems to be indistinct. (orig.)

The transcriptional landscape of hematopoietic stem cell ontogeny

Science.gov (United States)

McKinney-Freeman, Shannon; Cahan, Patrick; Li, Hu; Lacadie, Scott A.; Huang, Hsuan-Ting; Curran, Matthew; Loewer, Sabine; Naveiras, Olaia; Kathrein, Katie L.; Konantz, Martina; Langdon, Erin M.; Lengerke, Claudia; Zon, Leonard I.; Collins, James J.; Daley, George Q.

2012-01-01

Transcriptome analysis of adult hematopoietic stem cells (HSC) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSC purified from >2500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knock-down in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSC, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource (http://hsc.hms.harvard.edu) will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification. PMID:23122293

Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1

NARCIS (Netherlands)

Oostvogels, R.; Minnema, M. C.; van Elk, M.; Spaapen, R. M.; te Raa, G. D.; Giovannone, B.; Buijs, A.; van Baarle, D.; Kater, A. P.; Griffioen, M.; Spierings, E.; Lokhorst, H. M.; Mutis, T.

2013-01-01

Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the

Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma

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Spyros Darmanis

2017-10-01

Full Text Available Summary: Glioblastoma (GBM is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration. : Darmanis et al. perform single-cell transcriptomic analyses of neoplastic and stromal cells within and proximal to primary glioblastomas. The authors describe a population of neoplastic-infiltrating glioblastoma cells as well as a putative role of tumor-infiltrating immune cells in supporting tumor growth. Keywords: single cell, RNA-seq, glioma, glioblastoma, GBM, brain, heterogeneity, infiltrating, diffuse, checkpoint

Aging of hematopoietic stem cells : Intrinsic changes or micro-environmental effects?

NARCIS (Netherlands)

Woolthuis, Carolien M.; de Haan, Gerald; Huls, Gerwin

During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell

An in vitro model of hemogenic endothelium commitment and hematopoietic production

NARCIS (Netherlands)

Yvernogeau, Laurent; Gautier, Rodolphe; Khoury, Hanane; Menegatti, Sara; Schmidt, Melanie; Gilles, Jean Francois; Jaffredo, Thierry

2016-01-01

Adult-type hematopoietic stem and progenitor cells are formed during ontogeny from a specialized subset of endothelium, termed the hemogenic endothelium, via an endothelial-to-hematopoietic transition (EHT) that occurs in the embryonic aorta and the associated arteries. Despite efforts to generate

Effect of cotransplantation of hematopoietic stem cells and embryonic AGM stromal cells on hematopoietic reconstitution in mice after bone marrow transplantation

International Nuclear Information System (INIS)

Tao Si; Sun Hanying; Liu Wenli

2007-01-01

Objective: To explore the effects of cotransplantation of hematopoietic stem cells and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoietic reconstitution in mice after bone marrow transplantation (BMT). Methods: The typical mice model of syngeneic BMT was established and the mice were randomly divided into 4 groups: the control group, the BMT group, the group of cotransplantation of HSC with AGM stromal cells (the cotransplantation group) and the ligustrazine group (the LT group). On days 3, 7, 10, 14, 21 and 28 after BMT, the peripheral blood cells and bone marrow mononuclear cells (BMMNC) were counted, and histology changes of bone marrow were detected. Results: The levels of peripheral WBC, RBC, platelet, and BMMNC in the contransplantation group were significantly higher than those in the single BMT group and the LT group (P<0.05). Conclusions: Cotransplantation with AGM stromal cells could significantly promote hematopoietic reconstruction in mice after BMT. (authors)

Hyaluronic Acid in Normal and Neoplastic Colorectal Tissue: Electrospray Ionization Mass Spectrometric and Fluor Metric Analysis

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Ana Paula Cleto Marolla

2016-01-01

Conclusions: The expression of HA was found to be slightly lower in tumor tissue than in colorectal non-neoplastic mucosa, although this difference was not statistically significant. This finding probably influenced the lower expression of HA in tumor tissue than in colorectal non-neoplastic mucosa. Compared to normal tissues, HA levels are significantly increased in the tumor tissues unless they exhibit lymph node metastasis. Otherwise, the expression of HA in tumor tissue did not correlated with the other clinicopathological parameters.

Mechanical Properties of Human Cells Change during Neoplastic Processes

Science.gov (United States)

Guthold, Martin; Guo, Xinyi; Bonin, Keith; Scarpinato, Karin

2014-03-01

Using an AFM with a spherical probe of 5.3 μm, we determined mechanical properties of individual human mammary epithelial cells that have progressed through four stages of neoplastic transformation: normal, immortal, tumorigenic, and metastatic. Measurements on cells in all four stages were taken over both the nucleus and the cytoplasm. Moreover, the measurements were made for cells outside of a colony (isolated), on the periphery of a colony, and inside a colony. By fitting the AFM force vs. indentation curves to a Hertz model, we determined the Young's modulus, E. We found a distinct contrast in the influence a cell's colony environment has on its stiffness depending on whether the cells are normal or cancer cells. We also found that cells become softer as they advance to the tumorigenic stage and then stiffen somewhat in the final step to metastatic cells. For cells averaged over all locations the stiffness values of the nuclear region for normal, immortal, tumorigenic, and metastatic cells were (mean +/- sem) 880 +/- 50, 940+/-50, 400 +/- 20, and 600 +/-20 Pa respectively. Cytoplasmic regions followed a similar trend. These results point to a complex picture of the mechanical changes that occur as cells undergo neoplastic transformation. This work is supported by NSF Materials and Surface Engineering grant CMMI-1152781.

Critical care of the hematopoietic stem cell transplant recipient.

Science.gov (United States)

Afessa, Bekele; Azoulay, Elie

2010-01-01

An estimated 50,000 to 60,000 patients undergo hematopoietic stem cell transplantation (HSCT) worldwide annually, of which 15.7% are admitted to the intensive care unit (ICU). The most common reason for ICU admission is respiratory failure and almost all develop single or multiorgan failure. Most HSCT recipients admitted to ICU receive invasive mechanical ventilation (MV). The overall short-term mortality rate of HSCT recipients admitted to ICU is 65%, and 86.4% for those receiving MV. Patient outcome has improved over time. Poor prognostic indicators include advanced age, poor functional status, active disease at transplant, allogeneic transplant, the severity of acute illness, and the development of multiorgan failure. ICU resource limitations often lead to triage decisions for admission. For HSCT recipients, the authors recommend (1) ICU admission for full support during their pre-engraftment period and when there is no evidence of disease recurrence; (2) no ICU admission for patients who refuse it and those who are bedridden with disease recurrence and without treatment options except palliation; (3) a trial ICU admission for patients with unknown status of disease recurrence with available treatment options.

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

Science.gov (United States)

Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S; D'Souza, Aloma; Nishikii, Hidekazu; Chuang, Hui-Yen; Ilovich, Ohad; Lin, Chih-Feng; Reeves, Robert; Shuhendler, Adam; Hoehne, Aileen; Chan, Carmel T; Baker, Jeanette; Yaghoubi, Shahriar S; VanBrocklin, Henry F; Hawkins, Randall; Franc, Benjamin L; Jivan, Salma; Slater, James B; Verdin, Emily F; Gao, Kenneth T; Benjamin, Jonathan; Negrin, Robert; Gambhir, Sanjiv Sam

2017-06-01

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR . ©2017 American Association for Cancer Research.

Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation

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Javier Pilcante

2015-12-01

Full Text Available ABSTRACT Introduction: Patients submitted to hematopoietic stem cell transplantation have an increased risk of Clostridium difficile infection and multiple risk factors have been identi- fied. Published reports have indicated an incidence from 9% to 30% of transplant patients however to date there is no information about infection in these patients in Chile. Methods: A retrospective analysis was performed of patients who developed C. difficile infection after hematopoietic stem cell transplantations from 2000 to 2013. Statistical analysis used the Statistical Package for the Social Sciences software. Results: Two hundred and fifty patients were studied (mean age: 39 years; range: 17-69, with 147 (59% receiving allogeneic transplants and 103 (41% receiving autologous trans- plants. One hundred and ninety-two (77% patients had diarrhea, with 25 (10% cases of C. difficile infection being confirmed. Twenty infected patients had undergone allogeneic trans- plants, of which ten had acute lymphoblastic leukemia, three had acute myeloid leukemia and seven had other diseases (myelodysplastic syndrome, chronic myeloid leukemia, severe aplastic anemia. In the autologous transplant group, five patients had C. difficile infection; two had multiple myeloma, one had amyloidosis, one had acute myeloid leukemia and one had germinal carcinoma. The overall incidence of C. difficile infection was 4% within the first week, 6.4% in the first month and 10% in one year, with no difference in overall survival between infected and non-infected groups (72.0% vs. 67.6%, respectively; p-value = 0.56. Patients infected after allogeneic transplants had a slower time to neutrophil engraftment compared to non-infected patients (17.5 vs. 14.9 days, respectively; p-value = 0.008. In the autologous transplant group there was no significant difference in the neutrophil engraftment time between infected and non-infected patients (12.5 days vs. 11.8 days, respectively; p

Cord blood hematopoietic cells from preterm infants display altered DNA methylation patterns.

Science.gov (United States)

de Goede, Olivia M; Lavoie, Pascal M; Robinson, Wendy P

2017-01-01

Premature infants are highly vulnerable to infection. This is partly attributable to the preterm immune system, which differs from that of the term neonate in cell composition and function. Multiple studies have found differential DNA methylation (DNAm) between preterm and term infants' cord blood; however, interpretation of these studies is limited by the confounding factor of blood cell composition. This study evaluates the epigenetic impact of preterm birth in isolated hematopoietic cell populations, reducing the concern of cell composition differences. Genome-wide DNAm was measured using the Illumina 450K array in T cells, monocytes, granulocytes, and nucleated red blood cells (nRBCs) isolated from cord blood of 5 term and 5 preterm (blood cells (nRBCs) showed the most extensive changes in DNAm, with 9258 differentially methylated (DM) sites (FDR  0.10) discovered between preterm and term infants compared to the blood cell populations. The direction of DNAm change with gestational age at these prematurity-DM sites followed known patterns of hematopoietic differentiation, suggesting that term hematopoietic cell populations are more epigenetically mature than their preterm counterparts. Consistent shifts in DNAm between preterm and term cells were observed at 25 CpG sites, with many of these sites located in genes involved in growth and proliferation, hematopoietic lineage commitment, and the cytoskeleton. DNAm in preterm and term hematopoietic cells conformed to previously identified DNAm signatures of fetal liver and bone marrow, respectively. This study presents the first genome-wide mapping of epigenetic differences in hematopoietic cells across the late gestational period. DNAm differences in hematopoietic cells between term and <31 weeks were consistent with the hematopoietic origin of these cells during ontogeny, reflecting an important role of DNAm in their regulation. Due to the limited sample size and the high coincidence of prematurity and

Two hemocyte lineages exist in silkworm larval hematopoietic organ.

Science.gov (United States)

Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

2010-07-28

Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

Early CD3+/CD15+ peripheral blood leukocyte chimerism patterns correlate with long-term engraftment in non-malignant hematopoietic SCT.

Science.gov (United States)

Ketterl, T G; Flesher, M; Shanley, R; Miller, W

2014-04-01

Following hematopoietic SCT (HSCT) for non-malignant disorders (NMDs) variable donor chimerism among lympho-hematopoietic lines may be observed. We retrospectively evaluated early post-HSCT, lineage-sorted (CD3+ and CD15+) peripheral blood leukocyte chimerism data to characterize patterns and assess for association with long-term CD15+ engraftment. 'Early' was defined as the first value obtained between days +14 and +42, 'late' as the last recorded value after day +90. 'High' donor chimerism was defined as 80% on either fraction at all time-points. Patients were classified into four subgroups with respect to early CD3+/CD15+ chimerism patterns (high/low) then analyzed for long-term CD15+ chimerism status. A total of 135 transplants were evaluable, with all three time-points available in 97. Underlying disease, graft source, patient age and conditioning intensity varied. 'Split' early chimerism (discordant high/low CD3+/CD15+ status) was common. Multivariable analysis revealed strong association between conditioning regimen and primary disease on early CD3+/CD15+ chimerism patterns and a dominant predictive effect of early CD15+ chimerism on long-term CD15+ donor engraftment (observed at median day +365). These data may guide real-time clinician decisions (restraint vs intervention, when available) when faced with unfavorable or unusual early lympho-hematopoietic chimerism patterns following HSCT for NMD.

Effects of hematopoietic growth factors on purified bone marrow progenitor cells

NARCIS (Netherlands)

F.J. Bot (Freek)

1992-01-01

textabstractWe have used highly enriched hematopoietic progenitor cells and in-vitro culture to examine the following questions: 1. The effects of recombinant lL-3 and GM-CSF on proliferation and differentiation of enriched hematopoietic progenitor cells have not been clearly defined: - how do IL~3

Evaluation of Quality of Life and Care Needs of Turkish Patients Undergoing Hematopoietic Stem Cell Transplantation

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Neslisah Yasar

2016-01-01

Full Text Available This descriptive study explored the quality of life and care needs of Turkish patients who underwent hematopoietic stem cell transplantation. The study sample consisted of 100 hematopoietic stem cell transplant patients. Their quality of life was assessed using Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale. The mean patient age was 44.99 ± 13.92 years. Changes in sexual functions, loss of hair, loss of taste, loss of appetite, and sleep disturbances were the most common symptoms. The quality of life of transplant patients was moderately affected; the functional well-being and social/family well-being subscales were the most adversely and least negatively affected (12.13 ± 6.88 dimensions, respectively. Being female, being between 50 and 59 years of age, being single, having a chronic disease, and having a history of hospitalization were associated with lower quality of life scores. Interventions to improve functional status, physical well-being, and emotional status of patients during the transplantation process may help patients cope with treatment-related impairments more effectively. Frequent screening and management of patient symptoms in order to help patients adapt to life following allogeneic hematopoietic stem cell transplantation are crucial for meeting care needs and developing strategies to improve their quality of life.

Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency

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Andrea Z. Tuckett

2017-05-01

Full Text Available Abstract Background Even though hematopoietic stem cell transplantation can be curative in patients with severe combined immunodeficiency, there is a need for additional strategies boosting T cell immunity in individuals suffering from genetic disorders of lymphoid development. Here we show that image-guided intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice is feasible and facilitates the generation of functional T cells conferring protective immunity. Methods Hematopoietic stem and progenitor cells were isolated from the bone marrow of healthy C57BL/6 mice (wild-type, Luciferase+, CD45.1+ and injected intravenously or intrathymically into both male and female, young or aged NOD-scid IL2rγnull recipients. The in vivo fate of injected cells was analyzed by bioluminescence imaging and flow cytometry of thymus- and spleen-derived T cell populations. In addition to T cell reconstitution, we evaluated mice for evidence of immune dysregulation based on diabetes development and graft-versus-host disease. T cell immunity following intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice was assessed in a B cell lymphoma model. Results Despite the small size of the thymic remnant in NOD-scid IL2rγnull mice, we were able to accomplish precise intrathymic delivery of hematopoietic stem and progenitor cells by ultrasound-guided injection. Thymic reconstitution following intrathymic injection of healthy allogeneic hematopoietic cells was most effective in young male recipients, indicating that even in the setting of severe immunodeficiency, sex and age are important variables for thymic function. Allogeneic T cells generated in intrathymically injected NOD-scid IL2rγnull mice displayed anti-lymphoma activity in vivo, but we found no evidence for severe auto/alloreactivity in T cell-producing NOD-scid IL2rγnull mice, suggesting that immune dysregulation is not a major concern

Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

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Hahn, M; Böttcher, S; Dietrich, S; Hegenbart, U; Rieger, M; Stadtherr, P; Bondong, A; Schulz, R; Ritgen, M; Schmitt, T; Tran, T H; Görner, M; Herth, I; Luft, T; Schönland, S; Witzens-Harig, M; Zenz, T; Kneba, M; Ho, A D; Dreger, P

2015-10-01

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

Hematopoietic cell crisis: An early stage of evolving myeloid leukemia following radiation exposure

International Nuclear Information System (INIS)

Seed, T.M.

1990-01-01

Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event ''sets the stage'' for preleukemic progression by initiating progression from preclinical phase 1 to 2. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the ''immortalization'' step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictates governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia. 35 refs., 2 tabs

Hematopoietic cell crisis: An early stage of evolving myeloid leukemia following radiation exposure

Energy Technology Data Exchange (ETDEWEB)

Seed, T.M.

1990-01-01

Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event sets the stage'' for preleukemic progression by initiating progression from preclinical phase 1 to 2. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the immortalization'' step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictates governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia. 35 refs., 2 tabs.

Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis

DEFF Research Database (Denmark)

Hjalgrim, Henrik; Rostgaard, Klaus; Askling, Johan

2002-01-01

BACKGROUND: Young adults with a history of Epstein-Barr virus (EBV)-related infectious mononucleosis have an increased risk for Hodgkin's lymphoma. EBV is detected in Hodgkin's lymphoma Reed-Sternberg cells from some patients, but in young adult patients, it is detected at a relatively low...... frequency in these cells. Hodgkin's lymphoma and infectious mononucleosis are both associated with high social class, and unknown confounding factors that are also associated with socioeconomic status might explain or contribute to the apparent association between these diseases. To indirectly assess...... the importance of socioeconomic status on the association between these diseases, we determined the risk for hematopoietic and lymphatic cancers in first-degree relatives of patients with confirmed EBV-related infectious mononucleosis. METHODS: We identified parents, siblings, and offspring of 17,045 persons...

Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

International Nuclear Information System (INIS)

Fukuda, Seiji; Pelus, Louis M.

2004-01-01

Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34 + cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G 0 /G 1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

SBR-Blood: systems biology repository for hematopoietic cells.

Science.gov (United States)

Lichtenberg, Jens; Heuston, Elisabeth F; Mishra, Tejaswini; Keller, Cheryl A; Hardison, Ross C; Bodine, David M

2016-01-04

Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles. Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation

NARCIS (Netherlands)

Woolthuis, Carolien M; Mariani, Niccoló; Verkaik-Schakel, Rikst Nynke; Brouwers-Vos, Annet Z.; Schuringa, Jan Jacob; Vellenga, Edo; de Wolf, Joost T M; Huls, Gerwin

Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (<35 years) and old (>60 years)

Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation

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Yiannis Drosos

2016-03-01

Full Text Available The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness.

Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

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2017-10-01

Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

VE-cadherin expression allows identification of a new class of hematopoietic stem cells within human embryonic liver.

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Oberlin, Estelle; Fleury, Maud; Clay, Denis; Petit-Cocault, Laurence; Candelier, Jean-Jacques; Mennesson, Benoît; Jaffredo, Thierry; Souyri, Michèle

2010-11-25

Edification of the human hematopoietic system during development is characterized by the production of waves of hematopoietic cells separated in time, formed in distinct embryonic sites (ie, yolk sac, truncal arteries including the aorta, and placenta). The embryonic liver is a major hematopoietic organ wherein hematopoietic stem cells (HSCs) expand, and the future, adult-type, hematopoietic cell hierarchy becomes established. We report herein the identification of a new, transient, and rare cell population in the human embryonic liver, which coexpresses VE-cadherin, an endothelial marker, CD45, a pan-hematopoietic marker, and CD34, a common endothelial and hematopoietic marker. This population displays an outstanding self-renewal, proliferation, and differentiation potential, as detected by in vitro and in vivo hematopoietic assays compared with its VE-cadherin negative counterpart. Based on VE-cadherin expression, our data demonstrate the existence of 2 phenotypically and functionally separable populations of multipotent HSCs in the human embryo, the VE-cadherin(+) one being more primitive than the VE-cadherin(-) one, and shed a new light on the hierarchical organization of the embryonic liver HSC compartment.

Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver

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Laghi Luigi

2006-04-01

Full Text Available Abstract Background Epigenetic changes during ageing and their relationship with cancer are under the focus of intense research. RASSF1A and NORE1A are novel genes acting in concert in the proapoptotic pathway of the RAS signalling. While NORE1A has not been previously investigated in the human liver, recent reports have suggested that RASSF1A is frequently epigenetically methylated not only in HCC but also in the cirrhotic liver. Methods To address whether epigenetic changes take place in connection to age and/or to the underlying disease, we investigated RASSF1A and NORE1A gene promoter methylation by conventional methylation specific PCR and Real-Time MSP in a series of hepatitic and non-hepatitic livers harboring regenerative/hyperplastic (cirrhosis/focal nodular hyperplasia, dysplastic (large regenerative, low and high grade dysplastic nodules and neoplastic (hepatocellular adenoma and carcinoma growths. Results In the hepatitic liver (chronic hepatitic/cirrhosis, hepatocellular nodules and HCC we found widespread RASSF1A gene promoter methylation with a methylation index that increased from regenerative conditions (cirrhosis to hepatocellular nodules (p RASSF1A gene promoter methylation, NORE1A gene was never found epigenetically alterated in both hepatitic and non-hepatitic liver. Conclusion We have shown that in non-lesional, regenerative and neoplastic liver the RASSF1A gene is increasingly methylated, that this condition takes place as an age-related phenomenon and that the early setting and spreading over time of an epigenetically methylated hepatocyte subpopulation, might be related to liver tumorigenesis.

STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells

NARCIS (Netherlands)

Schepers, Hein; Wierenga, Albertus T. J.; Vellenga, Edo; Schuringa, Jan Jacob

2012-01-01

The level of transcription factor activity critically regulates cell fate decisions such as hematopoietic stem cell self-renewal and differentiation. The balance between hematopoietic stem cell self-renewal and differentiation needs to be tightly controlled, as a shift toward differentiation might

Two hemocyte lineages exist in silkworm larval hematopoietic organ.

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Yuichi Nakahara

Full Text Available BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. CONCLUSIONS/SIGNIFICANCE: From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

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Popov, Dmitri

Key Words: Aplastic Anemia (AA), Pluripotential Stem Cells (PSC) Introduction: Aplastic Anemia (AA) is a disorder of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. The etiology of AA include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-proliferative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodskyet al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation-Acquired Aplastic Anemia) is the acute toxic syndrome which usually occurs with a dose of irradiation between 0.7 and 10 Gy (70- 1000 rads), depending on the species irradiated. [Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of bone marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and other specific toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders, in cases such as the acute radiation-acquired form of AA. AA results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit{granulocyte-macrophage (CFU-GM) and burst forming unit {erythroid (BFU{E) are reduced markedly in patients with AA. [Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally

Therapeutic approaches of hematopoietic syndrome after serious accidental global irradiation. Ex vivo expansion interest of hematopoietic cells

International Nuclear Information System (INIS)

Thierry, D.

1994-01-01

Aplasia is one of the main syndrome, appearing after one global accidental irradiation by one ionizing radiation source. The hematopoietic syndrome is characterized by a peripheric blood cell number fall; the cell marrow is reduced too

Mechanisms of chemical modification of neoplastic cell transformation by ionizing radiation

International Nuclear Information System (INIS)

Yang, T.C.; Tobias, C.A.

1985-01-01

During space travel, astronauts will be continuously exposed to ionizing radiation; therefore, it is necessary to minimize the radiation damage by all possible means. The authors' studies show that DMSO (when present during irradiation) can protect cells from being killed and transformed by X rays and that low concentration of DMSO can reduce the transformation frequency significantly when it is applied to cells, even many days after irradiation. The process of neoplastic cell transformation is a complicated one and includes at least two different stages: induction and expression. DMSO apparently can modify the radiation damage during both stages. There are several possible mechanisms for the DMSO effect: (1) changing the cell membrane structure and properties; (2) inducing cell differentiation by acting on DNA; and (3) scavanging free radicals in the cell. Recent studies with various chemical agents, e.g., 5-azacytidine, dexamethane, rhodamin-123, etc., indicate that the induction of cell differentiation by acting on DNA may be an important mechanism for the suppression of expression of neoplastic cell transformation by DMSO

Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

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Cécile eCoste

2015-06-01

Full Text Available Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL12-abundant reticular (CAR cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs, which have been recently identified as neural crest-derived cells (NCSCs. Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-to-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

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Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

2015-01-01

Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

Genetic biomarkers for neoplastic colorectal cancer in peripheral lymphocytes.

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Ionescu, Mirela; Ciocirlan, Mihai; Ionescu, Cristina; Becheanu, Gabriel; Gologan, Serban; Teiusanu, Adriana; Arbanas, Tudor; Mircea, Diculescu

2011-04-01

Loss of genomic stability appears as a key step in colorectal carcinogenesis. Micronucleus (MN) designates a chromosome fragment or an entire chromosme which lags behind mitosis. MN may be noticed as an additional nucleus within the cytoplasm cell during the intermediate mitosis phases. We tested the hypothesis that MN and its related anomalies may be associated with the presence of neoplastic colorectal lesions. Peripheral blood lymphocytes were cultured and microscopically examined. The frequency of micronuclei (FMN) and the presence of nucleoplasmic bridges (NPB) in binucleated cells were compared in patients with of without colorectal neoplastic lesions. We included 45 patients undergoing colonoscopy, 23 males and 22 females, with a median age of 59. 17 patients had polyps, 11 colorectal cancer (CRC) and 17 had a normal colonoscopy. The FMN was significantly higher in women than in men (8.14 vs 4.17, p=0.008); NPB were significantly less frequent in patients with advanced adenomas (>10mm or vilous) or CRC (p=0.044) when compared with patients with normal colonoscopy, hiperplastic polyps or non-advanced adenomas. Micronuclei are more frequent in women, but its frequency was not significantly different in patients with advanced adenomas or CRC. Null or low frequency values for nucleoplasmic bridges presence in peripheral lymphocyte may be predictive for advanced adenomas and colorectal cancer.

Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

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Hetzel, Miriam; Mucci, Adele; Blank, Patrick; Nguyen, Ariane Hai Ha; Schiller, Jan; Halle, Olga; Kühnel, Mark-Philipp; Billig, Sandra; Meineke, Robert; Brand, Daniel; Herder, Vanessa; Baumgärtner, Wolfgang; Bange, Franz-Christoph; Goethe, Ralph; Jonigk, Danny; Förster, Reinhold; Gentner, Bernhard; Casanova, Jean-Laurent; Bustamante, Jacinta; Schambach, Axel; Kalinke, Ulrich; Lachmann, Nico

2018-02-01

Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 ( IFNGR1 or IFNGR2 ) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that express Ifnγr1 either constitutively or myeloid specifically. Transduction of mouse Ifnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifnγr1 -/- mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. © 2018 by The American Society of Hematology.

Onconeuronal and antineuronal antibodies in patients with neoplastic and non-neoplastic pulmonary pathologies and suspected for paraneoplastic neurological syndrome

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Michalak S

2009-12-01

Full Text Available Abstract Objective Onconeuronal antibodies are important diagnostic tool in patients with suspicion of paraneoplastic neurological syndromes (PNS. However, their role in PNS pathophysiology and specificity for particular neurological manifestation remains unclear. The aim of this study was to evaluate onconeuronal and antineuronal antibodies in patients with pulmonary pathologies and suspected for PNS. Materials and methods Twenty one patients with pulmonary pathologies were selected from the database of 525 consecutive patients with suspicion of PNS. Patients' sera were screened for the presence of onconeuronal and antineuronal antibodies by means of indirect immunofluorescence; the presence was confirmed by Western blotting. Clinical data were obtained from medical records, hospital data base, and questionnaire-based direct telephone contact with patients. Results Among 21 patients, aged 54 ± 11, with pulmonary pathologies, the most frequent neurological manifestations were neuropathies. Typical PNS included paraneoplastic cerebellar degeneration (PCD and limbic encephalitis (LE. We found cases with multiple onconeuronal antibodies (anti-Ri and anti-Yo and coexisting PNS (PCD/LE. Well-defined onconeuronal antibodies were identified in 23.8% of patients. Among antineuronal antibodies, the most frequent were anti-MAG (23.8%. ROC curves analysis revealed high sensitivity of onconeuronal and antineuronal antibodies for typical PNS and lower for pulmonary malignancies. Conclusions Tests for antibodies are highly sensitive for the diagnosis of typical paraneoplastic neurological syndromes. Anti-myelin and anti-MAG antibodies are associated with non-neoplastic pulmonary diseases. Patients with well-defined onconeuronal antibodies require careful screening and follow-up, because the PNS diagnosis indicates a high probability of an underlying malignancy.

Stem cell therapy for severe autoimmune diseases

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Marmont Alberto M.

2002-01-01

Full Text Available Intense immunosuppresion followed by alogenic or autogenic hematopoietic stem cell transplantation is a relatively recent procedure which was used for the first time in severe, refractory cases of systemic lupus erythematosus. Currently three agressive procedures are used in the treatment of autoimmune diseases: high dose chemotherapy without stem cell rescue, intense immunosuppression with subsequent infusion of the alogenic hematopoietic stem cell transplantation combined with or without the selection of CD34+ cells, and the autogenic hematopoietic stem cell transplantation. Proof of the graft-versus-leukemia effect observed define SCT as a form of immunotherapy, with additional evidence of an similar Graft-vs-Autoimmunity effect which is suggestive of a cure for autoimmune diseases in this type of therapy. The use of alogenic SCT improved due to its safety compared to autogenic transplantations. In this report, data of multiply sclerosis and systemic lupus erythematosus are reported, with the conclusion that Immunoablation followed by SCT is clearly indicated in such cases.

IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

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Siegemund, Sabine; Rigaud, Stephanie; Conche, Claire; Broaten, Blake; Schaffer, Lana; Westernberg, Luise; Head, Steven Robert

2015-01-01

Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb−/− mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb−/− HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb−/− HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb−/− mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb−/− hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb−/− HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb−/− HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb−/− HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms. PMID:25788703

Diagnostic accuracy of transabdominal high-resolution US for staging gallbladder cancer and differential diagnosis of neoplastic polyps compared with EUS.

Science.gov (United States)

Lee, Jeong Sub; Kim, Jung Hoon; Kim, Yong Jae; Ryu, Ji Kon; Kim, Yong-Tae; Lee, Jae Young; Han, Joon Koo

2017-07-01

To compare the diagnostic accuracy of transabdominal high-resolution ultrasound (HRUS) for staging gallbladder cancer and differential diagnosis of neoplastic polyps compared with endoscopic ultrasound (EUS) and pathology. Among 125 patients who underwent both HRUS and EUS, we included 29 pathologically proven cancers (T1 = 7, T2 = 19, T3 = 3) including 15 polypoid cancers and 50 surgically proven polyps (neoplastic = 30, non-neoplastic = 20). We reviewed formal reports and assessed the accuracy of HRUS and EUS for diagnosing cancer as well as the differential diagnosis of neoplastic polyps. Statistical analyses were performed using chi-square tests. The sensitivity, specificity, PPV, and NPV for gallbladder cancer were 82.7 %, 44.4 %, 82.7 %, and 44 % using HRUS and 86.2 %, 22.2 %, 78.1 %, and 33.3 % using EUS. HRUS and EUS correctly diagnosed the stage in 13 and 12 patients. The sensitivity, specificity, PPV, and NPV for neoplastic polyps were 80 %, 80 %, 86 %, and 73 % using HRUS and 73 %, 85 %, 88 %, and 69 % using EUS. Single polyps (8/20 vs. 21/30), larger (1.0 ± 0.28 cm vs. 1.9 ± 0.85 cm) polyps, and older age (52.5 ± 13.2 vs. 66.1 ± 10.3 years) were common in neoplastic polyps (p diagnostic accuracy for GB cancer compared with EUS. • HRUS and EUS showed similar diagnostic accuracy for differentiating neoplastic polyps. • Single, larger polyps and older age were common in neoplastic polyps. • HRUS is less invasive compared with EUS.

Adaptive Response Against Spontaneous Neoplastic Transformation In Vitro Induced by Ionizing Radiation

International Nuclear Information System (INIS)

Redpath, J. Leslie

2003-01-01

The goal of this project was to establish a dose response curve for radiation-induced neoplastic transformation of HeLa x skin fibroblast human hybrid cells in vitro under experimental conditions were an adaptive response, if it were induced, would have an opportunity to be expressed. During the first two years of the grant an exhaustive series of experiments were performed and the resulting data were reported at the 2000 Annual Meeting of the Radiation Research Society and then Subsequently published. The data showed that an adaptive response against spontaneous neoplastic transformation was seen up to doses of 10cGy of Cs-137 gamma rays. At dose of 30, 50 and 100 cGy the transformation frequencies were above background. This indicated that for this system, under the specific experimental conditions used, there was a threshold of somewhere between 10 and 30 cGy. The results also indicated some unexpected, though very interesting, correlations with relative risk estimates made from human epidemiologic studies

Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

Science.gov (United States)

Lucarelli, Guido; Isgrò, Antonella; Sodani, Pietro; Gaziev, Javid

2012-01-01

The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class–based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation. PMID:22553502

Chondroblastoma and chondromyxoid fibroma : disentangling the neoplastic chondrogenesis of two rare cartilaginous tumours

NARCIS (Netherlands)

Romeo, Salvatore

2010-01-01

The scope of this study was to disentangle neoplastic chondrogenesis in two rare cartilaginous tumours: chondroblastoma and chondromyxoid fibroma. It was addressed: 1 The spectrum of phenotypic differentiation in chondroblastoma and chondromyxoid fibroma, 2 The signalling pathways driving

Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1

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Zhou, Bo O; Ding, Lei; Morrison, Sean J

2015-01-01

Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. DOI: http://dx.doi.org/10.7554/eLife.05521.001 PMID:25821987

Comparison of upper gastrointestinal radiographic findings to histopathologic observations: a retrospective study of 41 dogs and cats with suspected small bowel infiltrative disease (1985 to 1990)

International Nuclear Information System (INIS)

Weichselbaum, R.C.; Feeney, D.A.; Hayden, D.W.

1994-01-01

It was the intent of this study to define which, if any, radiographic observations corresponded with specific causes of diffuse infiltrative small bowel disease and if radiographic findings could differentiate inflammatory disease from neoplastic disease and either of them from normal. Bowel spasticity, luminal narrowing, and thumb printing tend to indicate the presence of tumor more often than inflammatory disease. Increased bowel gas in cats and barium adhesion in dogs and cats suggest that a component of enteritis is present. Decreased bowel gas in dogs is more often associated with obstructive disease, but is not helpful in differentiating diffuse inflammatory disease from diffuse neoplastic disease. While several observations that can foster differentiation of neoplastic from inflammatory disease were found, this study also indicated that the UGI lacks a high degree of predictive value other than to indicate the presence of infiltrative small bowel disease

The role of hematopoietic SCT in adult Burkitt lymphoma.

Science.gov (United States)

Ahmed, S O; Sureda, A; Aljurf, M

2013-05-01

Adult Burkitt lymphoma (BL) is an aggressive disease characterized by frequent extranodal presentation, bulky disease and a rapid clinical course. Although intensive chemotherapeutic regimes result in long-term disease-free survival in most patients, a significant proportion of patients will have high-risk disease that may be refractory or that will relapse. In these patients, the role of hematopoietic SCT is not well defined, especially in the era of modern chemoimmunotherapy. Upfront auto-SCT has been reported to be feasible in patients who have high-risk features at presentation, and in whom it is a clinical option. In patients with relapsed disease, auto-SCT can result in a PFS of 30-40%. Allo-SCT is an option in relapsing patients with a sibling or matched related donor who may not be eligible for, or may have previously received, an auto-SCT; the role of RIC and T-cell depletion is not well defined. Disease status at transplant is the most significant predictor of outcome in patients undergoing SCT. Here we review the available evidence pertaining to SCT in patients with BL, including in those who are HIV positive (HIV+) and those with B-cell lymphoma unclassified (BCLU). Prospective studies in the era of modern intensive chemoimmunotherapeutic regimes are required to delineate the precise role of transplantation for BL. Developments in molecular diagnostics, incorporation of FDG-PET and minimal residual disease monitoring along with new therapies may further assist in refining treatment algorithms.

Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells

International Nuclear Information System (INIS)

Wilson, J.M.; Danos, O.; Grossman, M.; Raulet, D.H.; Mulligan, R.C.

1990-01-01

Recombinant retroviruses encoding human adenosine deaminase have been used to infect murine hematopoietic stem cells. In bone marrow transplant recipients reconstituted with the genetically modified cells, human ADA was detected in peripheral blood mononuclear cells of the recipients for at least 6 months after transplantation. In animals analyzed in detail 4 months after transplantation, human ADA and proviral sequences were detected in all hematopoietic lineages; in several cases, human ADA activity exceeded the endogenous activity. These studies demonstrate the feasibility of introducing a functional human ADA gene into hematopoietic stem cells and obtaining expression in multiple hematopoietic lineages long after transplantation. This approach should be helpful in designing effective gene therapies for severe combined immunodeficiency syndromes in humans

Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases

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Neslihan Edeer Karaca

2016-01-01

Full Text Available Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation

DEFF Research Database (Denmark)

Fagius, J.; Lundgren, J.; Oberg, G.

2009-01-01

BACKGROUND: During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been...... minor or moderate. PATIENTS: Since 2004, we have performed HSCT in nine young patients with "malignant" relapsing-remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong...... immunosuppression. FINDINGS: Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS...

Degradation of type IV collagen by neoplastic human skin fibroblasts

International Nuclear Information System (INIS)

Sheela, S.; Barrett, J.C.

1985-01-01

An assay for the degradation of type IV (basement membrane) collagen was developed as a biochemical marker for neoplastic cells from chemically transformed human skin fibroblasts. Type IV collagen was isolated from basement membrane of Syrian hamster lung and type I collagen was isolated from rat tails; the collagens were radioactively labelled by reductive alkylation. The abilities of normal (KD) and chemically transformed (Hut-11A) human skin fibroblasts to degrade the collagens were studied. A cell-associated assay was performed by growing either normal or transformed cells in the presence of radioactively labelled type IV collagen and measuring the released soluble peptides in the medium. This assay also demonstrated that KD cells failed to synthesize an activity capable of degrading type IV collagen whereas Hut-11A cells degraded type IV collagen in a linear manner for up to 4 h. Human serum at very low concentrations, EDTA and L-cysteine inhibited the enzyme activity, whereas protease inhibitors like phenylmethyl sulfonyl fluoride, N-ethyl maleimide or soybean trypsin inhibitor did not inhibit the enzyme from Hut-11A cells. These results suggest that the ability to degrade specifically type IV collagen may be an important marker for neoplastic human fibroblasts and supports a role for this collagenase in tumor cell invasion

Impact of Pretransplantation Indices in Hematopoietic Stem Cell Transplantation: Knowledge of Center-Specific Outcome Data Is Pivotal before Making Index-Based Decisions.

Science.gov (United States)

Törlén, Johan; Remberger, Mats; Le Blanc, Katarina; Ljungman, Per; Mattsson, Jonas

2017-04-01

Outcome after allogeneic hematopoietic stem cell transplantation is influenced by patient comorbidity, disease type, and status before treatment. We performed a retrospective study involving 521 consecutive adult hematopoietic stem cell transplantation patients who underwent transplantation for hematological malignancy at our center from 2000 to 2012 to compare the predictive value of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the disease risk index (DRI) for overall survival and transplantation-related mortality. Patients in the highest HCT-CI risk group (HCT-CI score ≥3) had a lower 5-year overall survival rate (50%) than the low-risk group (63%; P 6 [n = 9]). Five-year overall survival in the highest DRI risk group was significantly poorer (44%) than in the low-risk group (63%; P indices failed to predict differences in transplantation-related mortality (HCT-CI, P = .54; DRI, P = .17). We conclude that HCT-CI and DRI were predictive of overall survival in our patient population. Even so, our data show that different patient groups may have different outcomes despite sharing the same index risk group and that indices should, therefore, be evaluated according to local data before clinical implementation at the single-center level. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

High-Dose Methylprednisolone for Veno-Occlusive Disease of the Liver in Pediatric Hematopoietic Stem Cell Transplantation Recipients

Science.gov (United States)

Myers, Kasiani C.; Lawrence, Julia; Marsh, Rebecca A.; Davies, Stella M.; Jodele, Sonata

2017-01-01

Veno-occlusive disease (VOD) of the liver is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT), with few successful treatment modalities available for severe disease. Some reports have demonstrated success in adults with the use of high-dose steroid therapy, but experience in the pediatric population is lacking. We retrospectively reviewed HSCT patients treated at our institution since 2003 and identified 15 (2.4%) who developed VOD. Of these, nine (60%) were treated with intravenous high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for six doses). Steroid therapy was initiated at or before first ultrasound evidence of reversal of portal venous flow and before meeting criteria for initiation of defibrotide therapy. Four patients were also treated with defibrotide starting 2 to 5 days after initiation of steroids. Eight of nine patients (88%) with VOD were diagnosed with multiorgan failure. Response to high-dose steroid therapy as defined by decrease in bilirubin by 50% in 10 days from therapy initiation was noted in six of nine patients (67%), occurring within 3 to 6 days of steroid therapy. Two patients died from multiorgan failure due to VOD. Seven survivors of VOD recovered at the median 6 days (range, 5 to 38) from VOD diagnosis. Overall, VOD survival as a group was 78%; however, survival among responders was 100%. No serious toxicities related to high-dose steroid therapy were observed. We conclude that high-dose steroid therapy if initiated early may reverse VOD of the liver in pediatric HSCT patients, abrogating the need for defibrotide therapy with its associated toxicities and regulatory difficulties. PMID:23211838

Viral Pneumonia in Patients with Hematologic Malignancy or Hematopoietic Stem Cell Transplantation.

Science.gov (United States)

Vakil, Erik; Evans, Scott E

2017-03-01

Viral pneumonias in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation cause significant morbidity and mortality. Advances in diagnostic techniques have enabled rapid identification of respiratory viral pathogens from upper and lower respiratory tract samples. Lymphopenia, myeloablative and T-cell depleting chemotherapy, graft-versus-host disease, and other factors increase the risk of developing life-threatening viral pneumonia. Chest imaging is often nonspecific but may aid in diagnoses. Bronchoscopy with bronchoalveolar lavage is recommended in those at high risk for viral pneumonia who have new infiltrates on chest imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells.

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Yasushi Hara

Full Text Available Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs, acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt pathway and the signal transducer and activator of transcription 5 (STAT5 but only on endolysosomes and on the endoplasmic reticulum (ER, respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide, an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM. Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is

M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells.

Science.gov (United States)

Hara, Yasushi; Obata, Yuuki; Horikawa, Keita; Tasaki, Yasutaka; Suzuki, Kyohei; Murata, Takatsugu; Shiina, Isamu; Abe, Ryo

2017-01-01

Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the signal transducer and activator of transcription 5 (STAT5) but only on endolysosomes and on the endoplasmic reticulum (ER), respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide), an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM). Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is unable to

Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression.

Science.gov (United States)

Cheng, Chia-Wei; Adams, Gregor B; Perin, Laura; Wei, Min; Zhou, Xiaoying; Lam, Ben S; Da Sacco, Stefano; Mirisola, Mario; Quinn, David I; Dorff, Tanya B; Kopchick, John J; Longo, Valter D

2014-06-05

Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration. Copyright © 2014 Elsevier Inc. All rights reserved.

Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.

Science.gov (United States)

Ebens, Christen L; MacMillan, Margaret L; Wagner, John E

2017-01-01

Hematopoietic cell transplantation for Fanconi Anemia (FA) has improved dramatically over the past 40 years. With an enhanced understanding of the intrinsic DNA-repair defect and pathophysiology of hematopoietic failure and leukemogenesis, sequential changes to conditioning and graft engineering have significantly improved the expectation of survival after allogeneic hematopoietic cell transplantation (alloHCT) with incidence of graft failure decreased from 35% to 40% to <10%. Today, five-year overall survival exceeds 90% in younger FA patients with bone marrow failure but remains about 50% in those with hematologic malignancy. Areas covered: We review the evolution of alloHCT contributing to decreased rates of transplant related complications; highlight current challenges including poorer outcomes in cases of clonal hematologic disorders, alloHCT impact on endocrine function and intrinsic FA risk of epithelial malignancies; and describe investigational therapies for prevention and treatment of the hematologic manifestations of FA. Expert commentary: Current methods allow for excellent survival following alloHCT for FA associated BMF irrespective of donor hematopoietic cell source. Alternative curative approaches, such as gene therapy, are being explored to eliminate the risks of GVHD and minimize therapy-related adverse effects.

Studies on hematopoietic cell apoptosis and the relative gene expression in irradiated mouse bone marrow

International Nuclear Information System (INIS)

Peng Ruiyun; Wang Dewen; Xiong Chengqi; Gao Yabing; Yang Hong; Cui Yufang; Wang Baozhen

2001-01-01

Objective: To study apoptosis and expressions bcl-2 and p53 in irradiated mouse bone marrow. Methods: LACA mice were irradiated with 60 Co γ-rays. By means of in situ terminal labelling, in situ hybridization and image analysis, the authors studied radiation-induced apoptosis of hematopoietic cells and the expressions of bcl-2 and p53. Results: The characteristics of apoptosis appeared in hematopoietic cells at 6 hrs after irradiation. The expression of bcl-2 was obviously decreased when apoptosis of hematopoietic cells occurred, whereas it increased in the early recovery phase; p53 protein increased during both apoptosis of hematopoietic cells and the recovery phase, and mutant type p53 DNA was positive only in the recovery phase. Conclusion: Radiation may induced apoptosis of hematopoietic cells in a dose-dependent manner; Both bcl-2 and p53 genes play an important role in apoptosis and recovery phase

Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine.

Science.gov (United States)

Rozov, F N; Grinenko, T S; Levit, G L; Krasnov, V P; Belyavsky, A V

2010-09-15

Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the O(6)-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders. 2010 Elsevier Inc. All rights reserved.

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

Science.gov (United States)

Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal; Kourtzelis, Ioannis; Economopoulou, Matina; Kajikawa, Tetsuhiro; Troullinaki, Maria; Ziogas, Athanasios; Ruppova, Klara; Hosur, Kavita; Maekawa, Tomoki; Wang, Baomei; Subramanian, Pallavi; Tonn, Torsten; Verginis, Panayotis; von Bonin, Malte; Wobus, Manja; Bornhäuser, Martin; Grinenko, Tatyana; Di Scala, Marianna; Hidalgo, Andres; Wielockx, Ben; Hajishengallis, George; Chavakis, Triantafyllos

2017-10-02

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

PET/CT and beta-2-microglobulin in staging and therapeutic control after hematopoietic stem cell transplantation

International Nuclear Information System (INIS)

Vassileva, D.; Garcheva, M.; Kostadinova, I.

2013-01-01

Full text: Introduction: The transplantation of hematopoietic stem cells is used in lymphomas refractory to standard treatment. An exact re-staging is critical and the use of hybrid imaging methods has increased. The determined serum levels of beta-2 - microglobulin levels are also related to the progress of the disease and may be involved in determining the therapeutic effect. Materials and Methods: PET / CT studies were performed before and after transplantation of hematopoietic stem cells in patients with Hodgkin's disease and non-Hodgkin's lymphomas according to a the standard protocol, 60 minutes after injection of 18F-FDG using the apparatus Discovery 600. At the same time, the serum levels of beta-2 - microglobulin were determined. Results: Prior to transplantation nodal and extra nodal tumor infiltrates were visualized in the lungs and bones. In some of the patients a residual tumor was observed after the stem cell transplantation, which shows a partial response to the therapy. The serum levels of beta-2 - microglobulin were increased in the active phase of the disease and were normalized at remission. In the patients with partial response the values of the beta -2- microglobulin remain elevated. Conclusion: The use of PET / CT allows an accurate staging in patients with refractory lymphomas directed for transplantation and allows to register the effect of the therapy. The scintigraphic data show a good correlation with the beta-2 – microglobulin values in the serum

Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation.

Directory of Open Access Journals (Sweden)

Aurélie Bedel

Full Text Available Chronic myeloid leukemia disease (CML found effective therapy by treating patients with tyrosine kinase inhibitors (TKI, which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs derived from CD34⁺ blood cells isolated from CML patients (CML-iPSCs as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents.

Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

Energy Technology Data Exchange (ETDEWEB)

Amano, Yasuo; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan); Arai, Nobuyuki

1997-04-01

The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

International Nuclear Information System (INIS)

Amano, Yasuo; Kumazaki, Tatsuo; Arai, Nobuyuki.

1997-01-01

The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

Neoplastic meningitis: a retrospective review of clinical presentations, radiological and cerebrospinal fluid findings.

Science.gov (United States)

Jearanaisilp, Sorrawit; Sangruji, Tumthip; Danchaivijitr, Chotipat; Danchaivijitr, Nasuda

2014-08-01

To review the clinical, radiological, and laboratory presentations of patients with neoplastic meningitis. Patients with neoplastic meningitis were recruited by a retrospective search of cerebrospinal fluid (CSF) cytopathological report database of Siriraj Hospital between 1997 and 2006. Clinical information and CSF result of these patients were extracted from their medical records. Neuroimagings were reviewed by a neuroradiologist. The present study revealed 40 cases of neoplastic meningitis, which comprised of 17 cases with carcinomatous meningitis (CM) and 23 lymphoma/leukemia meningitis (LM) cases. In patients with CM, the majority (70%) had adenocarcinoma of lung or breast. Three of 17 cases with unknown primary tumor had carcinomatous meningitis as an initial presentation. In LM most of the cases (70%) were diagnosed with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The most common symptom among patients with CM and LM was headache follow by cranial nerve palsy. In CM cases, CSF cytology was positive in the first specimen in 15 cases (82.35%) and in 22 from 23 cases (95.7%) in LM cases. Overall CSF showed pleocytosis in 36 cases (90%), most of which were lymphocyte predominant. The most common findings from brain imagings were leptomeningeal enhancement and hydrocephalus. The common primary sites were lung and breast cancer in the CM group and ALL and NHL in the LM group. The common symptoms were headache and cranial nerve palsy. Routine CSF examination was abnormal in virtually all cases. Positive CSF cytology was a gold standard for a diagnosis of leptomeningeal metastasis. High index of suspicious and awareness were required to avoid miss diagnosis.

Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency

NARCIS (Netherlands)

Wang, Mi; Subramanian, Manikandan; Abramowicz, Sandra; Murphy, Andrew J.; Gonen, Ayelet; Witztum, Joseph; Welch, Carrie; Tabas, Ira; Westerterp, Marit; Tall, Alan R.

2014-01-01

Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE(-/-) mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the

Nuclear Division Index may Predict Neoplastic Colorectal Lesions.

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Ionescu, Mirela E; Ciocirlan, Mihai; Becheanu, Gabriel; Nicolaie, Tudor; Ditescu, Cristina; Teiusanu, Adriana G; Gologan, Serban I; Arbanas, Tudor; Diculescu, Mircea M

2011-07-01

Colorectal cancer (CRC) develops by accumulation of multiple genetic damages leading to genetic instability that can be evaluated by cytogenetic methods. In the current study we used Cytokinesis-Blocked Micronucleus Assay (CBMN) technique to assess the behavior of Nuclear Division Index(NDI) in peripheral lymphocytes of patients with CRC and polyps versus patients with normal colonoscopy. Blood samples were collected from patients after informed consent. By CBMN technique we assessed the proportion of mono-nucleated, bi-nucleated, tri-nucleated and tetra-nucleated cells/500 cells, to calculate NDI. Data were statistically analyzed using the SPSS 11.0 package. 45 patients were available for analysis, 23 men and 22 women, with a mean age of 58.7±13.5. 17 had normal colonoscopy, 17 colonic polyps and 11 CRC. The mean NDI values were significantly smaller for patients with CRC or polyps than in patients with normal colonoscopy (1.57 vs 1.73, p=0.013). The difference persisted for patients with neoplastic lesions (adenomas and carcinomas) when compared with patients with normal colonoscopy or non neoplastic (hyperplastic) polyps (1.56 vs.1.71, p=0.018). The NDI cut-off value to predict the presence of adenomas or carcinomas was equal to 1.55 with a 54.2% sensitivity and 81% specificity of lower values (p=0.019). The NDI cut off value to predict the presence of advanced adenomas or cancer was 1.525 for a sensitivity of 56.3% and a specificity of 82.8% (p=0.048). NDI may be useful in screening strategies for colorectal cancer as simple, noninvasive, inexpensive cytogenetic biomarker.

2-[(aminopropyl)amino]ethanethiol (WR1065) is anti-neoplastic and anti-mutagenic when given during 60Coγ-ray irradiation

International Nuclear Information System (INIS)

Hill, C.K.; Nagy, B.; Peraino, C.; Grdina, D.

1986-01-01

The effect of 2[(aminopropyl)amino]ethanethiol (WR1065) has been studied on the induction of neoplastic transformation using 10T1/2 cells and on mutation of the hypoxanthine guanine phosphoribosyl transferase (HGPRT) locus using Chinese hamster V79 cells. The first observations that treatment of 10T1/2 cells with 1 mM WR1065 for a total of 35 min during irradiation with 60 C γ-rays significantly reduces the incidence of neoplastic transformation while having no effect on cell viability are reported. In a similar experiment with V79 cells in which 4mM WR1065 was used, a significant reduction in mutation frequency at the HGPRT locus and significant protection against cell killing was found. These results suggest that WR1965 acts to modulate both acute damage and sub-lethal processes that lead to mutation and neoplastic transformation. Beyond the purely mechanistic approach of these studies, the potential application of these agents to minimizing the long-term neoplastic effects of radiation or chemotherapeutic agents currently in use for treating potentially curable cancer patients should be further investigated. (author)

Adenocarcinoma of the rete testis with prominent papillary structure and clear neoplastic cells: Morphologic and immunohistochemical findings and differential diagnosis

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Pei-Wen Huang

2015-01-01

Full Text Available Adenocarcinoma of the rete testis is rare, and its etiology is unknown. The definite diagnosis merely depends on the exclusion of other tumors and histological features. We first describe a 38-year-old man with a carcinoma arising in the rete testis. The tumor was characterized by clear neoplastic cells and branching papillary growth. Focal stromal invasion and transition of normal rete epithelium to neoplastic cells were seen. The neoplastic cells were positive for epithelial membrane antigen, Ber-Ep4, vimentin, renal cell carcinoma marker, and CD10, while negative for Wilms′ tumor 1, thyroid transcription factor-1, estrogen receptor, prostate specific antigen, placental alkaline phosphate, CD117, and alpha-1-fetoprotein. According to the above features, we diagnosed this tumor as adenocarcinoma of the rete testis. To our best knowledge, this is the first reported case of adenocarcinoma of the rete testis with prominently papillary structure and clear neoplastic cells. The rarity of adenocarcinoma of the rete testis and the unique features in our case cause diagnostic pitfalls. A complete clinicopathological study and thorough differential diagnosis are crucial for the correct result.

Hematopoietic stem cell origin of connective tissues.

Science.gov (United States)

Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

2010-07-01

Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications. Copyright 2010 ISEH - Society for Hematology and Stem Cells. All rights reserved.

Proteomic cornerstones of hematopoietic stem cell differentiation

DEFF Research Database (Denmark)

Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon

2012-01-01

Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors...... which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem....../progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5,000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical...

The slippery slope of hematopoietic stem cell aging.

Science.gov (United States)

Wahlestedt, Martin; Bryder, David

2017-12-01

The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age. However, the recent realization that not all HSCs are alike with regard to fundamental stem cell properties such as self-renewal and lineage potential has several implications for HSC aging, including the synchrony and the stability of the aging HSC state. To approach HSC aging from a clonal perspective, we recently took advantage of technical developments in cellular barcoding and combined this with the derivation of induced pluripotent stem cells (iPSCs). This allowed us to selectively approach HSCs functionally affected by age. The finding that such iPSCs were capable of fully regenerating multilineage hematopoiesis upon morula/blastocyst complementation provides compelling evidence that many aspects of HSC aging can be reversed, which indicates that a central mechanism underlying HSC aging is a failure to uphold the epigenomes associated with younger age. Here we discuss these findings in the context of the underlying causes that might influence HSC aging and the requirements and prospects for restoration of the aging HSC epigenome. Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Analysis and manipulation of hematopoietic progenitor and stem cells from murine embryonic tissues

NARCIS (Netherlands)

A. Medvinsky (Alexander); S. Taoudi (Samir); S.C. Mendes (Sandra); E.A. Dzierzak (Elaine)

2008-01-01

textabstractHematopoietic development begins in several locations in the mammalian embryo: yolk sac, aorta-gonad-mesonephros region (AGM), and the chorio-allantoic placenta. Generation of the most potent cells, adult definitive hematopoietic stem cells (HSCs), occurs within the body of the mouse

A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors.

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Akira Niwa

Full Text Available Elucidating the in vitro differentiation of human embryonic stem (ES and induced pluripotent stem (iPS cells is important for understanding both normal and pathological hematopoietic development in vivo. For this purpose, a robust and simple hematopoietic differentiation system that can faithfully trace in vivo hematopoiesis is necessary. In this study, we established a novel serum-free monolayer culture that can trace the in vivo hematopoietic pathway from ES/iPS cells to functional definitive blood cells via mesodermal progenitors. Stepwise tuning of exogenous cytokine cocktails induced the hematopoietic mesodermal progenitors via primitive streak cells. These progenitors were then differentiated into various cell lineages depending on the hematopoietic cytokines present. Moreover, single cell deposition assay revealed that common bipotential hemoangiogenic progenitors were induced in our culture. Our system provides a new, robust, and simple method for investigating the mechanisms of mesodermal and hematopoietic differentiation.

Stem cell therapy for inflammatory bowel disease

OpenAIRE

Duijvestein, Marjolijn

2012-01-01

Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal antigens. MSCs have the capacity to differentiate into a wide variety of distinct cell lineages and to suppress immune responses in vitro and in vivo. The main goal of this thesis was to study the s...

OP9-Lhx2 stromal cells facilitate derivation of hematopoietic progenitors both in vitro and in vivo

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Xiaoli Chen

2015-09-01

Full Text Available Generating engraftable hematopoietic stem cells (HSCs from pluripotent stem cells (PSCs is an ideal approach for obtaining induced HSCs for cell therapy. However, the path from PSCs to robustly induced HSCs (iHSCs in vitro remains elusive. We hypothesize that the modification of hematopoietic niche cells by transcription factors facilitates the derivation of induced HSCs from PSCs. The Lhx2 transcription factor is expressed in fetal liver stromal cells but not in fetal blood cells. Knocking out Lhx2 leads to a fetal hematopoietic defect in a cell non-autonomous role. In this study, we demonstrate that the ectopic expression of Lhx2 in OP9 cells (OP9-Lhx2 accelerates the hematopoietic differentiation of PSCs. OP9-Lhx2 significantly increased the yields of hematopoietic progenitor cells via co-culture with PSCs in vitro. Interestingly, the co-injection of OP9-Lhx2 and PSCs into immune deficient mice also increased the proportion of hematopoietic progenitors via the formation of teratomas. The transplantation of phenotypic HSCs from OP9-Lhx2 teratomas but not from the OP9 control supported a transient repopulating capability. The upregulation of Apln gene by Lhx2 is correlated to the hematopoietic commitment property of OP9-Lhx2. Furthermore, the enforced expression of Apln in OP9 cells significantly increased the hematopoietic differentiation of PSCs. These results indicate that OP9-Lhx2 is a good cell line for regeneration of hematopoietic progenitors both in vitro and in vivo.

Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

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Christine Richardson

2015-01-01

Full Text Available Reactive oxygen species (ROS can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.

Lysosomal cross-correction by hematopoietic stem cell-derived macrophages via tunneling nanotubes

Science.gov (United States)

Naphade, Swati; Sharma, Jay; Chevronnay, Héloïse P. Gaide; Shook, Michael A.; Yeagy, Brian A.; Rocca, Celine J.; Ur, Sarah N.; Lau, Athena J.; Courtoy, Pierre J.; Cherqui, Stephanie

2014-01-01

Despite controversies on the potential of hematopoietic stem cells (HSCs) to promote tissue repair, we previously showed that HSC transplantation could correct cystinosis, a multi-systemic lysosomal storage disease, caused by a defective lysosomal membrane cystine transporter, cystinosin (CTNS). Addressing the cellular mechanisms, we here report vesicular cross-correction after HSC differentiation into macrophages. Upon co-culture with cystinotic fibroblasts, macrophages produced tunneling nanotubes (TNTs) allowing transfer of cystinosin-bearing lysosomes into Ctns-deficient cells, which exploited the same route to retrogradely transfer cystine-loaded lysosomes to macrophages, providing a bidirectional correction mechanism. TNT formation was enhanced by contact with diseased cells. In vivo, HSCs grafted to cystinotic kidneys also generated nanotubular extensions resembling invadopodia that crossed the dense basement membranes and delivered cystinosin into diseased proximal tubular cells. This is the first report of correction of a genetic lysosomal defect by bidirectional vesicular exchange via TNTs and suggests broader potential for HSC transplantation for other disorders due to defective vesicular proteins. PMID:25186209

Osteoblastic and Vascular Endothelial Niches, Their Control on Normal Hematopoietic Stem Cells, and Their Consequences on the Development of Leukemia

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Bella S. Guerrouahen

2011-01-01

Full Text Available Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called “niches.” The best-characterized stem cell is the hematopoietic stem cell (HSC. Self-renewal and differentiation ability of HSC are regulated by two major elements: endosteal and vascular regulatory elements. The osteoblastic niche localized at the inner surface of the bone cavity might serve as a reservoir for long-term HSC storage in a quiescent state. Whereas the vascular niche, which consists of sinusoidal endothelial cell lining blood vessel, provides an environment for short-term HSC proliferation and differentiation. Both niches act together to maintain hematopoietic homeostasis. In this paper, we provide some principles applying to the hematopoietic niches, which will be useful in the study and understanding of other stem cell niches. We will discuss altered microenvironment signaling leading to myeloid lineage disease. And finally, we will review some data on the development of acute myeloid leukemia from a subpopulation called leukemia-initiating cells (LIC, and we will discuss on the emerging evidences supporting the influence of the microenvironment on chemotherapy resistance.

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.

Science.gov (United States)

Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D Wade; Yang, Feng-Chun

2017-06-01

Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

Flotillins are involved in the polarization of primitive and mature hematopoietic cells.

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Lawrence Rajendran

Full Text Available BACKGROUND: Migration of mature and immature leukocytes in response to chemokines is not only essential during inflammation and host defense, but also during development of the hematopoietic system. Many molecules implicated in migratory polarity show uniform cellular distribution under non-activated conditions, but acquire a polarized localization upon exposure to migratory cues. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present evidence that raft-associated endocytic proteins (flotillins are pre-assembled in lymphoid, myeloid and primitive hematopoietic cells and accumulate in the uropod during migration. Furthermore, flotillins display a polarized distribution during immunological synapse formation. Employing the membrane lipid-order sensitive probe Laurdan, we show that flotillin accumulation in the immunological synapse is concomittant with membrane ordering in these regions. CONCLUSIONS: Together with the observation that flotillin polarization does not occur in other polarized cell types such as polarized epithelial cells, our results suggest a specific role for flotillins in hematopoietic cell polarization. Based on our results, we propose that in hematopoietic cells, flotillins provide intrinsic cues that govern segregation of certain microdomain-associated molecules during immune cell polarization.

The many faces of hematopoietic stem cell heterogeneity

Science.gov (United States)

2016-01-01

Not all hematopoietic stem cells (HSCs) are alike. They differ in their physical characteristics such as cell cycle status and cell surface marker phenotype, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. The growing body of evidence that supports heterogeneity within HSCs, which constitute the most robust cell fraction at the foundation of the adult hematopoietic system, is currently of great interest and raises questions as to why HSC subtypes exist, how they are generated and whether HSC heterogeneity affects leukemogenesis or treatment options. This Review provides a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity. PMID:27965438

The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

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Xiaoying Zhou

2015-07-01

Full Text Available Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx. Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

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Yi Liu

2017-04-01

Full Text Available Summary: Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC function. Latexin (Lxn is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit. : In this article, Liang and colleagues show that loss of latexin in vivo expands the HSC population and increases their survival and engraftment. Latexin regulates HSC function and hematopoiesis via the Thbs1 signaling pathway. Keywords: latexin, hematopoietic stem cell, repopulating advantage, expansion, survival, thrombospondin 1

Defibrotide for the prevention of hepatic veno-occlusive disease after hematopoietic stem cell transplantation: a systematic review.

Science.gov (United States)

Zhang, Lifei; Wang, Yebo; Huang, He

2012-01-01

Prophylactic use of defibrotide (DF) to prevent veno-occlusive disease (VOD), a relatively common and high-risk complication of hematopoietic stem cell transplantation (HSCT), may be an encouraging modality to reduce morbidity and mortality from VOD. However, conclusions remain unclear. We carried out a systematic review to summarize the state of knowledge. One randomized controlled trial (RCT), four cohort studies and eight case series studies were found, including a total of 1230 patients. The overall mean incidence of VOD in patients using DF was 4.7% (95% CI, 3.3-6.1) which was significantly lower than the data 13.7% (95% CI, 13.3-14.1) across 135 studies using no VOD prophylaxis (p < 0.005). The meta-analysis of the incidence of VOD in controlled trials revealed a statistical reduction in VOD incidence in the DF group (RR = 0.47, 95% CI, 0.31-0.73). The overall mean incidence of severe VOD was 0.8% (95% CI, 0.2-1.4). The RR was 0.31 (95% CI, 0.09-1.06). However, the lack of RCTs and the methodological weaknesses of the studies may preclude making generalizable conclusions. Our review described that DF appears promising for VOD prevention and large RCT is needed for further confirmation. © 2012 John Wiley & Sons A/S.

Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: Successful engraftment and mild GVHD

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Wu Yamei

2014-01-01

Full Text Available Haploidentical hematopoietic stem-cell transplantation (haplo-HSCT is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD. Mesenchymal stromal cells (MSCs have been shown to support in vivo normal hematopoiesis and to display potent immunesuppressive effects. We cotransplanted the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs in 21 young people with severe aplastic anemia (SAA undergoing haplo-HSCT without T-cell-depleted. We observed that all patients had sustained hematopoietic engraftment without any adverse UC-MSC infusion-related events. Furthermore, we did not observe any increase in severe aGVHD. These data suggest that UC-MSCs, possibly thanks to their potent immunosuppressive effect on allo-reactive host T lymphocytes escaping the preparative regimen, reduce the risk of graft failure and severe GVHD in haplo-HSCT.

Recent advances in hematopoietic stem cell biology

DEFF Research Database (Denmark)

Bonde, Jesper; Hess, David A; Nolta, Jan A

2004-01-01

PURPOSE OF REVIEW: Exciting advances have been made in the field of hematopoietic stem cell biology during the past year. This review summarizes recent progress in the identification, culture, and in vivo tracking of hematopoietic stem cells. RECENT FINDINGS: The roles of Wnt and Notch proteins...... in regulating stem cell renewal in the microenvironment, and how these molecules can be exploited in ex vivo stem cell culture, are reviewed. The importance of identification of stem cells using functional as well as phenotypic markers is discussed. The novel field of nanotechnology is then discussed...... in the context of stem cell tracking in vivo. This review concludes with a section on the unexpected potential of bone marrow-derived stem cells to contribute to the repair of damaged tissues. The contribution of cell fusion to explain the latter phenomenon is discussed. SUMMARY: Because of exciting discoveries...

Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review.

Science.gov (United States)

Pollack, Seth M; O'Connor, Thomas P; Hashash, Jana; Tabbara, Imad A

2009-12-01

Allogeneic hematopoietic stem cell transplantation provides many patients, with hematological and malignant diseases, hope of remission and in some cases cure. Because the toxicities of this approach are severe, its use has been limited to younger healthier patients. Nonmyeloablative and reduced intensity conditioning regimens depend more on donor cellular immune effects and less on the cytotoxic effects of the conditioning regimen to eradicate the underlying disease. This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocytes infusions. Accumulated clinical data have been encouraging, and prospective studies are underway to compare this approach to conventional myeloablative allogeneic stem cell transplantation with regard to outcome, durability of responses, effects on the immune system, and the consequences of late complications such as chronic graft-versus-host disease.

Hematopoietic stem cell development requires transient Wnt/β-catenin activity

DEFF Research Database (Denmark)

Ruiz-Herguido, Cristina; Guiu, Jordi; D'Altri, Teresa

2012-01-01

in the aorta-gonad-mesonephros (AGM) region. We show here that β-catenin is nuclear and active in few endothelial nonhematopoietic cells closely associated with the emerging hematopoietic clusters of the embryonic aorta during mouse development. Importantly, Wnt/β-catenin activity is transiently required...... of mutant cells toward the hematopoietic lineage; however, these mutant cells still contribute to the adult endothelium. Together, those findings indicate that Wnt/β-catenin activity is needed for the emergence but not the maintenance of HSCs in mouse embryos....

Role of nuclear medicine in pulmonary neoplastic processes

International Nuclear Information System (INIS)

Waxman, A.D.

1986-01-01

It has been demonstrated that the single most important factor in determining survival in patients with bronchogenic carcinoma is the extent of spread of metastasis from the primary lesion. This explains the extensive efforts in developing accurate staging tests for pulmonary tumors, both primary and metastatic, with special emphasis on the determination of pulmonary hilar and mediastinal spread of disease. Continued improvements in nuclear medicine instrumentation along with the development of tumor specific radiopharmaceuticals, as well as agents that have the capability of tracking tumor viability, have changed the orientation of scintigraphic techniques in the evaluation of pulmonary neoplastic processes. Gallium scintigraphy is no longer considered as a primary imaging modality in the staging of pulmonary tumors, and in most institutions has been replaced by computed tomography (CT) for this purpose. It has been demonstrated that gallium, relative to other imaging modalities, is a sensitive indicator of hilar spread of tumor. However, because of the normally high background activity within the sternum and spine, mediastinal abnormalities are poorly detected. Since most pulmonary tumors metastasize via regional nodes to the pulmonary hilum and then to the mediastinum, the high sensitivity for the detection of pulmonary hilar abnormalities and the high specificity for mediastinal lesion detection suggest that gallium scintigraphy is a valuable adjunctive test when used appropriately. Thallium 201 as a tumor agent is being studied by several institutions. Preliminary results indicate a high degree of sensitivity for the detection of pulmonary hilar and mediastinal lesions and there are early indications that thallium is a promising agent to evaluate tumor viability. 52 references

Gastric diffuse large B cell lymphoma presenting as para neoplastic cerebellar degeneration: Case report and review of literature

International Nuclear Information System (INIS)

Lakshmaiah, K.C.; Viveka, B.K.; Kumar, N.A.; Saini, M.L.; Sinha, S.; Saini, K.S.

2013-01-01

Para neoplastic cerebellar degeneration (PCD) is a type of para neoplastic neurological disorder (PND) that is associated with many solid tumors, Hodgkins lymphoma (HL) and very rarely with non-Hodgkin lymphoma (NHL). We report a case of PCD associated with gastric diffuse large B-cell lymphoma (DLBCL) in a patient who presented with acute onset of giddiness and double vision and had complete remission of the gastric lesion and marked improvement of cerebellar syndrome with rituximab-based combination chemotherapy. A brief review of the literature is also presented.

Use of transfer learning to detect diffuse degenerative hepatic diseases from ultrasound images in dogs: A methodological study.

Science.gov (United States)

Banzato, T; Bonsembiante, F; Aresu, L; Gelain, M E; Burti, S; Zotti, A

2018-03-01

The aim of this methodological study was to develop a deep convolutional neural network (DNN) to detect degenerative hepatic disease from ultrasound images of the liver in dogs and to compare the diagnostic accuracy of the newly developed DNN with that of serum biochemistry and cytology on the same samples, using histopathology as a standard. Dogs with suspected hepatic disease that had no prior history of neoplastic disease, no hepatic nodular pathology, no ascites and ultrasonography performed 24h prior to death were included in the study (n=52). Ultrasonography and serum biochemistry were performed as part of the routine clinical evaluation. On the basis of histopathology, dogs were categorised as 'normal' (n=8), or having 'vascular abnormalities'(n=8), or 'inflammatory'(n=0), 'neoplastic' (n=4) or 'degenerative'(n=32) disease; dogs with 'neoplastic' disease were excluded from further analysis. On cytological evaluation, dogs were categorised as 'normal' (n=11), or having 'inflammatory' (n=0), 'neoplastic' (n=4) or 'degenerative' (n=37) disease. Dogs were categorised as having 'degenerative' (n=32) or 'non-degenerative' (n=16) liver disease for analysis due to the limited sample size. The DNN was developed using a transfer learning methodology on a pre-trained neural network that was retrained and fine-tuned to our data set. The resultant DNN had a high diagnostic accuracy for degenerative liver disease (area under the curve 0.91; sensitivity 100%; specificity 82.8%). Cytology and serum biochemical markers (alanine transaminase and aspartate transaminase) had poor diagnostic accuracy in the detection of degenerative liver disease. The DNN outperformed all the other non-invasive diagnostic tests in the detection of degenerative liver disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: cytological and histopathological assessment

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Leão João

2010-09-01

Full Text Available Abstract Backgroud Extramedullary hematopoiesis (EMH is defined as the presence of hematopoietic stem cells such as erythroid and myeloid lineage plus megakaryocytes in extramedullary sites like liver, spleen and lymph nodes and is usually associated with either bone marrow or hematological disorders. Mammary EMH is a rare condition either in human and veterinary medicine and can be associated with benign mixed mammary tumors, similarly to that described in this case. Case presentation Hematopoietic stem cells were found in a benign mixed mammary tumor of a 7-year-old female mongrel dog that presents a nodule in the left inguinal mammary gland. The patient did not have any hematological abnormalities. Cytological evaluation demonstrated two distinct cell populations, composed of either epithelial or mesenchymal cells, sometimes associated with a fibrillar acidophilic matrix, apart from megakaryocytes, osteoclasts, metarubricytes, prorubricytes, rubricytes, rubriblasts, promyelocytes, myeloblasts. Histological examination confirmed the presence of an active hematopoietic bone marrow within the bone tissue of a benign mammary mixed tumor. Conclusions EMH is a rare condition described in veterinary medicine that can be associated with mammary mixed tumors. It's detection can be associated with several neoplastic and non-neoplastic mammary lesions, i.e. osteosarcomas, mixed tumors and bone metaplasia.

Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Science.gov (United States)

Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

2016-01-01

The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

Late non-infectious lung damage in children after allogeneic hematopoietic stem cells transplantation

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Yu. V. Skvortsova

2015-06-01

Full Text Available Hematopoietic stem cells transplantation (HSCT technology currently allows curing a lot of malignant and non-malignant diseases in adults and children. However, HSCT is highly toxic treatment. HSCT complications include the possibility of prolonged immunodeficiency, alloand autoimmune reactions and various organs dysfunction. These conditions require careful monitoring by specialists, early diagnosis and appropriate treatment. This article discusses the clinical features, diagnosis and treatment options of such late complications as non-infectious lung disease. These conditions can lead to disability of patients. Relevance and importance of timely diagnosis of these pathological conditions, including the range of clinical tests available on a residence, with a view to effective treatment can improve the quality of life ofchildren with complications after HSCT. Theoretical issues are illustrated by case report.

Angelica Sinensis Polysaccharide Prevents Hematopoietic Stem Cells Senescence in D-Galactose-Induced Aging Mouse Model

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Xinyi Mu

2017-01-01

Full Text Available Age-related regression in hematopoietic stem/progenitor cells (HSC/HPCs limits replenishment of the blood and immune system and hence contributes to hematopoietic diseases and declined immunity. In this study, we employed D-gal-induced aging mouse model and observed the antiaging effects of Angelica Sinensis Polysaccharide (ASP, a major active ingredient in dong quai (Chinese Angelica Sinensis, on the Sca-1+ HSC/HPCs in vivo. ASP treatment prevents HSC/HPCs senescence with decreased AGEs levels in the serum, reduced SA-β-Gal positive cells, and promoted CFU-Mix formation in the D-gal administrated mouse. We further found that multiple mechanisms were involved: (1 ASP treatment prevented oxidative damage as total antioxidant capacity was increased and levels of reactive oxygen species (ROS, 8-OHdG, and 4-HNE were declined, (2 ASP reduced the expression of γ-H2A.X which is a DNA double strand breaks (DSBs marker and decreased the subsequent ectopic expressions of effectors in p16Ink4a-RB and p19Arf-p21Cip1/Waf senescent pathways, and (3 ASP inhibited the excessive activation of Wnt/β-catenin signaling in aged HSC/HPCs, as the expressions of β-catenin, phospho-GSK-3β, and TCF-4 were decreased, and the cyto-nuclear translocation of β-catenin was inhibited. Moreover, compared with the positive control of Vitamin E, ASP exhibited a better antiaging effect and a weaker antioxidation ability, suggesting a novel protective role of ASP in the hematopoietic system.

Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells.

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Yulan Qing

Full Text Available Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs, creating a preleukemic stem cell (PLSC. Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC. Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM, but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.

Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

NARCIS (Netherlands)

Jokubaitis, Vanta J.; Sinka, Lidia; Driessen, Rebecca; Whitty, Genevieve; Haylock, David N.; Bertoncello, Ivan; Smith, Ian; Peault, Bruno; Tavian, Manuela; Simmons, Paul J.

2008-01-01

Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map B89 expression throughout hernatopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and

Compton scattering spectrum as a source of information of normal and neoplastic breast tissues' composition

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Antoniassi, M.; Conceicao, A.L.C. [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 14040-901 Sao Paulo (Brazil); Poletti, M.E., E-mail: poletti@ffclrp.usp.br [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 14040-901 Sao Paulo (Brazil)

2012-07-15

In this work we measured X-ray scatter spectra from normal and neoplastic breast tissues using photon energy of 17.44 keV and a scattering angle of 90 Degree-Sign , in order to study the shape (FWHM) of the Compton peaks. The obtained results for FWHM were discussed in terms of composition and histological characteristics of each tissue type. The statistical analysis shows that the distribution of FWHM of normal adipose breast tissue clearly differs from all other investigated tissues. Comparison between experimental values of FWHM and effective atomic number revealed a strong correlation between them, showing that the FWHM values can be used to provide information about elemental composition of the tissues. - Highlights: Black-Right-Pointing-Pointer X-ray scatter spectra from normal and neoplastic breast tissues were measured. Black-Right-Pointing-Pointer Shape (FWHM) of Compton peak was related with elemental composition and characteristics of each tissue type. Black-Right-Pointing-Pointer A statistical hypothesis test showed clear differences between normal and neoplastic breast tissues. Black-Right-Pointing-Pointer There is a strong correlation between experimental values of FWHM and effective atomic number. Black-Right-Pointing-Pointer Shape (FWHM) of Compton peak can be used to provide information about elemental composition of the tissues.

Risk of Hematopoietic and Lymphoproliferative Malignancies among U. S. Radiologic Technologists

International Nuclear Information System (INIS)

Linet, M. S.; Fredman, D. M.; Mohan, A.; Morin Doody, M.; Ron, E.; Mabuchi, K.; Alexander, B. B.; Sigurdson, A.; Matanoski, G.; Hauptmann, M.

2004-01-01

To evaluate risks of hematopoietic and lymphoproliferative malignancies among medical workers exposed to protracted low-to-moderate-dose radiation exposures, a follow-up investigation was conducted in a nation wide cohort of U. S. radiologic technologists. eligible for this study were 71.894 technologists (78% female) certified for at least 2 years during 1926-82, who had responded to a baseline mail questionnaire during 1983-89, were cancer-free except for non-melanoma skin cancer at completion of the questionnaire, and completed a second questionnaire during 1994-98 or died through August 1998. There were 241 technologists with hematopoietic or lymphoproliferative malignancies, including 41 with leukemia subtypes associated with radiation exposures (specifically acute myeloid, acute lymphoid and chronic myeloid leukemias, hereafter designated radiogenic leukemias), 23 with chronic lymphocytic leukemia, 28 with multiple myeloma, 118 with non-Hodgkin lymphoma, and 31 with Hodgkin lymphoma. Of the 241 hematopoietic or lymphoproliferative malignancies identified among radiologic technologists, 85 percent were confirmed by medical records or death certificates, including 98 percent of radiogenic leukemia. Risks of the hematopoietic or lymphoproliferative malignancies were evaluated in relation to questionnaire-derived information on employment as a radiologic technologist, including procedures, work practices, and protective measures. cox proportional hazards regression analysis was used to compute relative risks and 95% confidence intervals, using age at diagnosis as the response, stratifying at baseline for birth cohort in 5-year intervals, and adjusting for potential confounding. Risks were not increased for any of the hematopoietic or lymphoproliferative neoplasms according to year first worked or total duration of years worked as radiologic technologist. For the combined radiogenic leukemias, risks rose significantly with an increasing number of years worked

Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.

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Tamura, Shinichi; Imamura, Toshihiko; Urata, Takayo; Kobayashi, Miki; Gen, Mari; Tomii, Toshihiro; Do, Junko; Osone, Shinya; Ishida, Hiroyuki; Hosoi, Hajime; Kuroda, Hiroshi

2017-10-01

Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.

Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy.

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Kohn, Donald B

2017-10-01

Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials. Copyright © 2017 Elsevier Inc. All rights reserved.

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

NARCIS (Netherlands)

van Pel, M; van Os, R; Velders, GA; Hagoort, H; Heegaard, PMH; Lindley, IJD; Willemze, R; Fibbe, WE

2006-01-01

Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

DEFF Research Database (Denmark)

van Pel, M.; van Os, R.; Velders, G.A.

2006-01-01

Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulat...

The Hematopoietic Stem Cell Therapy for Exploration of Space

Science.gov (United States)

Ohi, S.

Departments of Biochemistry &Molecular Biology, Genetics &Human Genetics, Pediatrics &Child Long-duration space missions require countermeasures against severe/invasive disorders in astronauts that are caused by space environments, such as hematological/cardiac abnormalities, bone/muscle losses, immunodeficiency, neurological disorders, and cancer. Some, if not all, of these disorders may be amenable to hematopoietic stem cell therapy and gene therapy. Growing evidence indicates that hematopoietic stem cells (HSCs) possess extraordinary plasticity to differentiate not only to all types of blood cells but also to various tissues, including bone, muscle, skin, liver and neuronal cells. Therefore, our working hypothesis is that the hematopoietic stem cell-based therapy, herein called as the hematopoietic stem cell therapy (HSCT), might provide countermeasure/prevention for hematological abnormalities, bone and muscle losses in space, thereby maintaining astronauts' homeostasis. Our expertise lies in recombinant adeno-associated virus (rAAV)-mediated gene therapy for the hemoglobinopathies, -thalassemia and sickle cell disease (Ohi S, Kim BC, J Pharm Sci 85: 274-281, 1996; Ohi S, et al. Grav Space Biol Bull 14: 43, 2000). As the requisite steps in this protocol, we established procedures for purification of HSCs from both mouse and human bone marrow in 1 G. Furthermore, we developed an easily harvestable, long-term liquid suspension culture system, which lasts more than one year, for growing/expanding HSCs without stromal cells. Human globin cDNAs/gene were efficiently expressed from the rAAVs in the mouse HSCs in culture. Additionally, the NASA Rotating Wall Vessel (RWV) culture system is being optimized for the HSC growth/expansion. Thus, using these technologies, the above hypothesis is being investigated by the ground-based experiments as follows: 1) -thalassemic mice (C57BL/6-Hbbth/Hbbth, Hbd-minor) are transplanted with normal isologous HSCs to correct the

Cellular memory and, hematopoietic stem cell aging

NARCIS (Netherlands)

Kamminga, Leonie M.; de Haan, Gerald

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

Hematopoietic stem cell transplantation in multiple sclerosis

DEFF Research Database (Denmark)

Rogojan, C; Frederiksen, J L

2009-01-01

Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least...

Human hematopoietic cell culture, transduction, and analyses

DEFF Research Database (Denmark)

Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B

2008-01-01

This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long-te...

Functional analysis of human hematopoietic stem cell gene expression using zebrafish.

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2005-08-01

Full Text Available Although several reports have characterized the hematopoietic stem cell (HSC transcriptome, the roles of HSC-specific genes in hematopoiesis remain elusive. To identify candidate regulators of HSC fate decisions, we compared the transcriptome of human umbilical cord blood and bone marrow (CD34+(CD33-(CD38-Rho(lo(c-kit+ cells, enriched for hematopoietic stem/progenitor cells with (CD34+(CD33-(CD38-Rho(hi cells, enriched in committed progenitors. We identified 277 differentially expressed transcripts conserved in these ontogenically distinct cell sources. We next performed a morpholino antisense oligonucleotide (MO-based functional screen in zebrafish to determine the hematopoietic function of 61 genes that had no previously known function in HSC biology and for which a likely zebrafish ortholog could be identified. MO knock down of 14/61 (23% of the differentially expressed transcripts resulted in hematopoietic defects in developing zebrafish embryos, as demonstrated by altered levels of circulating blood cells at 30 and 48 h postfertilization and subsequently confirmed by quantitative RT-PCR for erythroid-specific hbae1 and myeloid-specific lcp1 transcripts. Recapitulating the knockdown phenotype using a second MO of independent sequence, absence of the phenotype using a mismatched MO sequence, and rescue of the phenotype by cDNA-based overexpression of the targeted transcript for zebrafish spry4 confirmed the specificity of MO targeting in this system. Further characterization of the spry4-deficient zebrafish embryos demonstrated that hematopoietic defects were not due to more widespread defects in the mesodermal development, and therefore represented primary defects in HSC specification, proliferation, and/or differentiation. Overall, this high-throughput screen for the functional validation of differentially expressed genes using a zebrafish model of hematopoiesis represents a major step toward obtaining meaningful information from global

Veno-Occlusive Disease of the Liver in the Absence of Elevation in Bilirubin in Pediatric Patients after Hematopoietic Stem Cell Transplantation

Science.gov (United States)

Myers, Kasiani C.; Dandoy, Christopher; El-Bietar, Javier; Davies, Stella M.; Jodele, Sonata

2016-01-01

Veno-occlusive disease (VOD) of the liver is a well-described and significant complication of hematopoietic stem cell transplantation (HSCT), with limited successful therapeutic options in severe cases. Prompt diagnosis and initiation of treatment is crucial to restrict the extent of disease. However, a subset of patients may not meet all current diagnostic criteria at presentation, and waiting for these to be met may delay therapy. We retrospectively reviewed 794 HSCT patients treated at our institution between 2003 and 2013, identifying 17 (2.1%) who developed VOD. Of these, 5 (29%) were noted to have an absence of elevated bilirubin at the time of VOD diagnosis and reversal of portal venous flow on ultrasound. Median total and conjugated bilirubin at VOD diagnosis were 1.0 and 0.2 mg/dL, respectively. All 5 patients were subsequently diagnosed with multiorgan failure associated with VOD, including 1 with encephalopathy. Four were treated with intravenous high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for 6 doses). One patient received defibrotide therapy in addition to steroids and another supportive care alone. VOD resolved in 4 of 5 patients, with median time to resolution of VOD, defined as recovery of all organ function and normalization of bilirubin and portal venous flow, of 8 days. Two patients died later from progressive primary disease and chronic graft-versus-host disease, respectively. We conclude that a high index of suspicion for VOD should be maintained in patients despite lack of bilirubin elevation in the presence of other diagnostic criteria such as hepatomegaly, abdominal pain, ascites, or weight gain. Early ultrasound evaluation in these patients may lead to more timely diagnosis and therapeutic interventions. PMID:25300869

Proliferative capacity of murine hematopoietic stem cells

International Nuclear Information System (INIS)

Hellman, S.; Botnick, L.E.; Hannon, E.C.; Vigneulle, R.M.

1978-01-01

The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferatively quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cells progress in the continuum in one direction and such progression is not reversible

Fine-tuning Hematopoiesis: Microenvironmental factors regulating self-renewal and differentiation of hematopoietic stem cells

NARCIS (Netherlands)

T.C. Luis (Tiago)

2010-01-01

markdownabstract__Abstract__ Hematopoietic stem cells (HSCs) have the ability to self renew and generate all lineages of blood cells. Although it is currently well established that hematopoietic stem cells (HSCs) regenerate the blood compartment, it was only in the 1960s that was introduced the

Computed tomography manifestations of peritoneal diseases

International Nuclear Information System (INIS)

Gordon, K.; Lee, W.K.; Hennessy, O.

2005-01-01

The peritoneal cavity is a potential space that is divided by the peritoneal reflections into various complex subspaces. It can be involved in many disease processes including developmental, inflammatory, neoplastic and traumatic conditions. Computed tomography is highly sensitive and consistent in detecting peritoneal pathology. This pictorial essay aims to emphasize and illustrate the CT features of the spectrum of peritoneal diseases. Copyright (2005) Blackwell Science Pty Ltd

Arising podosomal structures are associated with neoplastic cell morphological phenotype induced by the microenvironment

Czech Academy of Sciences Publication Activity Database

Veselý, Pavel; Blase, C.; Matoušková, Eva; Bereiter-Hahn, J.

2006-01-01

Roč. 26, - (2006), s. 967-972 ISSN 0250-7005 R&D Projects: GA MZd(CZ) NR8145 Institutional research plan: CEZ:AV0Z50520514 Keywords : podosomes * neoplastic cell morphotype * phenotypic plasticity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.479, year: 2006

Investigation of radioprotective effect of indraline of hematopoietic system in different species of animal

International Nuclear Information System (INIS)

Vasin, M.V.; Antipov, V.V.; Chernov, G.A.

1996-01-01

The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes thrombocytes and erytrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed. 22 refs.; 8 figs.; 4 tabs

Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells

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Lise ePasquet

2011-12-01

Full Text Available The major obstacle in transplantation medicine is rejection of donor tissues by the host’s immune system. Immunosuppressive drugs can delay but not prevent loss of transplants, and their efficiency is strongly impacted by inter-individual pharmacokinetic differences. Moreover, due to the global immunosuppression induced and to the broad distribution of their targets amongst human tissues, these drugs have severe side effects. Induction of donor-specific non-responsiveness (i.e. immunological tolerance to transplants would solve these problems and would substantially ameliorate patients’ quality of life. It is widely believed that bone marrow or hematopoietic stem cell transplantation, and resulting (mixed hematopoietic chimerism, invariably leads to immunological tolerance to organs of the same donor. A careful analysis of the literature, reviewed here, indeed shows that chimerism consistently prolongs allograft survival. However, in absence of additional conditioning leading to the development of active regulatory mechanisms, it does not prevent chronic rejection. A central role for active tolerance in transplantation-tolerance is also supported by recent data showing that genuine immunological tolerance to organ allografts can be achieved by combining induction of hematopoietic chimerism with infusion of regulatory T lymphocytes. Therefore, conditioning regimens that lead to the establishment of hematopoietic chimerism plus active regulatory mechanisms appear required for induction of genuine tolerance to allogeneic grafts.

Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.

Science.gov (United States)

Guo, Peipei; Poulos, Michael G; Palikuqi, Brisa; Badwe, Chaitanya R; Lis, Raphael; Kunar, Balvir; Ding, Bi-Sen; Rabbany, Sina Y; Shido, Koji; Butler, Jason M; Rafii, Shahin

2017-12-01

Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia

Directory of Open Access Journals (Sweden)

Cary N. Weiss

2015-03-01

Full Text Available In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.

Science.gov (United States)

Granger, D L; Lehninger, A L

1982-11-01

Previous work has shown that injury of neoplastic cells by cytotoxic macrophages (CM) in cell culture is accompanied by inhibition of mitochondrial respiration. We have investigated the nature of this inhibition by studying mitochondrial respiration in CM-injured leukemia L1210 cells permeabilized with digitonin. CM-induced injury affects the mitochondrial respiratory chain proper. Complex I (NADH-coenzyme Q reductase) and complex II (succinate-coenzyme Q reductase) are markedly inhibited. In addition a minor inhibition of cytochrome oxidase was found. Electron transport from alpha-glycerophosphate through the respiratory chain to oxygen is unaffected and permeabilized CM-injured L1210 cells oxidizing this substrate exhibit acceptor control. However, glycerophosphate shuttle activity was found not to occur within CM-injured or uninjured L1210 cells in culture hence, alpha-glycerophosphate is apparently unavailable for mitochondrial oxidation in the intact cell. It is concluded that the failure of respiration of intact neoplastic cells injured by CM is caused by the nearly complete inhibition of complexes I and II of the mitochondrial electron transport chain. The time courses of CM-induced electron transport inhibition and arrest of L1210 cell division are examined and the possible relationship between these phenomena is discussed.

Molecular regulation of human hematopoietic stem cells

NARCIS (Netherlands)

van Galen, P.L.J.

2014-01-01

Peter van Galen focuses on understanding the determinants that maintain the stem cell state. Using human hematopoietic stem cells (HSCs) as a model, processes that govern self-renewal and tissue regeneration were investigated. Specifically, a role for microRNAs in balancing the human HSC

Endogenous pyrogen production by Hodgkin's disease and human histiocytic lymphoma cell lines in vitro.

Science.gov (United States)

Bodel, P; Ralph, P; Wenc, K; Long, J C

1980-02-01

Fever not explained by infection may occur in patients with malignant lymphoma presumably caused by a release of endogenous pyrogen. Although pyrogen has been found in some tumors with a mixed cell population, production of endogenous pyrogen by the neoplastic cells has not been demonstrated. This report documents the apparently spontaneous synthesis and release of such pyrogen by two human tumor cell lines derived from patients with Hodgkin's disease and histiocytic lymphoma. The endogenous pyrogen from the two cell lines was similar and closely resembled that produced by normal human monocytes in antigenic properties as well as heat and pronase sensitivity. The Hodgkin's disease and histiocytic lymphoma cell lines do not require specific stimulation for the production of endogenous pyrogen suggesting that the mechanism of pyrogen release by neoplastic macrophage-related cells differs from that of normal phagocytic cells. The tumor-associated fever in some patients with malignant lymphoma may be caused by a release of endogenous pyrogen by proliferating neoplastic cells.

Genetic modification of hematopoietic stem cells with nonviral systems: past progress and future prospects.

Science.gov (United States)

Papapetrou, E P; Zoumbos, N C; Athanassiadou, A

2005-10-01

Serious unwanted complications provoked by retroviral gene transfer into hematopoietic stem cells (HSCs) have recently raised the need for the development and assessment of alternative gene transfer vectors. Within this context, nonviral gene transfer systems are attracting increasing interest. Their main advantages include low cost, ease of handling and large-scale production, large packaging capacity and, most importantly, biosafety. While nonviral gene transfer into HSCs has been restricted in the past by poor transfection efficiency and transient maintenance, in recent years, biotechnological developments are converting nonviral transfer into a realistic approach for genetic modification of cells of hematopoietic origin. Herein we provide an overview of past accomplishments in the field of nonviral gene transfer into hematopoietic progenitor/stem cells and we point at future challenges. We argue that episomally maintained self-replicating vectors combined with physical methods of delivery show the greatest promise among nonviral gene transfer strategies for the treatment of disorders of the hematopoietic system.

Transient loading of CD34+ hematopoietic progenitor cells with polystyrene nanoparticles

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Deville S

2017-01-01

Full Text Available Sarah Deville,1,2 Wahyu Wijaya Hadiwikarta,1 Nick Smisdom,1,2 Bart Wathiong,1,3 Marcel Ameloot,2 Inge Nelissen,1 Jef Hooyberghs1,3 1VITO, Flemish Institute for Technological Research, Mol, Belgium; 2Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium; 3Theoretical Physics, Hasselt University, Diepenbeek, Belgium Abstract: CD34+ hematopoietic progenitor cells (HPCs offer great opportunities to develop new treatments for numerous malignant and non-malignant diseases. Nanoparticle (NP-based strategies can further enhance this potential, and therefore a thorough understanding of the loading behavior of HPCs towards NPs is essential for a successful application. The present study focusses on the interaction kinetics of 40 nm sized carboxylated polystyrene (PS NPs with HPCs. Interestingly, a transient association of the NPs with HPCs is observed, reaching a maximum within 1 hour and declining afterwards. This behavior is not seen in dendritic cells (CD34-DCs differentiated from HPCs, which display a monotonic increase in NP load. We demonstrate that this transient interaction requires an energy-dependent cellular process, suggesting active loading and release of NPs by HPCs. This novel observation offers a unique approach to transiently equip HPCs. A simple theoretical approach modeling the kinetics of NP loading and release is presented, contributing to a framework of describing this phenomenon. Keywords: nanoparticles, hematopoietic progenitor cells, dendritic cells, uptake, release

Gallium SPECT detection of neoplastic intravascular obstruction of the superior vena cava

International Nuclear Information System (INIS)

Swayne, L.C.; Kaplan, I.L.

1989-01-01

A rare case of an intravascular neoplastic obstruction of the superior vena cava is discussed. The lesion was detected with gallium single photon emission computed tomography (SPECT) despite a normal appearance on a concurrent radiographic CT study. A computer-generated composite SPECT-CT image confirmed the intravascular localization of the radioisotope, and a subsequent CT-guided transthoracic needle biopsy revealed a poorly differentiated adenocarcinoma

Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

Science.gov (United States)

Geiselhart, Anja; Lier, Amelie; Walter, Dagmar; Milsom, Michael D.

2012-01-01

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. PMID:22675615

Circulating hematopoietic progenitors and CD34(+) cells predicted successful hematopoietic stem cell harvest in myeloma and lymphoma patients: experiences from a single institution.

Science.gov (United States)

Yu, Jui-Ting; Cheng, Shao-Bin; Yang, Youngsen; Chang, Kuang-Hsi; Hwang, Wen-Li; Teng, Chieh-Lin Jerry

2016-01-01

Previous studies have shown that the numbers of both circulating hematopoietic progenitor cell (HPC) and CD34(+) cell are positively correlated with CD34(+) cell harvest yield. However, the minimal numbers of both circulating HPCs and CD34(+) cells required for performing an efficient hematopoietic stem cell (HSC) harvest in lymphoma and myeloma patients have not been defined in our institution. Medical records of 50 lymphoma and myeloma patients undergoing peripheral blood HSC harvest in our institution were retrospectively reviewed. The minimal and optimal HSC harvest yield required for the treatment was considered to be ≥2×10(6) CD34(+) cells/kg and ≥5×10(6) CD34(+) cells/kg, respectively. The minimally required or optimal HSC yield obtained was not influenced by age (≥60 years), sex, underlying malignancies, disease status, multiple rounds of chemotherapy, or history of radiotherapy. The numbers of both circulating HPC and CD34(+) cell were higher in patients with minimally required HSC yields (P=0.000 for HPC and P=0.000 for CD34(+) cell) and also in patients with optimal HSC yields (P=0.011 for HPC and P=0.006 for CD34(+) cell). The cell count cutoff for obtaining minimally required HSC harvest was determined to be 20/mm(3) for HPCs and 10/mm(3) for CD34(+) cells. Furthermore, the cell count cutoff for obtaining optimal HSC harvest was determined to be 60/mm(3) for HPCs and 35/mm(3) for CD34(+) cells. A total of 60/mm(3) of HPCs and 35/mm(3) of CD34(+) cells in peripheral blood predicted optimal HSC harvest in lymphoma and myeloma patients.

Generation of induced pluripotent stem cells from peripheral blood CD34+ hematopoietic progenitors of a 31 year old healthy woman

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Amornrat Tangprasittipap

2017-04-01

Full Text Available The MUi019-A human induced pluripotent stem cell line was generated from peripheral blood CD34+ hematopoietic progenitors of a healthy woman using a non-integrative reprogramming method. Episomal vectors carrying reprogramming factors OCT4, SOX2, KLF4, L-MYC, LIN28, and shRNA of TP53 and EBNA-1 were delivered using electroporation. The iPSC line can be used as a control in studying disease mechanisms. Furthermore, gene editing approaches can be used to introduce specific mutations into the MUi019-A to model disease while the cell type affected by the disease is inaccessible.

Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells.

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David M Harris

Full Text Available Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza and the growth factors (GF granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy.

Rhizomucor and Scedosporium Infection Post Hematopoietic Stem-Cell Transplant

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Dânia Sofia Marques

2011-01-01

Full Text Available Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis, its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies.

Abnormal muscle and hematopoietic gene expression may be important for clinical morbidity in primary hyperparathyroidism

DEFF Research Database (Denmark)

Reppe, Sjur; Stilgren, Lis; Abrahamsen, Bo

2007-01-01

out in biopsies obtained before and 1 yr after parathyroidectomy in seven patients discovered by routine blood [Ca(2+)] screening. The tissue distribution of PTH receptor (PTHR1 and PTHR2) mRNAs were quantitated using real-time RT-PCR in unrelated persons to define PTH target tissues. Of about 10......, muscle, and hematopoietic cells have to be considered as one independent, important cause of molecular disease in PHPT leading to profound alterations in gene expression that may help explain symptoms like muscle fatigue, cardiovascular pathology, and precipitation of psychiatric illness....

Comparison of chemotherapy and hematopoietic stem cell ...

African Journals Online (AJOL)

2013-02-19

Feb 19, 2013 ... scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy. Materials and Methods: Thirty-six patients undergoing HSCT were included in the study. A pre-HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of ...

Hematopoietic stem cell aging and self-renewal

NARCIS (Netherlands)

Dykstra, Brad; de Haan, Gerald

A functional decline of the immune system occurs during organismal aging that is attributable, in large part, to changes in the hematopoietic stem cell (HSC) compartment. In the mouse, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC

Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.

Science.gov (United States)

Farace, Francoise; Prestoz, Laetitita; Badaoui, Sabrina; Guillier, Martine; Haond, Celine; Opolon, Paule; Thomas, Jean-Leon; Zalc, Bernard; Vainchenker, William; Turhan, Ali G

2004-02-01

Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation.

Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

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Chien-Ting Chen

Full Text Available Chronic graft-versus-host-disease (cGvHD is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT. Among various organ-specific cGvHD, the cGvHD of liver is less well-characterized. In this study, we applied the National Institutes of Health 2014 scoring criteria of cGvHD to analyze a retrospective cohort of 362 allo-HSCT recipients focusing on cGvHD of liver. The overall incidence of liver cGvHD with a score of 3 by 1.5 years post-transplant was 5.8% (21/362. Poor outcome, in terms of overall survival (OS, were observed in patients with scores of 3 liver cGvHD, comparing to those with scores less than 3 (hazard ratio [HR] 2.037, 95% confidence interval [CI] 1.123-3.696, P = 0.019. In multivariate analysis, male gender (HR 4.004, P = 0.042 and chronic hepatitis C virus (HCV infection status (HR 19.087, P < 0.001 were statistically significant risk factors for scores of 3 liver cGvHD. Our results indicate that liver cGvHD with scores of 3 has a grave prognosis following allo-HSCT, and that HCV carrier status and male are risk factors. Early recognition of this devastating complication might help in prompt immunosuppressive therapy and reducing late poor outcome.

[The role of endothelial cells and endothelial precursor cells in angiogenesis].

Science.gov (United States)

Poreba, Małgorzata; Usnarska-Zubkiewicz, Lidia; Kuliczkowski, Kazimierz

2006-01-01

Endothelium plays a key role in maintenance of vascular homeostasis in human organism. According to new data endothelial cells and hematopoietic cells have a common precursor in prenatal life--a hemangioblast, which explains the fact of sharing the same determinants on the surface of both type of cells. Circulating endothelial precursors were identified in adults and this suggests that hemangioblasts may be present not only during embriogenesis. In some clinical situations the increased numbers of endothelial cells and endothelial precursors were noted, and especially in patients with neoplastic diseases, which is probably the result of increased angiogenesis. Endothelial precursors are thought to be the promice for therapeutic purposes in future--to increase local angiogenesis.

Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma.

Science.gov (United States)

Nair, Velu; Sharma, Ajay; Sharma, Sanjeevan; Das, Satyaranjan; Bhakuni, Darshan S; Narayanan, Krishnan; Nair, Vivek; Shankar, Subramanian

2015-03-01

Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

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Patrizia Tosi

2012-11-01

Full Text Available Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

Establishing an autologous versus allogeneic hematopoietic cell transplant program in nations with emerging economies.

Science.gov (United States)

Chaudhri, Naeem A; Aljurf, Mahmoud; Almohareb, Fahad I; Alzahrani, Hazzaa A; Bashir, Qaiser; Savani, Bipin; Gupta, Vikas; Hashmi, Shahrukh K

2017-12-01

More than 70,000 hematopoietic cell transplants are currently performed each year, and these continue to increase every year. However, there is a significant variation in the number of absolute transplants and transplant rates between centers, countries, and global regions. The prospect for emerging countries to develop a hematopoietic cell transplantation (HCT) program, as well as to decide on whether autologous HCT (auto-HCT) or allogeneic HCT (allo-HCT) should be established to start with, relies heavily on factors that can explain differences between these two procedures. Major factors that will influence a decision about establishing the type of HCT program are macroeconomic factors such as organization of the healthcare network, available resources and infrastructure. Prevalence of specific diseases in the region as well genetic background of donors and recipients will also influence the mandate or priority of the HCT in the national healthcare plan to explain some of the country-specific differences. Furthermore, microeconomic factors play a role, such as center-specific experience in treating various disorders requiring hematopoietic stem cell transplantation, along with accreditation status and patient volume. The objective of the transplant procedure was to improve the survival and quality of life of patients. The regional difference that one notices in emerging countries about the higher number of allo-HCT compared with auto-HCT procedures performed is primarily based on suboptimal healthcare network in treating various malignant disorders that are the primary indication for auto-stem cell transplantation. In this context, nonmalignant disorders such as bone marrow failure syndromes, inherited genetic disorders and hemoglobinopathies have become the major indication for stem cell transplantation. Better understanding of these factors will assist in establishing new transplant centers in the emerging countries to achieve their specific objectives and

Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a.

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Jackson, Jacob T; Shields, Benjamin J; Shi, Wei; Di Rago, Ladina; Metcalf, Donald; Nicola, Nicos A; McCormack, Matthew P

2017-08-01

The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957. © 2017 AlphaMed Press.

MR study of intracranial disease with three-dimensional FLASH

International Nuclear Information System (INIS)

Runge, V.M.; Wood, M.L.; Kaufman, D.M.; Nelson, K.L.; Traill, M.R.; Wolpert, S.M.

1987-01-01

A three-dimensional FLASH technique was used to study 36 patients with intracranial disease at 1 T (Siemens Magnetom). This included 15 cases of intracranial neoplastic disease, four with the application of intravenous Gd-DTPA. Contiguous thin sections (1-2 mm thick) were acquired of the entire intracranial contents using one acquisition (scan time of 5-15 minutes). A MIPRON (KONTRON Instruments) image processing work station was used for rapid image display and 3D reconstruction. 3D FLASH was found to be superior to spin-echo imaging at 1 T for the detection of hemorrhage. 3D acquisition also provided superior localization of neoplastic disease. The T1 contrast achieved was comparable to spin-echo technique with a repetition time/echo time of .6/17. The advantages in terms of lesion localization and thin-section imaging with high spatial resolution of the entire brain may lead to use of 3D FLASH in place of conventional spin-echo imaging

Quantitative and qualitative assessment of reactive hematopoietic bone marrow in aplastic anemia using MR spectroscopy with variable echo times

Energy Technology Data Exchange (ETDEWEB)

Amano, Yasuo; Kumazaki, Tatsuo [Department of Radiology, Nippon Medical School, Tokyo (Japan)

2002-01-01

Objective: To assess quantitative and qualitative differences in water components between normal bone marrow and reactive hematopoietic marrow in aplastic anemia using magnetic resonance (MR) spectroscopy with variable echo times (TEs). Design: Water content, T2 value of the water component, and signal change in water related to TE were assessed in normal bone marrow and reactive hematopoietic bone marrow by a stimulated echo acquisition mode with TEs of 30, 45, 60, and 90 ms. Patients: Six patients with aplastic anemia (13-84 years) and seven normal volunteers (25-38 years) were examined. Results and conclusion: Reactive hematopoietic marrow showed significantly higher water content than normal bone marrow. The T2 value of water components tended to be longer in reactive hematopoietic marrow. Water signal ratio related to TE was significantly higher in reactive hematopoietic marrow. These results suggest a quantitative and qualitative difference in water components between normal and reactive hematopoietic bone marrow. (orig.)

Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

Science.gov (United States)

Ruud, Johan; Wilhelms, Daniel Björk; Nilsson, Anna; Eskilsson, Anna; Tang, Yan-Juan; Ströhle, Peter; Caesar, Robert; Schwaninger, Markus; Wunderlich, Thomas; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

2013-05-01

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Reconstruction of hematopoietic inductive microenvironment after transplantation of VCAM-1-modified human umbilical cord blood stromal cells.

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Yao Liu

Full Text Available The hematopoietic inductive microenvironment (HIM is where hematopoietic stem/progenitor cells grow and develop. Hematopoietic stromal cells were the key components of the HIM. In our previous study, we had successfully cultured and isolated human cord blood-derived stromal cells (HUCBSCs and demonstrated that they could secret hemopoietic growth factors such as GM-CSF, TPO, and SCF. However, it is still controversial whether HUCBSCs can be used for reconstruction of HIM. In this study, we first established a co-culture system of HUCBSCs and cord blood CD34(+ cells and then determined that using HUCBSCs as the adherent layer had significantly more newly formed colonies of each hematopoietic lineage than the control group, indicating that HUCBSCs had the ability to promote the proliferation of hematopoietic stem cells/progenitor cells. Furthermore, the number of colonies was significantly higher in vascular cell adhesion molecule-1 (VCAM-1-modified HUCBSCs, suggesting that the ability of HUCBSCs in promoting the proliferation of hematopoietic stem cells/progenitor cells was further enhanced after having been modified with VCAM-1. Next, HUCBSCs were infused into a radiation-damaged animal model, in which the recovery of hematopoiesis was observed. The results demonstrate that the transplanted HUCBSCs were "homed in" to bone marrow and played roles in promoting the recovery of irradiation-induced hematopoietic damage and repairing HIM. Compared with the control group, the HUCBSC group had significantly superior effectiveness in terms of the recovery time for hemogram and myelogram, CFU-F, CFU-GM, BFU-E, and CFU-Meg. Such differences were even more significant in VCAM-1-modified HUCBSCs group. We suggest that HUCBSCs are able to restore the functions of HIM and promote the recovery of radiation-induced hematopoietic damage. VCAM-1 plays an important role in supporting the repair of HIM damage.

Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples.

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Annika Mohr

Full Text Available Immunohistochemistry (IHC is currently considered the method of choice for steroid hormone receptor status evaluation in human breast cancer and, therefore, it is commonly utilized for assessing canine mammary tumors. In case of low hormone receptor expression, IHC is limited and thus is complemented by molecular analyses. In the present study, a multiplex bDNA assay was evaluated as a method for hormone receptor gene expression detection in canine mammary tissues. Estrogen receptor (ESR1, progesterone receptor (PGR, prolactin receptor (PRLR and growth hormone receptor (GHR gene expressions were evaluated in neoplastic and non-neoplastic canine mammary tissues. A set of 119 fresh frozen and 180 formalin-fixed, paraffin-embedded (FFPE was comparatively analyzed and used for assay evaluation. Furthermore, a possible association between the hormone receptor expression in different histological subtypes of canine malignant mammary tumors and the castration status, breed and invasive growth of the tumor were analyzed. The multiplex bDNA assay proved to be more sensitive for fresh frozen specimens. Hormone receptor expression found was significantly decreased in malignant mammary tumors in comparison to non-neoplastic tissue and benign mammary tumors. Among the histological subtypes the lowest gene expression levels of ESR1, PGR and PRLR were found in solid, anaplastic and ductal carcinomas. In summary, the evaluation showed that the measurement of hormone receptors with the multiplex bDNA assay represents a practicable method for obtaining detailed quantitative information about gene expression in canine mammary tissue for future studies. Still, comparison with IHC or quantitative real-time PCR is needed for further validation of the present method.

Experimental control of neoplastic progression in cell populations: Foulds' rules revisited.

OpenAIRE

Rubin, H

1994-01-01

Foulds introduced six rules of tumor progression based on his observations of spontaneous mammary cancer in mice and generalized them to all forms of neoplasia [Foulds, L. (1954) Cancer Res. 14, 327-339 and Foulds, L. (1969) Neoplastic Development (Academic, New York), Vol. 1, preface and pp. 72-74.] Rules III, IV, and V are considered controversial, and research in animals seems inadequate to resolve the controversies. A subline of NIH 3T3 cells undergoes progressive transformation to produc...

Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome).

Science.gov (United States)

Braunlin, Elizabeth; Steinberger, Julia; DeFor, Todd; Orchard, Paul; Kelly, Aaron S

2018-02-01

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome-a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose-is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children

[Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank].

Science.gov (United States)

Barriga, Francisco; Wietstruck, Angélica; Rojas, Nicolás; Bertin, Pablo; Pizarro, Isabel; Carmona, Amanda; Guilof, Alejandro; Rojas, Iván; Oyarzún, Enrique

2013-08-01

Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

Anxiety, fatigue, and attentional bias toward threat in patients with hematopoietic tumors.

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Kohei Koizumi

Full Text Available Cancer patients with hematopoietic tumors exhibit particularly high rates of anxiety disorders and depression, and often develop negative affect. In addition, psychological problems experienced by cancer patients impair their quality of life. When cancer patients feel anxious, they tend to direct their attention toward stimuli associated with threat in the surrounding environment. If attentional bias occurs in patients with hematopoietic tumors, who are at particular risk of developing negative affect, resolution of the bias could be useful in alleviating their anxiety. The current study examined the association between attentional bias and negative affect in patients with hematopoietic tumors and tested the hypothesis that negative affect would be more severe in those who exhibited greater attentional bias. Twenty-seven patients with hematopoietic tumors participated in the study. Reaction time (RT was measured as the time between the presentation of the threatening and neutral images, and the subject's button press to indicate choice (neutral expressions. Eight combinations of "threatening" expressions with high emotional valence and "neutral" expressions with low emotional valence were presented. The images used to measure attentional bias were taken from the Japanese Female Facial Expression Database and had been rated as expressive of anger, sadness, or neutrality, with predetermined emotional valence. Psychological testing was performed with the Profile of Mood States (POMS. To examine the association between attentional bias and negative affect, we calculated Spearman's rank correlation coefficients for RTs and POMS. Subjects' mean RT was 882.9 (SD = 100.9 ms, and 19 of the 27 subjects exhibited slower RTs relative to healthy individuals. RT was significantly positively correlated with Tension-Anxiety (r = .679, p < .01 and Fatigue (r = .585, p < .01 subscale scores. The results of the study suggested that attentional bias toward

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.

Science.gov (United States)

Peled, Jonathan U; Devlin, Sean M; Staffas, Anna; Lumish, Melissa; Khanin, Raya; Littmann, Eric R; Ling, Lilan; Kosuri, Satyajit; Maloy, Molly; Slingerland, John B; Ahr, Katya F; Porosnicu Rodriguez, Kori A; Shono, Yusuke; Slingerland, Ann E; Docampo, Melissa D; Sung, Anthony D; Weber, Daniela; Alousi, Amin M; Gyurkocza, Boglarka; Ponce, Doris M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Taur, Ying; Pamer, Eric G; Jenq, Robert R; van den Brink, Marcel R M

2017-05-20

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

O transplante de células-tronco hematopoéticas na infância: situação atual e perspectivas Hematopoietic stem cell transplantation in childhood: current status and perspectives

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Adriana Seber

2009-05-01

Full Text Available O transplante de células-tronco hematopoéticas (TCTH é uma opção terapêutica para um grande número de crianças com doenças malignas e não malignas. O objetivo deste artigo é apresentar a situação atual dos TCTH em pediatria para o tratamento de doenças hematológicas malignas, incluindo dados de nosso país e perspectivas futuras.Hematopoietic stem cell transplantation is a treatment option for a large number of children with malignant and non-malignant diseases. The objective of this article is to present the current status of hematopoietic stem cell transplantation in the treatment of malignant hematological diseases in pediatrics, including results in Brazil, and future perspectives.

Bronchoscopic examinations for evaluating chest abnormal shadows associated with hematological disease

International Nuclear Information System (INIS)

Nakayama, Masayuki; Bando, Masashi; Kobayashi, Akira; Yamasawa, Hideaki; Ohno, Shoji; Sugiyama, Yukihiko

2006-01-01

Hematological diseases cause various respiratory complications, but their differentiation only by blood tests and chest radiology is often difficult. To clarify the characteristics of respiratory complications associated with hematological diseases and the diagnostic usefulness of bronchoscopic examinations for these complications, we clinically evaluated mainly underlying diseases, chest radiological findings, and bronchoscopic findings in 31 patients in whom we performed bronchoscopy for chest abnormal shadows associated with hematological disease during the past 13-year period. Among hematological disease, leukemia was most frequently observed, followed by malignant lymphoma and myelodysplastic syndrome. The most frequently observed chest CT findings were localized consolidation and diffuse Ground-glass opacity. Bronchoscopic examinations provided a definitive diagnosis in 20 patients (64.5%), and the most frequent diagnosis was pulmonary invasion by neoplastic cells (7 patients). Pulmonary invasion by neoplastic cells showed various images, and transbronchial lung biopsy : TBLB was useful for definitive diagnosis. After consideration of the general condition of patients and the risk of complications, bronchoscopy including TBLB should be performed when possible. (author)

Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma: Focus on Longitudinal Assessment of Donor Chimerism, Extramedullary Disease, and High-Risk Cytogenetic Features.

Science.gov (United States)

Rasche, Leo; Röllig, Christoph; Stuhler, Gernot; Danhof, Sophia; Mielke, Stephan; Grigoleit, Goetz Ulrich; Dissen, Lea; Schemmel, Lea; Middeke, Jan Moritz; Rücker, Viktoria; Schreder, Martin; Schetelig, Johannes; Bornhäuser, Martin; Einsele, Hermann; Thiede, Christian; Knop, Stefan

2016-11-01

Although generally not applied as first-line treatment of multiple myeloma, allogeneic hematopoietic cell transplantation (allo-SCT) can still be chosen as ultimate escalation approach in high-risk patients, preferentially within the framework of clinical trials. In this study, we investigated whether decreasing donor chimerism (DC) is predictive for relapse. In addition, we comprehensively determined the impact of several other disease- and treatment-related factors on outcome. One hundred fifty-five multiple myeloma patients whose DC status was followed serially by the short tandem repeat-based techniques at a single lab were included in this retrospective study. Outcome variables were studied in univariate and multivariable analyses. Available were 2.324 DC samples (median, 12 per patient). Loss of full DC was associated with shorter progression-free survival (PFS) (HR, 1.7; 95% CI, 1.1 to 2.6) but did not impact overall survival. Two-thirds of patients with International Myeloma Working Group-defined relapses still displayed a full DC in peripheral blood or bone marrow. Extramedullary manifestations were observed in 33% of patients, accounting for the discrepancy between DC analysis and the actual disease status. In multivariable analysis, the 2 most relevant variables for an unfavorable PFS were progressive disease before allo-SCT (HR, 3.0; 95% CI, 1.5 to 5.9) and allo-SCT at least the second relapse (HR, 2.8; 95% CI, 1.5 to 4.9), whereas for overall survival progressive disease or partial response before allo-SCT had the strongest negative effects (HR, 4.2; 95% CI, 1.9 to 9, and HR, 2.0; 95% CI, 1.0 to 3.8, respectively). Adverse cytogenetics such as del17p, t(4,14) or amp(1q21) were not associated with shorter survival after allo-SCT. Extensive DC sampling beyond robust engraftment does not appear to provide additional information helpful for disease management in most patients and is challenged by a significant incidence of extramedullary disease. In our

Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT

DEFF Research Database (Denmark)

Koenecke, C; Hertenstein, B; Schetelig, J

2010-01-01

To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984...... for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT....

Factors affecting autologous peripheral blood hematopoietic stem cell collections by large-volume leukapheresis: a single center experience

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Araci Massami Sakashita

2011-06-01

Full Text Available Objective: To evaluate factors affecting peripheral bloodhematopoietic stem cell yield in patients undergoing large-volumeleukapheresis for autologous peripheral blood stem cell collection.Methods: Data from 304 consecutive autologous peripheral bloodstem cell donors mobilized with hematopoietic growth factor (usually G-CSF, associated or not with chemotherapy, at Hospital Israelita Albert Einstein between February 1999 and June 2010 were retrospectively analyzed. The objective was to obtain at least 2 x 106CD34+ cells/kg of body weight. Pre-mobilization factors analyzedincluded patient’s age, gender and diagnosis. Post mobilizationparameters evaluated were pre-apheresis peripheral white bloodcell count, immature circulating cell count, mononuclear cell count,peripheral blood CD34+ cell count, platelet count, and hemoglobinlevel. The effect of pre and post-mobilization factors on hematopoietic stem cell collection yield was investigated using logistic regression analysis (univariate and multivariate approaches. Results: Premobilization factors correlating to poor CD34+ cell yield in univariate analysis were acute myeloid leukemia (p = 0.017 and other hematological diseases (p = 0.023. Significant post-mobilization factors included peripheral blood immature circulating cells (p = 0.001, granulocytes (p = 0.002, hemoglobin level (p = 0.016, and CD34+ cell concentration (p < 0.001 in the first harvesting day. However, according to multivariate analysis, peripheral blood CD34+ cell content (p < 0.001 was the only independent factor that significantly correlated to poor hematopoietic stem cell yield. Conclusion: In this study, peripheral blood CD34+ cell concentration was the only factor significantly correlated to yield in patients submitted to for autologous collection.

Aging of hematopoietic stem cells: DNA damage and mutations?

Science.gov (United States)

Moehrle, Bettina M; Geiger, Hartmut

2016-10-01

Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Placenta as a source of hematopoietic stem cells

NARCIS (Netherlands)

E.A. Dzierzak (Elaine); C. Robin (Catherine)

2010-01-01

textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

Gene expression profiling identifies HOXB4 as a direct downstream target of GATA-2 in human CD34+ hematopoietic cells.

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Tohru Fujiwara

Full Text Available Aplastic anemia is characterized by a reduced hematopoietic stem cell number. Although GATA-2 expression was reported to be decreased in CD34-positive cells in aplastic anemia, many questions remain regarding the intrinsic characteristics of hematopoietic stem cells in this disease. In this study, we identified HOXB4 as a downstream target of GATA-2 based on expression profiling with human cord blood-derived CD34-positive cells infected with control or GATA-2 lentiviral shRNA. To confirm the functional link between GATA-2 and HOXB4, we conducted GATA-2 gain-of-function and loss-of-function experiments, and HOXB4 promoter analysis, including luciferase assay, in vitro DNA binding analysis and quantitative ChIP analysis, using K562 and CD34-positive cells. The analyses suggested that GATA-2 directly regulates HOXB4 expression through the GATA sequence in the promoter region. Furthermore, we assessed GATA-2 and HOXB4 expression in CD34-positive cells from patients with aplastic anemia (n = 10 and idiopathic thrombocytopenic purpura (n = 13, and demonstrated that the expression levels of HOXB4 and GATA-2 were correlated in these populations (r = 0.6573, p<0.01. Our results suggested that GATA-2 directly regulates HOXB4 expression in hematopoietic stem cells, which may play an important role in the development and/or progression of aplastic anemia.

Filiform serrated adenomatous polyposis arising in a diverted rectum of an inflammatory bowel disease patient

DEFF Research Database (Denmark)

Klarskov, Louise; Mogensen, Anne Mellon; Jespersen, Niels

2011-01-01

Klarskov L, Mogensen AM, Jespersen N, Ingeholm P, Holck S. Filiform serrated adenomatous polyposis arising in a diverted rectum of an inflammatory bowel disease patient. APMIS 2011; 119: 393-8. A 54-year-old man, previously colectomized for inflammatory bowel disease, developed carcinoma in the i......Klarskov L, Mogensen AM, Jespersen N, Ingeholm P, Holck S. Filiform serrated adenomatous polyposis arising in a diverted rectum of an inflammatory bowel disease patient. APMIS 2011; 119: 393-8. A 54-year-old man, previously colectomized for inflammatory bowel disease, developed carcinoma...... during the adenoma carcinoma sequence included the acquisition of CK7 expression in the malignant portion. Gastric mucin may play a role in the initial step of the neoplastic evolution and CK7 may denote neoplastic progression. This case confirms the notion of a widely variegated morphology of precursor...

Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.

Science.gov (United States)

Baba, Masaya; Toyama, Hirofumi; Sun, Lei; Takubo, Keiyo; Suh, Hyung-Chan; Hasumi, Hisashi; Nakamura-Ishizu, Ayako; Hasumi, Yukiko; Klarmann, Kimberly D; Nakagata, Naomi; Schmidt, Laura S; Linehan, W Marston; Suda, Toshio; Keller, Jonathan R

2016-04-01

Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The Microtubule Plus-End Tracking Protein CLASP2 Is Required for Hematopoiesis and Hematopoietic Stem Cell Maintenance

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Ksenija Drabek

2012-10-01

Full Text Available Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.

In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice.

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Río, Paula; Segovia, José Carlos; Hanenberg, Helmut; Casado, José Antonio; Martínez, Jesús; Göttsche, Kerstin; Cheng, Ngan Ching; Van de Vrugt, Henri J; Arwert, Fré; Joenje, Hans; Bueren, Juan A

2002-09-15

Fanconi anemia (FA) is a rare autosomal recessive disease, characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors. The hematopoiesis of these animals was characterized by a modest though significant thrombocytopenia, consistent with reduced numbers of BM megakaryocyte progenitors. As observed in other FA models, the hematopoietic progenitors from Fanca(-/-) mice were highly sensitive to mitomycin C (MMC). In addition, we observed for the first time in a FA mouse model a marked in vitro growth defect of Fanca(-/-) progenitors, either when total BM or when purified Lin(-)Sca-1(+) cells were subjected to in vitro stimulation. Liquid cultures of Fanca(-/-) BM that were stimulated with stem cell factor plus interleukin-11 produced low numbers of granulocyte macrophage colony-forming units, contained a high proportion of apoptotic cells, and generated a decreased proportion of granulocyte versus macrophage cells, compared to normal BM cultures. Aiming to correct the phenotype of Fanca(-/-) progenitors, purified Lin(-)Sca-1(+) cells were transduced with retroviral vectors encoding the enhanced green fluorescent protein (EGFP) gene and human FANCA genes. Lin(-)Sca-1(+) cells from Fanca(-/-) mice were transduced with an efficiency similar to that of samples from wild-type mice. More significantly, transductions with FANCA vectors corrected both the MMC hypersensitivity as well as the impaired ex vivo expansion ability that characterized the BM progenitors of Fanca(-/-) mice.

Contrast enhancement and morphological findings of hematopoietic regions of bone marrow on MR imaging. Comparative study with spondylitis and vertebral tumors

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Amano, Yasuo; Hayashi, Hiromitsu; Matsuura, Maki; Watari, Jun; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan)

1995-06-01

The enhanced MR findings of hematopoietic regions in aplastic anemia were compared with those of spondylitis, metastatic vertebral tumors and hematologic neoplasms. The enhanced MR images showed hematopoietic regions to homogeneously enhance and occupy the margin of vertebral bodies, while spondylitis and metastatic tumors appeared as round, inhomogeneously enhancing lesions. MR images of leukemia and myelodysplastic syndrome showed homogeneous enhancement at the margins of vertebrae that was difficult to differentiate from hematopoietic regions. Enhanced MR images were useful in detecting the hematopoietic areas in marrow and differentiating them from spondylitis and metastatic tumors, although further experience is needed to distinguish between tumorous hyperplastic regions and benign hematopoietic regions in marrow. (author).

TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

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Nidhi Jain

2016-06-01

Full Text Available Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs in mice through engagement of Toll-like receptors (TLRs is widely studied as a partial model for some forms of human nephrotic syndrome (NS. In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

In vitro effects of recombinant human stem cell factor on hematopoietic cells from patients with acute radiation sickness

International Nuclear Information System (INIS)

Li Chuansheng; Cheng Tao; Xu Yanqun

1994-01-01

The effects of rhSCF, rhPIXY 321, rhGM-CSF and rhIL-3 on clonal proliferation of hematopoietic cells from five cases of acute radiation sickness were studied. The results showed that rhSCF could stimulate clonal proliferation of normal hematopoietic cells and the best results were obtained when the concentration of rhSCF was 5 x 10 4 ng/L. Clonal proliferation of hematopoietic cells from four cases of acute radiation sickness was stimulated while that from one case was inhibited. Moreover, the responsiveness of cells to rhSCF was correlated with the doses of radiation. Analysis of cell surface antigen, cell morphology and histochemistry revealed that rhSCF promoted predominantly the proliferation of granulocyte-macrophage lineage. rhSCF in combination with other three factors could further enhance the clonal proliferation of hematopoietic cells. The effects of rhPIXY 321, a fusion protein of GM-CSF and IL-3, were also analysed and found it to be a novel valuable hematopoietic growth factor

Accelerated postirradiation recovery of hematopoietic marrow following priming with low doses of vincristine

International Nuclear Information System (INIS)

Johnke, R.M.; Abernathy, R.S.

1990-01-01

The present investigation is a continuation of efforts to characterize the radioprotective potential of priming with vincristine (VcR). In this study, the postirradiation recovery kinetics of the marrow's hematopoietic stem cell, progenitor cell, and stromal cell compartments were monitored following exposure to a range of sublethal radiation doses to determine (a) the optimal VcR/radiation intertreatment interval for achieving maximal hematopoietic protection, (b) whether this optimal interval is influenced by the dose of radiation administered, and (c) whether the radioprotection observed involves the hematopoietic stroma. The results demonstrate that the degree of radioprotection observed was significantly influenced by the scheduling of the VcR priming dose with respect to the radiation exposure. An intertreatment interval of 24 h provided maximal radioprotective benefit irrespective of the radiation dose administered. Additionally, the radioprotection following VcR priming appeared to be more the result of an accelerated recovery in the hematopoietic stem cell and progenitor cell compartments than a change in their intrinsic radiosensitivity. The data also suggest that this accelerated recovery was not a consequence of greater radioprotection of marrow stroma. Finally, the radioprotection observed following VcR priming did not appear to involve a selective lineage response by either the erythroid or the granulomonocytic progenitor compartments

Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

DEFF Research Database (Denmark)

Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

2009-01-01

OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International......, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early...

Depression and anxiety following hematopoietic stem cell transplantation

DEFF Research Database (Denmark)

Kuba, K; Esser, P; Mehnert, A

2017-01-01

In this prospective multicenter study, we investigated the course of depression and anxiety during hematopoietic stem cell transplantation (HSCT) until 5 years after transplantation adjusting for medical information. Patients were consulted before HSCT (n=239), at 3 months (n=150), 12 months (n=102...

Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

NARCIS (Netherlands)

Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

Atlantic salmon, Salmo salar L. are broadly susceptible to isolates representing the North American genogroups of infectious hematopoietic necrosis virus

Science.gov (United States)

Kurath, Gael; Winton, James R.; Dale, Ole B.; Purcell, Maureen K.; Falk, Knut; Busch, Robert D.

2016-01-01

Beginning in 1992, three epidemic waves of infectious hematopoietic necrosis, often with high mortality, occurred in farmed Atlantic salmon Salmo salar L. on the west coast of North America. We compared the virulence of eleven strains of infectious hematopoietic necrosis virus (IHNV), representing the U, M and L genogroups, in experimental challenges of juvenile Atlantic salmon in freshwater. All strains caused mortality and there was wide variation within genogroups: cumulative mortality for five U-group strains ranged from 20 to 100%, four M-group strains ranged 30-63% and two L-group strains varied from 41 to 81%. Thus, unlike Pacific salmonids, there was no apparent correlation of virulence in a particular host species with virus genogroup. The mortality patterns indicated two different phenotypes in terms of kinetics of disease progression and final per cent mortality, with nine strains having moderate virulence and two strains (from the U and L genogroups) having high virulence. These phenotypes were investigated by histopathology and immunohistochemistry to describe the variation in the course of IHNV disease in Atlantic salmon. The results from this study demonstrate that IHNV may become a major threat to farmed Atlantic salmon in other regions of the world where the virus has been, or may be, introduced.

Localized extramedullary relapse after autologous hematopoietic stem cell transplantation in multiple myeloma

International Nuclear Information System (INIS)

Erkus, Muhan; Meteoglu, Ibrahim; Bolaman, Zahit; Kadikoylu, Gurhan

2005-01-01

Extramedullary plasmacytomas are rare manifestation of plasma cell malignancies. After hematopoietic stem cell transplantation HSCT, presentation of localized plasmacytoma with extramedullary growth is very unusual. We report a case of a 56-year-old woman with Dune-Salmon stage IIIA immunoglobulin A-kappa multiple myeloma, which presented 120 days after autologous HSCT with extramedullary plasmacytoma arising from a lymph node in supraclavicular region. The patient had no pretransplant-history related with extramedullary disease. There was no increase of plasma cells in bone marrow or monoclonal protein in urine or serum. Aspiration smears of lymph node revealed a population of plasmacytoid cells at various stages of maturation. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 20 months. (author)

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells

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Mauro Di Ianni

2018-04-01

Full Text Available To investigate chronic lymphocytic leukemia (CLL-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs. In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38− HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38− and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

Science.gov (United States)

Di Ianni, Mauro; Baldoni, Stefano; Del Papa, Beatrice; Aureli, Patrizia; Dorillo, Erica; De Falco, Filomena; Albi, Elisa; Varasano, Emanuela; Di Tommaso, Ambra; Giancola, Raffaella; Accorsi, Patrizia; Rotta, Gianluca; Rompietti, Chiara; Silva Barcelos, Estevão Carlos; Campese, Antonio Francesco; Di Bartolomeo, Paolo; Screpanti, Isabella; Rosati, Emanuela; Falzetti, Franca; Sportoletti, Paolo

2018-01-01

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

Casein kinase II is elevated in solid human tumours and rapidly proliferating non-neoplastic tissue

DEFF Research Database (Denmark)

Münstermann, U; Fritz, G; Seitz, G

1990-01-01

Protein kinase CKII (i.e. casein kinase II, CKII, NII) is expressed at a higher level in rapidly proliferating tissues and in solid human tumours (e.g. colorectal carcinomas) when compared to the corresponding non-neoplastic colorectal mucosa. This could be shown by (a) Western blotting of cellular...

Progenitor Hematopoietic Cells Implantation Improves Functional Capacity of End Stage Coronary Artery Disease Patients with Advanced Heart Failure

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Yoga Yuniadi

2016-01-01

Full Text Available Background. Proangiogenic Hematopoietic Cells (PHC which comprise diverse mixture of cell types are able to secrete proangiogenic factors and interesting candidate for cell therapy. The aim of this study was to seek for benefit in implantation of PHC on functional improvement in end stage coronary artery disease patients with advanced heart failure. Methods. Patients with symptomatic heart failure despite guideline directed medical therapy and LVEF less than 35% were included. Peripheral blood mononuclear cells were isolated, cultivated for 5 days, and then harvested. Flow cytometry and cell surface markers were used to characterize PHC. The PHC were delivered retrogradely via sinus coronarius. Echocardiography, myocardial perfusion, and clinical and functional data were analyzed up to 1-year observation. Results. Of 30 patients (56.4±7.40 yo preimplant NT proBNP level is 5124.5±4682.50 pmol/L. Harvested cells characterized with CD133, CD34, CD45, and KDR showed 0.87±0.41, 0.63±0.66, 99.00±2.60, and 3.22±3.79%, respectively. LVEF was improved (22±5.68 versus 26.8±7.93, p<0.001 during short and long term observation. Myocardial perfusion significantly improved 6 months after treatment. NYHA Class and six-minute walk test are improved during short term and long term follow-up. Conclusion. Expanded peripheral blood PHC implantation using retrograde delivery approach improved LV systolic function, myocardial perfusion, and functional capacity.

Ionizing radiation induces apoptosis in hematopoietic stem and progenitor cells

International Nuclear Information System (INIS)

Meng, A.; Zhou, D.; Geiger, H.; Zant, G.V.

2003-01-01

The aims of this study was to determine if ionizing radiation (IR) induces apoptosis in hematopoietic stem (HSC) and progenitor cells. Lin-cells were isolated from mouse bone marrow (BM) and pretreated with vehicle or 100 μM z-VAD 1 h prior to exposure to 4 Gy IR. The apoptotic and/or necrotic responses of these cells to IR were analyzed by measuring the annexin V and/or 7-AAD staining in HSC and progenitor populations using flow cytometry, and hematopoietic function of these cells was determined by CAFC assay. Exposure of Lin-cells to IR selectively decreased the numbers of HSC and progenitors in association with an increase in apoptosis in a time-dependent manner. Pretreatment of Lin- cells with z-VAD significantly inhibited IR-induced apoptosis and the decrease in the numbers of HSC and progenitors. However, IR alone or in combination with z-VAD did not lead to a significant increase in necrotic cell death in either HSC or progenitors. In addition, pretreatment of BM cells with z-VAD significantly attenuated IR-induced reduction in the frequencies of day-7, -28 and -35 CAFC. Exposure of HSC and progenitors to IR induces apoptosis. The induction of HSC and progenitor apoptosis contributes to IR-induced suppression of their hematopoietic function

Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

Science.gov (United States)

Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

2015-01-01

Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

Neoplastic causes of abnormal puberty.

Science.gov (United States)

Wendt, Susanne; Shelso, John; Wright, Karen; Furman, Wayne

2014-04-01

Neoplasm-related precocious puberty (PP) is a rare presenting feature of childhood cancer. Moreover, evaluation of suspected PP in a child is complex, and cancer is often not considered. We characterized the clinicopathologic features of patients presenting with PP at a large pediatric cancer center, reviewed the relevant literature, and developed an algorithm for the diagnostic work-up of these patients. We examined the records of all patients with a neoplasm and concomitant PP treated at St. Jude Children's Research Hospital from January 1975 through October 2011, reviewed the available literature, and analyzed the demographic, clinical, endocrine, and neoplasm-related features. Twenty-four of 13,615 children and adolescents (0.18%) were diagnosed with PP within 60 days of presentation. Primary diagnoses included brain tumor (12), adrenocortical carcinoma (5), hepatoblastoma (4), and others (3). PP was observed 0-48 months before diagnosis of neoplasm; 17 patients had peripheral PP and 7 had central PP. Neoplasm-related PP is rare and takes the form of a paraneoplastic syndrome caused by tumor production of hormones or by alteration of physiologic gonadotropin production. PP can precede diagnosis of malignancy by months or years, and neoplastic causes should be considered early to avoid delayed cancer diagnosis. Treatment of the primary malignancy resolved or diminished PP in surviving patients with an intact hypothalamic-pituitary-gonadal axis. © 2013 Wiley Periodicals, Inc.

The claudin gene family: expression in normal and neoplastic tissues

International Nuclear Information System (INIS)

Hewitt, Kyle J; Agarwal, Rachana; Morin, Patrice J

2006-01-01

The claudin (CLDN) genes encode a family of proteins important in tight junction formation and function. Recently, it has become apparent that CLDN gene expression is frequently altered in several human cancers. However, the exact patterns of CLDN expression in various cancers is unknown, as only a limited number of CLDN genes have been investigated in a few tumors. We identified all the human CLDN genes from Genbank and we used the large public SAGE database to ascertain the gene expression of all 21 CLDN in 266 normal and neoplastic tissues. Using real-time RT-PCR, we also surveyed a subset of 13 CLDN genes in 24 normal and 24 neoplastic tissues. We show that claudins represent a family of highly related proteins, with claudin-16, and -23 being the most different from the others. From in silico analysis and RT-PCR data, we find that most claudin genes appear decreased in cancer, while CLDN3, CLDN4, and CLDN7 are elevated in several malignancies such as those originating from the pancreas, bladder, thyroid, fallopian tubes, ovary, stomach, colon, breast, uterus, and the prostate. Interestingly, CLDN5 is highly expressed in vascular endothelial cells, providing a possible target for antiangiogenic therapy. CLDN18 might represent a biomarker for gastric cancer. Our study confirms previously known CLDN gene expression patterns and identifies new ones, which may have applications in the detection, prognosis and therapy of several human cancers. In particular we identify several malignancies that express CLDN3 and CLDN4. These cancers may represent ideal candidates for a novel therapy being developed based on CPE, a toxin that specifically binds claudin-3 and claudin-4

Late biological effects of ionizing radiation as influenced by dose, dose rate, age at exposure and genetic sensitivity to neoplastic transformation

International Nuclear Information System (INIS)

Spalding, J.F.; Prine, J.R.; Tietjen, G.L.

1978-01-01

A most comprehensive investigation is in progress at the Los Alamos Scientific Laboratory to study the late biological effects of whole-body exposure to gamma irradiation as they may be influenced by total dose, dose rate, age at exposure and genetic background. Strain C57B1/6J mice of four age groups (newborn, 2, 6 and l5 months) were given five doses (20, 60, 180, 540, and 1620 rads) of gamma rays, with each dose being delivered at six dose rates (0.7, 2.1, 6.3, 18.9, 56.7 rads/day and 25 rads/min). Forty to sixty mice were used in each of the approximately 119 dose/dose-rate and age combinations. The study was done in two replications with an equal number of mice per replicaton. Strain RF/J mice were used in a companion study to investigate the influence of genetic background on the type and magnitude of effect. Results of the first and second replications of the l5-month-old age group and data on the influence of genetic background on biological response have been completed, and the results show no significant life shortening within the dose and dose-rate range used. It was also concluded that radiaton-induced neoplastic transformaton was significantly greater in mice with a known genetic sensitivity to neoplastic disease than in mammals which do not normally have a significant incidence of tumours. (author)

Haemopedia: An Expression Atlas of Murine Hematopoietic Cells

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Carolyn A. de Graaf

2016-09-01

Full Text Available Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest.

bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

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Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A., E-mail: rschulz@nd.edu

2014-10-24

Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.

bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

International Nuclear Information System (INIS)

Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A.

2014-01-01

Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche

Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice.

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Martine Bot

Full Text Available AIMS: Altered sphingosine 1-phosphate (S1P homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/- deficiency on leukocyte subsets relevant to atherosclerosis. METHODS AND RESULTS: LDL receptor deficient mice that were transplanted with Sgpl1(-/- bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/- chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response. CONCLUSIONS: Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.

An "age"-structured model of hematopoietic stem cell organization with application to chronic myeloid leukemia.

Science.gov (United States)

Roeder, Ingo; Herberg, Maria; Horn, Matthias

2009-04-01

Previously, we have modeled hematopoietic stem cell organization by a stochastic, single cell-based approach. Applications to different experimental systems demonstrated that this model consistently explains a broad variety of in vivo and in vitro data. A major advantage of the agent-based model (ABM) is the representation of heterogeneity within the hematopoietic stem cell population. However, this advantage comes at the price of time-consuming simulations if the systems become large. One example in this respect is the modeling of disease and treatment dynamics in patients with chronic myeloid leukemia (CML), where the realistic number of individual cells to be considered exceeds 10(6). To overcome this deficiency, without losing the representation of the inherent heterogeneity of the stem cell population, we here propose to approximate the ABM by a system of partial differential equations (PDEs). The major benefit of such an approach is its independence from the size of the system. Although this mean field approach includes a number of simplifying assumptions compared to the ABM, it retains the key structure of the model including the "age"-structure of stem cells. We show that the PDE model qualitatively and quantitatively reproduces the results of the agent-based approach.

Biological therapy and development of neoplastic disease in patients with juvenile rheumatic disease: a systematic review

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Vanessa Patricia L. Pereira

Full Text Available Abstract Juvenile rheumatic diseases affect the musculoskeletal system and begin before the age of 18. These conditions have varied, identifiable or unknown etiologies, but those of an autoimmune inflammatory nature have been associated with an increased risk of development of cancer, regardless of treatment. This study aims to assess, through a systematic review of the literature according to Prisma (Preferred Reporting Items for Systematic Reviews and Meta-Analyses quality criteria, the risk of cancer in patients with juvenile rheumatic disease, and its association with biological agents. The criteria described by the Strengthening the Reporting of Observational Studies in Epidemiology initiative were used in order to assess the methodological quality of those individual items selected in this study. We analyzed nine publications, from a total of 251 papers initially selected. There was an increase in cancer risk in the population with juvenile rheumatic disease versus the general population. Most specified cancers were of a lymphoproliferative nature. Seven studies did not specify the treatment or not defined an association between treatment and cancer risk. Only one study has suggested this association; in it, their authors observed high risk in patients diagnosed in the last 20 years, a period of the advent of new therapies. One study found an increased risk in a population not treated with biological agents, suggesting a disease in its natural course, and not an adverse effect of therapy. Studies have shown an increased risk of malignancy associated with juvenile rheumatic disease, and this may be related to disease activity and not specifically to the treatment with biological agents.

Skeletal Muscle-derived Hematopoietic Stem Cells: Muscular Dystrophy Therapy by Bone Marrow Transplantation

OpenAIRE

Asakura, Atsushi

2012-01-01

For postnatal growth and regeneration of skeletal muscle, satellite cells, a self-renewing pool of muscle stem cells, give rise to daughter myogenic precursor cells that contribute to the formation of new muscle fibers. In addition to this key myogenic cell class, adult skeletal muscle also contains hematopoietic stem cell and progenitor cell populations which can be purified as a side population (SP) fraction or as a hematopoietic marker CD45-positive cell population. These muscle-derived he...

Identification of a population of cells with hematopoietic stem cell properties in mouse aorta-gonad-mesonephros cultures

International Nuclear Information System (INIS)

Nobuhisa, Ikuo; Ohtsu, Naoki; Okada, Seiji; Nakagata, Naomi; Taga, Tetsuya

2007-01-01

The aorta-gonad-mesonephros (AGM) region is a primary source of definitive hematopoietic cells in the midgestation mouse embryo. In cultures of dispersed AGM regions, adherent cells containing endothelial cells are observed first, and then non-adherent hematopoietic cells are produced. Here we report on the characterization of hematopoietic cells that emerge in the AGM culture. Based on the expression profiles of CD45 and c-Kit, we defined three cell populations: CD45 low c-Kit + cells that had the ability to form hematopoietic cell colonies in methylcellulose media and in co-cultures with stromal cells; CD45 low c-Kit - cells that showed a granulocyte morphology; CD45 high c-Kit low/- that exhibited a macrophage morphology. In co-cultures of OP9 stromal cells and freshly prepared AGM cultures, CD45 low c-Kit + cells from the AGM culture had the abilities to reproduce CD45 low c-Kit + cells and differentiate into CD45 low c-Kit - and CD45 high c-Kit low/- cells, whereas CD45 low c-Kit - and CD45 high c-Kit low/- did not produce CD45 low c-Kit + cells. Furthermore, CD45 low c-Kit + cells displayed a long-term repopulating activity in adult hematopoietic tissue when transplanted into the liver of irradiated newborn mice. These results indicate that CD45 low c-Kit + cells from the AGM culture have the potential to reconstitute multi-lineage hematopoietic cells

A Study of the Pathomorphology of Non-Neoplastic Changes in Canine Mammary Glands

OpenAIRE

Knauer, Steffen

2010-01-01

Whilst neoplasia in canine mammae has been the subject of a considerable number of studies, little is known about non-neoplastic changes of the mammae. The aim of the present study was therefore to conduct pathological anatomical and histopathological examinations of mammary glands in order to draw up a survey of the type and frequency of non-tumorous changes in the lactiferous tissues. The material under examination consis...

Epithelial hyperplasia in human polycystic kidney diseases. Its role in pathogenesis and risk of neoplasia.

OpenAIRE

Bernstein, J.; Evan, A. P.; Gardner, K. D.

1987-01-01

The importance of tubular epithelial hyperplasia in polycystic kidney diseases has become apparent during the last decade. Micropapillary hyperplasia occurs in autosomal dominant polycystic kidney disease, in localized cystic disease, and in acquired cystic disease. Neoplastic or severely dysplastic epithelial hyperplasia occurs in von Hippel-Lindau disease. A histopathologically distinctive epithelial hyperplasia occurs in tuberous sclerosis. In each of these conditions, epithelial hyperplas...

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

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Theresa Vasko

2017-10-01

Full Text Available Leukocyte telomere length (TL has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML, indicates clinical outcomes in chronic lymphocytic leukemia (CLL, and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS. In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.

Responsiveness of fetal rat brain cells to glia maturation factor during neoplastic transformation in cell culture

DEFF Research Database (Denmark)

Haugen, A; Laerum, O D; Bock, E

1981-01-01

of gestation. The brains of the treated fetuses were transferred to cell culture and underwent neoplastic transformation with a characteristic sequence of phenotypic alterations which could be divided into five different stages. During the first 40 days after explantation (stage I & II) BE induced...

Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation.

Science.gov (United States)

Li, Wei; Wang, Guanjun; Cui, Jiuwei; Xue, Lu; Cai, Lu

2004-11-01

The aim of this study was to investigate the stimulating effect of low-dose radiation (LDR) on bone marrow hematopoietic progenitor cell (HPC) proliferation and peripheral blood mobilization. Mice were exposed to 25- to 100-mGy x-rays. Bone marrow and peripheral blood HPCs (BFU-E, CFU-GM, and c-kit+ cells) were measured, and GM-CSF, G-CSF, and IL-3 protein and mRNA expression were detected using ELISA, slot blot hybridization, and Northern blot methods. To functionally evaluate LDR-stimulated and -mobilized HPCs, repopulation of peripheral blood cells in lethally irradiated recipients after transplantation of LDR-treated donor HPCs was examined by WBC counts, animal survival, and colony-forming units in the recipient spleens (CFUs-S). 75-mGy x-rays induced a maximal stimulation for bone marrow HPC proliferation (CFU-GM and BFU-E formation) 48 hours postirradiation, along with a significant increase in HPC mobilization into peripheral blood 48 to 72 hours postradiation, as shown by increases in CFU-GM formation and proportion of c-kit+ cells in the peripheral mononuclear cells. 75-mGy x-rays also maximally induced increases in G-CSF and GM-CSF mRNA expression in splenocytes and levels of serum GM-CSF. To define the critical role of these hematopoietic-stimulating factors in HPC peripheral mobilization, direct administration of G-CSF at a dose of 300 microg/kg/day or 150 microg/kg/day was applied and found to significantly stimulate GM-CFU formation and increase c-kit+ cells in the peripheral mononuclear cells. More importantly, 75-mGy x-rays plus 150 microg/kg/day G-CSF (LDR/150-G-CSF) produced a similar effect to that of 300 microg/kg/day G-CSF alone. Furthermore, the capability of LDR-mobilized donor HPCs to repopulate blood cells was confirmed in lethally irradiated recipient mice by counting peripheral WBC and CFUs-S. These results suggest that LDR induces hematopoietic hormesis, as demonstrated by HPC proliferation and peripheral mobilization, providing a

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Presenting with Advanced Disease or Failing Treatment with Tyrosine Kinase Inhibitors.

Science.gov (United States)

Nair, Anish P; Barnett, Michael J; Broady, Raewyn C; Hogge, Donna E; Song, Kevin W; Toze, Cynthia L; Nantel, Stephen H; Power, Maryse M; Sutherland, Heather J; Nevill, Thomas J; Abou Mourad, Yasser; Narayanan, Sujaatha; Gerrie, Alina S; Forrest, Donna L

2015-08-01

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for chronic myeloid leukemia (CML); however, it is rarely utilized given the excellent long-term results with tyrosine kinase inhibitor (TKI) treatment. The purpose of this study is to examine HSCT outcomes for patients with CML who failed TKI therapy or presented in advanced phase and to identify predictors of survival, relapse, and nonrelapse mortality (NRM). Fifty-one patients with CML underwent HSCT for advanced disease at diagnosis (n = 15), TKI resistance as defined by the European LeukemiaNet guidelines (n = 30), TKI intolerance (n = 2), or physician preference (n = 4). At a median follow-up of 71.9 months, the 8-year overall survival (OS), event-free survival (EFS), relapse, and NRM were 68%, 46%, 41%, and 23%, respectively. In univariate analysis, predictors of OS included first chronic phase (CP1) disease status at HSCT (P = .0005), European Society for Blood and Marrow Transplantation score 1 to 4 (P = .04), and complete molecular response (CMR) to HSCT (P treatment to optimize transplantation outcomes. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The role of apoptosis in the development of AGM hematopoietic stem cells revealed by Bcl-2 overexpression

NARCIS (Netherlands)

C. Orelio; K.N. Harvey; C. Miles; R.A. Oostendorp (Robert); K. van der Horn; E.A. Dzierzak (Elaine)

2004-01-01

textabstractApoptosis is an essential process in embryonic tissue remodeling and adult tissue homeostasis. Within the adult hematopoietic system, it allows for tight regulation of hematopoietic cell subsets. Previously, it was shown that B-cell leukemia 2 (Bcl-2) overexpression in

Reexamination of the role of hematopoietic organs on the ...

African Journals Online (AJOL)

STORAGESEVER

2009-08-04

Aug 4, 2009 ... Sciences, 300 Fenglin Rd. Shanghai 200032, P.R. China. ... Key words: Hematopoietic organ, wing disc, hemocytes, surgical operation, silkworm, ... They were reared on artificial diet at 25°C under a 16 h ..... The image was.

UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

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Patrizia Tosi

2012-01-01

Full Text Available

Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

Hodgkin's disease following thorium dioxide angiography

Energy Technology Data Exchange (ETDEWEB)

Gotlieb, A I; Kirk, M E [McGill Univ., Montreal, Quebec (Canada). Dept. of Pathology; Hutchison, J L [Montreal General Hospital, Quebec (Canada)

1976-09-04

Hodgkin's disease occurred in a 53-year-old man who, 25 years previously, had undergone cerebral angiography, for which thorium dioxide suspension (Thorotrast) was used. Deposits of thorium dioxide were noted in reticuloendothelial cells in various locations. An association between thorium dioxide administration and the subsequent development of malignant tumours and neoplastic hematologic disorders has previously been reported.

MR imaging of hematopoietic regions in bone marrow of aplastic anemia. Diagnostic usefulness of opposed phase T1-weighted images

Energy Technology Data Exchange (ETDEWEB)

Amano, Yasuo; Tanabe, Yoshihiro; Amano, Maki; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan)

1996-01-01

The signal intensity of hematopoietic regions in the marrow of aplastic anemia were investigated on opposed phase T1-weighted images (op-T1WI) with a 0.5-Tesla MR unit. Hematopoietic regions were classified into two groups: low intensity hematopoietic areas (LH) isointense to normal marrow and high intensity hematopoietic regions (HH) with higher intensity than normal marrow on op-T1WI. The signal intensity of LH was significantly lower than that of HH on STIR. LH converted into HH with improvement of laboratory data after therapy, whereas HH decreased with impairment of data. HH were hyperintense to cerebrospinal fluid on op-T1WI. These results indicated that the signal intensity of hematopoietic regions on op-T1WI reflected the cellularity in these regions and that aplastic anemia included hypercellular regions relative to normal marrow. (author).

Identifying States along the Hematopoietic Stem Cell Differentiation Hierarchy with Single Cell Specificity via Raman Spectroscopy.

Science.gov (United States)

Ilin, Yelena; Choi, Ji Sun; Harley, Brendan A C; Kraft, Mary L

2015-11-17

A major challenge for expanding specific types of hematopoietic cells ex vivo for the treatment of blood cell pathologies is identifying the combinations of cellular and matrix cues that direct hematopoietic stem cells (HSC) to self-renew or differentiate into cell populations ex vivo. Microscale screening platforms enable minimizing the number of rare HSCs required to screen the effects of numerous cues on HSC fate decisions. These platforms create a strong demand for label-free methods that accurately identify the fate decisions of individual hematopoietic cells at specific locations on the platform. We demonstrate the capacity to identify discrete cells along the HSC differentiation hierarchy via multivariate analysis of Raman spectra. Notably, cell state identification is accurate for individual cells and independent of the biophysical properties of the functionalized polyacrylamide gels upon which these cells are cultured. We report partial least-squares discriminant analysis (PLS-DA) models of single cell Raman spectra enable identifying four dissimilar hematopoietic cell populations across the HSC lineage specification. Successful discrimination was obtained for a population enriched for long-term repopulating HSCs (LT-HSCs) versus their more differentiated progeny, including closely related short-term repopulating HSCs (ST-HSCs) and fully differentiated lymphoid (B cells) and myeloid (granulocytes) cells. The lineage-specific differentiation states of cells from these four subpopulations were accurately identified independent of the stiffness of the underlying biomaterial substrate, indicating subtle spectral variations that discriminated these populations were not masked by features from the culture substrate. This approach enables identifying the lineage-specific differentiation stages of hematopoietic cells on biomaterial substrates of differing composition and may facilitate correlating hematopoietic cell fate decisions with the extrinsic cues that

Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia

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Miguel Quijada-Álamo

2017-04-01

Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. Methods Amplicon-based deep next-generation sequencing (NGS studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56 to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19− early hematopoietic progenitors. Fluorescence in situ hybridization (FISH studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities. Results NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9 and XPO1 (4/4 mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2, FBXW7 (2/2, and SF3B1 (3/4 showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19− early hematopoietic progenitors (6/7. Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2 in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of

A Microbiomic Analysis in African Americans with Colonic Lesions Reveals Streptococcus sp.VT162 as a Marker of Neoplastic Transformation

Directory of Open Access Journals (Sweden)

Hassan Brim

2017-11-01

Full Text Available Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis (CRC. To detect bacterial markers of colorectal cancer in African Americans a metabolomic analysis was performed on fecal water extracts. DNA from stool samples of adenoma and healthy subjects and from colon cancer and matched normal tissues was analyzed to determine the microbiota composition (using 16S rDNA and genomic content (metagenomics. Metagenomic functions with discriminative power between healthy and neoplastic specimens were established. Quantitative Polymerase Chain Reaction (q-PCR using primers and probes specific to Streptococcus sp. VT_162 were used to validate this bacterium association with neoplastic transformation in stool samples from two independent cohorts of African Americans and Chinese patients with colorectal lesions. The metabolomic analysis of adenomas revealed low amino acids content. The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. Cross-mapping of metagenomic data led to 9 markers with significant discriminative power between normal and diseased specimens. These markers identified with Streptococcus sp. VT_162. Q-PCR data showed a statistically significant presence of this bacterium in advanced adenoma and cancer samples in an independent cohort of CRC patients. We defined metagenomic functions from Streptococcus sp. VT_162 with discriminative power among cancers vs. matched normal and adenomas vs. healthy subjects’ stools. Streptococcus sp. VT_162 specific 16S rDNA was validated in an independent cohort. These findings might facilitate non-invasive screening for colorectal cancer.

Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

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Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R

2017-03-06

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1 / Hoxa9 -driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. © 2017 Guitart et al.

Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells.

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Garba, Abubakar; Acar, Delphine D; Roukaerts, Inge D M; Desmarets, Lowiese M B; Devriendt, Bert; Nauwynck, Hans J

2017-09-01

Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell

Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

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Liu, Q-F; Ling, Y-W; Fan, Z-P; Jiang, Q-L; Sun, J; Wu, X-L; Zhao, J; Wei, Q; Zhang, Y; Yu, G-P; Wu, M-Q; Feng, R

2013-08-01

To evaluate the diagnostic and prognostic utility of monitoring the Epstein-Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV-associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 172 patients undergoing allo-HSCT were enrolled in the study. The EBV DNA levels of blood were monitored regularly in recipients of transplants for 3 years post transplantation. The EBV DNA levels of CSF were monitored in patients with EBV-associated CNS diseases before the treatment and at different points following the treatment. Post-transplant EBV-associated diseases developed in 27 patients, including 12 patients with EBV-associated CNS diseases. The 3-year cumulative incidences of EBV-associated diseases and EBV-associated CNS diseases were 19.5 ± 3.5% and 8.6 ± 2.4%, respectively. Patients with EBV-associated diseases showed higher loads of EBV DNA in their blood compared with patients with EBV DNA-emia. No difference was seen between the EBV DNA levels of blood in patients with CNS involvement and patients without CNS involvement. The EBV DNA loads of blood increased 3-14 days before the clinical manifestations of EBV-associated diseases emerged. The EBV DNA loads of CSF were higher than that of blood in patients with EBV-associated CNS diseases. In 12 patients with EBV-associated CNS diseases, EBV DNA levels were declining in both blood and CSF with the control of diseases, and the EBV DNA loads of CSF decreased faster than that of blood in 5 patients who responded to treatment, and the EBV DNA levels of CSF increased in 5 patients who were unresponsive to treatment. On multivariate analysis, the use of anti-thymocyte globulin and intensified conditioning regimens were independent risk factors for EBV-associated diseases and EBV-associated CNS diseases. EBV-associated CNS diseases are not rare after allo-HSCT. The EBV DNA loads of CSF could act as an important

Rehabilitative intervention during and after pediatric hematopoietic stem cell transplantation: An analysis of the existing literature.

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Rossi, Francesca; Coppo, Monica; Zucchetti, Giulia; Bazzano, Daniela; Ricci, Federica; Vassallo, Elena; Nesi, Francesca; Fagioli, Franca

2016-11-01

Hematopoietic stem cell transplantation is a therapeutic strategy for several oncohematological diseases. It increases survival rates but leads to a high incidence of related effects. The objective of this paper was to examine the existing literature on physical exercise interventions among pediatric HSCT recipients to explore the most often utilized rehabilitative assessment and treatment tools. Studies published from 2002 to April 1, 2015 were selected: 10 studies were included. A previous literary review has shown that rehabilitation programs have a positive impact on quality of life. Our analysis identified some significant outcome variables and shared intervention areas. © 2016 Wiley Periodicals, Inc.

Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation.

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Cole, Theresa; Pearce, Mark S; Cant, Andrew J; Cale, Catherine M; Goldblatt, David; Gennery, Andrew R

2013-11-01

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by serious infections and inflammation. It can be managed conservatively with prophylactic antimicrobial agents or curatively with hematopoietic stem cell transplantation (HSCT). In the United Kingdom and Ireland there are cohorts of children managed both conservatively and curatively. This study aimed to compare clinical outcomes (mortality and morbidity) in children managed conservatively and curatively. Children were identified from specialist centers and advertising through special interest groups. Clinical data were collected from medical records regarding infections, inflammatory complications and growth, other admissions, and curative treatment. Comparisons were made for patients not undergoing HSCT and patients after HSCT. Seventy-three living children were identified, 59 (80%) of whom were recruited. Five deceased children were also identified. Clinical information was available for 62 children (4 deceased). Thirty (48%) children had undergone HSCT. Children who did not undergo transplantation had 0.71 episodes of infection/admission/surgery per CGD life year (95% CI, 0.69-0.75 events per year). Post-HSCT children had 0.15 episodes of infection/admission/surgery per transplant year (95% CI, 0.09-0.21 events per year). The mean z score for height and body mass index (BMI) for age was significantly better in post-HSCT children. Survival in the non-HSCT group was 90% at age 15 years. Survival in the post-HSCT group was 90%. Children with CGD not undergoing transplantation have more serious infections, episodes of surgery, and admissions compared with post-HSCT children. Children undergoing transplantation have better height for age. Survival is good at the end of the pediatric age range and also after HSCT. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation

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T. M. Haverman

2014-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis.

Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

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Ju Huang

2017-06-01

Full Text Available Fabry disease is a rare lysosomal storage disorder (LSD. We designed multiple recombinant lentivirus vectors (LVs and tested their ability to engineer expression of human α-galactosidase A (α-gal A in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.

Diseases of the peritoneum and mesenterium

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Ba-Ssalamah, A.; Uffmann, M.; Bastati, N.; Schima, W.

2009-01-01

Peritoneal diseases can be seen in the different imaging modalities either as fluid collections or solid tumors along the ligaments, mesenteries, and spaces of the peritoneal cavity. The broad spectrum of different abnormalities includes inflammatory, infectious, traumatic, and neoplastic diseases. In this article, a large variety of peritoneal abnormalities such as ascites, peritonitis, intraperitoneal hemorrhage, and both primary and secondary peritoneal tumors are discussed. The different imaging modalities, characteristic radiological features, and typical pathways of anatomic spread are explained. (orig.) [de

Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases.

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Liu, Peng; Wang, Boshi; Yan, Xia; Cai, Jingjing; Wang, Yu

2016-12-01

To investigate the nutritional status of patients before and after hematopoietic stem cell transplantation (HSCT), and explore optimal methods for assessing nutritional status in patients with hematological diseases. This cohort study enrolled 170 patients who were diagnosed with hematological diseases and underwent allogeneic HSCT in the Department of Hematology, Peking University People's Hospital between May 2011 and April 2013. We used fixed-point continuous sampling and four nutritional screening tools, Nutritional Risk Screening 2002 (NRS-2002), Mini Nutritional Assessment (MNA), Subjective Global Assessment (SGA) and Malnutrition Universal Screening Tools (MUST), in combination with body measurements, to extensively screen and evaluate nutritional risks and status in patients receiving HSCT before entering and after leaving laminar air flow rooms. After HSCT, patients had significant reduction in weight, hip circumference, waist-hip ratio, calf circumference, mid-upper arm circumference, and suprailiac skinfold thickness compared with pre-HSCT measurements. Before HSCT, NRS-2002 identified that 21.2% of patients were at nutritional risks, compared with 100% after HSCT. MUST indicated that before HSCT, 11.77% of patients were at high nutritional risk, compared with 59.63% after HSCT. MNA assessed that 0.06% of patients were malnourished before HSCT, compared with 19.27% after HSCT. SGA identified that before HSCT, 1.76% of patients had mild to severe malnutrition, which increased to 83.3% after HSCT. There is a significant increase in the nutritional risk and malnutrition in patients who received HSCT. Before HSCT, some patients already had nutritional risk or nutritional deficiencies, and prompt and close nutritional screening or assessment should be performed. The nutritional status of patients after HSCT was generally deteriorated compared with that before transplantation. Body measurements should be taken more frequently during the subsequent treatment

Multistep change in epidermal growth factor receptors during spontaneous neoplastic progression in Chinese hamster embryo fibroblasts

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Wakshull, E.; Kraemer, P.M.; Wharton, W.

1985-01-01

Whole Chinese hamster embryo lineages have been shown to undergo multistep spontaneous neoplastic progression during serial passage in culture. The authors have studied the binding, internalization, and degradation of 125 I-labeled epidermal growth factor at four different stages of transformation. The whole Chinese hamster embryo cells lost cell surface epidermal growth factor receptors gradually during the course of neoplastic progression until only 10% of the receptor number present in the early-passage cells (precrisis) were retained in the late-passage cells (tumorigenic). No differences in internalization rates, chloroquine sensitivity, or ability to degrade hormone between the various passage levels were seen. No evidence for the presence in conditioned medium of transforming growth factors which might mask or down-regulate epidermal growth factor receptor was obtained. These results suggest that a reduction in cell surface epidermal growth factor receptor might be an early event during spontaneous transformation in whole Chinese hamster embryo cells

Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish.

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Tiffany J Glass

Full Text Available Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT. In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20 Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2 in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p ≤ 0.0001, and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b -/- zebrafish, (odysseus, cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI, Total body irradiation (TBI, SDF-1, Zebrafish, hematopoietic cell transplant.

HPV genotype distribution and anomalous association of HPV33 to cervical neoplastic lesions in San Luis Potosí, Mexico.

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DelaRosa-Martínez, Raúl; Sánchez-Garza, Mireya; López-Revilla, Rubén

2016-01-01

The association of human papillomavirus (HPV) types to neoplastic lesions increase as a function of their oncogenicity and the duration of the infection since lesion severity progresses from low-grade to high-grade and cancer. In an outbreak, the prevalence of the HPV type involved would increase and the proportion of the associated low-grade lesions would predominate over severe lesions. In this study, the prevalence of HPV types and their association to neoplastic lesions was determined in women subjected to colposcopy in San Luis Potosí, Mexico. DNA from high-risk (HR) and low-risk (LR) HPV types was identified by E6 nested multiplex PCR in cervical scrapes from 700 women with normal cytology, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL) or invasive cervical cancer (CC). Overall HPV-DNA prevalence was 67.7 %, that of HR-HPV was 63.1 %, and that of LR-HPV was 21.3 %. The highest prevalence (78.2 %) occurred in the 15-24 year group, whereas that of single infections was 52 % and that of multiple infections (i.e., by 2-6 HPV types) was 48 %. The most prevalent HR types were HPV33 (33.1 %), HPV16 (16.6 %), HPV18 and HPV51 (6.7 % each). HR-HPV prevalence was 29.6 % in normal cytology, 26.7 % in ASCUS, 63.3 % in LSIL, 68.2 % in HSIL, and 90.5 % in CC. Three prevalence trends for HR-HPV types were found in neoplastic lesions of increasing severity: increasing (LSIL  CC) for HPV33. Two-thirds of the women subjected to colposcopy from 2007 to 2010 in San Luis Potosí have HPV infections which predominate in the 15-24 years group. Around half of the infections are by one viral type and the rest by 2-6 types. HPV33 is the most prevalent type, followed by HPV16. Overall HR-HPV prevalence increases with the severity of neoplastic lesions. HPV33 prevalence is highest in LSIL and its U-shaped trend with progressing neoplastic lesions

Selenium, selenoenzymes, oxidative stress and risk of neoplastic progression from Barrett's esophagus: results from biomarkers and genetic variants.

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Yumie Takata

Full Text Available Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1 concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85. SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR = 3.95, 95% confidence intervals (CI = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58, but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69. Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1

Alcohol consumption and the neoplastic progression in Barrett's esophagus: a systematic review and meta-analysis.

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Zhifeng Lou

Full Text Available PURPOSE: In the developed countries, the incidence of esophageal adenocarcinoma (EAC is increasing over recent decades. The purpose of this meta-analysis was to arrive at quantitative conclusions about the contribution of alcohol intakes and the progression of Barrett's esophagus. METHODS: A comprehensive, systematic bibliographic search of medical literature published up to Oct 2013 was conducted to identify relevant studies. A meta-analysis was conducted for alcohol consumption on the Barrett's esophagus progression. RESULTS: A total of 882 cases in 6,867 individuals from 14 observational studies were indemnified in this meta-analysis. The result of this current meta-analysis, including 10 case-control and 4 cohort studies, indicated that alcohol consumption was not associated with the neoplastic progression in Barrett's esophagus (RR, 1.17; 95% CI, 0.93-1.48. When stratified by the study designs, no significant association was detected in either high vs low group or ever vs never group. CONCLUSIONS: Alcohol drinking is not associated with risk of neoplastic progression in Barrett's esophagus. Further well designed studies are needed in this area.

Improvement in the quality of hematopoietic prostaglandin D synthase crystals in a microgravity environment

International Nuclear Information System (INIS)

Tanaka, Hiroaki; Tsurumura, Toshiharu; Aritake, Kosuke; Furubayashi, Naoki; Takahashi, Sachiko; Yamanaka, Mari; Hirota, Erika; Sano, Satoshi; Sato, Masaru; Kobayashi, Tomoyuki; Tanaka, Tetsuo; Inaka, Koji; Urade, Yoshihiro

2011-01-01

Crystals of hematopoietic prostaglandin D synthase grown in microgravity show improved quality. Human hematopoietic prostaglandin synthase, one of the better therapeutic target enzymes for allergy and inflammation, was crystallized with 22 inhibitors and in three inhibitor-free conditions in microgravity. Most of the space-grown crystals showed better X-ray diffraction patterns than the terrestrially grown ones, indicating the advantage of a microgravity environment on protein crystallization, especially in the case of this protein

Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

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Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro

2016-01-01

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H 4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H 4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H 4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H 4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. - Highlights: • HL-60

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

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Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC.

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Scarpa, Marco; Scarpa, Melania; Castagliuolo, Ignazio; Erroi, Francesca; Kotsafti, Andromachi; Basato, Silvia; Brun, Paola; D'Incà, Renata; Rugge, Massimo; Angriman, Imerio; Castoro, Carlo

2016-03-01

BACKGROUND PROMOTER: hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC. The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC. Colonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. Methylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patient's surveillance interval and to select UC patients who should undergo intensive surveillance.

Oxidative stress in normal hematopoietic stem cells and leukemia.

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Samimi, Azin; Kalantari, Heybatullah; Lorestani, Marzieh Zeinvand; Shirzad, Reza; Saki, Najmaldin

2018-04-01

Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject. © 2018 APMIS. Published by John Wiley & Sons Ltd.

Collection and composition of autologous peripheral blood stem cells graft in patients with acute myeloid leukemia: influence on hematopoietic recovery and outcome.

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Raos, Mirela; Nemet, Damir; Bojanić, Ines; Sertić, Dubravka; Batinić, Drago; Dusak, Vesna; Dubravcić, Klara; Mazić, Sanja; Serventi-Seiwerth, Ranka; Mrsić, Mirando; Golubić-Cepulić, Branka; Labar, Boris

2010-03-01

Hematopoietic stem cell (HSC) transplantation is a standard approach in the treatment of hematological malignant diseases. For the last 15 years the main source of cells for transplantation have been peripheral blood stem cells (PBSC). With the availability of hematopoietic growth factors and understanding the advantages of treatment with PBSC, the application of bone marrow (BM) was supplanted. The aim of this survey was to explore the success of PBSC collection, the factors which influence the success of PBSC collection, the composition and the quality of graft and their influence on hematopoietic recovery and outcome after transplantation in patients with acute myeloid leukemia (AML). PBSC were collected by the method of leukapheresis after applying a combination of chemotherapy and growth factors or only growth factors. The quality of graft was determined with the clonogenic progenitor cell assay and with the flow cytometry analysis. Of the total 134 patients with AML, who were submitted to HSC mobilization, the collection was successful in 78 (58.2%) patients. The collection was more successful after the first than after the second attempt of HSC mobilization (49% vs. 11%). The criteria for effective mobilization were the number of leukocytes > 3 x 10(9)/L and the concentration of CD34+ cells > 20 x 10(3)/mL in the peripheral blood on the first day of leukapheresis. The number of CD34+ cells infused had the strongest impact on hematopoietic recovery. We noted significantly faster hematological recovery of neutrophils and platelets, fewer number of transfused units of red blood cells and platelets, shorter duration of the tranfusion support, shorter treatment with intravenous antibiotic therapy and shorter hospitalization after PBSC compared to BM transplantation. These advantages could provide their standard application in the treatment of patients with AML.

Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block

DEFF Research Database (Denmark)

Kirstetter, Peggy; Anderson, Kristina; Porse, Bo T

2006-01-01

Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression...... of hematopoietic stem cell function was associated with decreased expression of Cdkn1a (encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 (encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1...... of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss...

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Science.gov (United States)

Gloude, Nicholas J; Jodele, Sonata; Teusink-Cross, Ashley; Grimley, Michael; Davies, Stella M; Lane, Adam; Myers, Kasiani C

2018-01-01

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m 2 per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A case series of clinically undiagnosed hematopoietic neoplasms discovered at autopsy.

Science.gov (United States)

Podduturi, Varsha; Guileyardo, Joseph M; Soto, Luis R; Krause, John R

2015-06-01

In the United States, autopsy rates have diminished to less than 5% during the last half of the 20th century and the beginning of the 21st century for a multitude of reasons. Many believe this results in unrecognized malignancies that could have explained a patient's death. We describe six deaths in which hematopoietic neoplasms were identified at autopsy but were not diagnosed clinically. The six undiagnosed hematopoietic malignancy cases discovered at autopsy include four men and two women ranging from 50 to 78 years of age. One patient was African American and five patients were white, all with multiple comorbidities. The tumors included diffuse large B-cell lymphoma, activated B-cell type, intravascular large B-cell lymphoma, ALK-negative anaplastic large cell lymphoma arising in a setting of human immunodeficiency virus, and a myeloid sarcoma. These cases illustrate the importance of the traditional postmortem examination in not only confirming clinical diagnoses but also identifying previously unknown diagnoses. Hematologic malignancies may present with nonspecific clinical manifestations, and this series of cases also emphasizes the necessity for widening the differential diagnosis in patients with unexplained lactic acidosis and hepatic failure to include hematopoietic malignancies since prompt treatment may be lifesaving. Copyright© by the American Society for Clinical Pathology.

Regulation of the hematopoietic stem cell lifecycle by the endothelial niche.

Science.gov (United States)

Ramalingam, Pradeep; Poulos, Michael G; Butler, Jason M

2017-07-01

Hematopoietic stem cells (HSCs) predominantly reside either in direct contact or in close proximity to the vascular endothelium throughout their lifespan. From the moment of HSC embryonic specification from hemogenic endothelium, endothelial cells (ECs) act as a critical cellular-hub that regulates a vast repertoire of biological processes crucial for HSC maintenance throughout its lifespan. In this review, we will discuss recent findings in endothelial niche-mediated regulation of HSC function during development, aging and regenerative conditions. Studies employing genetic vascular models have unequivocally confirmed that ECs provide the essential instructive cues for HSC emergence during embryonic development as well as adult HSC maintenance during homeostasis and regeneration. Aging of ECs may impair their ability to maintain HSC function contributing to the development of aging-associated hematopoietic deficiencies. These findings have opened up new avenues to explore the therapeutic application of ECs. ECs can be adapted to serve as an instructive platform to expand bona fide HSCs and also utilized as a cellular therapy to promote regeneration of the hematopoietic system following myelosuppressive and myeloablative injuries. ECs provide a fertile niche for maintenance of functional HSCs throughout their lifecycle. An improved understanding of the EC-HSC cross-talk will pave the way for development of EC-directed strategies for improving HSC function during aging.

Epidemiologic Profile of Patients Transplanted With Hematopoietic Stem Cells in a Reference Service in the State of Rio Grande do Norte, Brazil.

Science.gov (United States)

Campos de Azevedo, I; Ferreira Júnior, M A; Pereira de Aquino, L A; de Oliveira, A A; Cruz, G K P; de Queiroz Cardoso, A I; Ivo, M L; Santos, V E P

2018-04-01

Hematopoietic stem cell transplantation (HSCT) consists of the intravenous infusion of healthy hematopoietic stem cells to restore the medullary and immunologic function of patients affected by a series of hematologic, oncologic, immunologic, malignant and nonmalignant inherited or acquired diseases, with the possibility of cure or increase of disease-free survival. To characterize the epidemiologic profile and the cases of death of patients who underwent HSCT. This is a cohort quantitative study, nested with a retrospective, descriptive, and analytical study of a hospital-based cohort that included the patients who underwent HSCT at a referral service in the state of Rio Grande do Norte, a region of northeastern Brazil. There was a slight male prevalence (52.94%), the age of the patients ranged from 2 to 73 years old, 18.38% were brown, 47.06% were married, 15.07% were students, 78.31% had a diagnosis of multiple myeloma, 93.38% developed gastrointestinal toxicities, all patients received chemotherapeutic treatment, 54.78% had allogeneic HSCT, and the cause of the most recorded deaths was septic shock (48.19%). This study showed relevant scientific evidence on the clinical and epidemiologic profile of patients who underwent HSCT. In general, sociodemographic data are similar to national and international research results. Copyright © 2018 Elsevier Inc. All rights reserved.

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors