Regina Garcia

Obesity short-circuits stemness gene network in human adipose multipotent stem cells

The discovery of adipose multipotent stem cells has provided new insights to explore cellular mechanisms involved in adipose tissue function. In the present work, we aimed to evaluate how the adipogenic environment influences the stemness of the resident multipotent stem cells. To achieve this goal, human omental multipotent stem cells (hO‐MSCs) were isolated, expanded, and characterized in both healthy lean and morbidly obese individuals. We observed decreased cell proliferation, premature senescence, and increased cytokine secretion associated with increasing body mass index of the patients. Consistent with the latter finding, the hO‐MSCs derived from patients with morbid obesity lose their multilineage differentiation capacity associated with a dysregulation in the Wnt, Notch, and Sonic Hedgehog signaling pathways. Moreover, microRNAs involved in the regulation of stemness, cell differentiation, and senescence were also up‐regulated in obese individuals. Altogether, our data show that obesity causes a general short circuit in the stemness gene network of hO‐MSCs.—Roldan, M., Macias‐Gonzalez, M., Garcia, R., Tinahones, F. J., Martin, M. Obesity short‐circuits stemness gene network in human adipose multipotent stem cells. FASEB J. 25, 4111–4126 (2011). www.fasebj.org

Effect of furosemide upon urinary kallikrein excretion

Having in mind the significant decrease of urinary kallikrein in rat with renal hypertension and in humans with essential hypertension, the effects of furosemide on kininogenase activity has been studied in urine of normal and hypertensive rats which received tap water or a 1% NaCl solution for drinking. Administration of 20 mg furosemide which produces maximal diuretic effect in normal rats, induced in these animals a 150–200% increase of the excretion of this enzyme after 8 hours, when compared to the activity measured before giving the drug. This increase which is observed in the normal rats drinking either water or a 1% NaCl solution shows a significant correlation with the excretion of sodium, potassium and water. In hypertensive rats, in 7 or 9 cases, an increase of kallikrein excretion (200–600%) is observed, which does not reach the levels of excretion in normal untreated rats. Furosemide did not produce increase of urinary kallikrein in hypertensive rats drinking 1% NaCl solution.

Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease

Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and marrow hypoplasia. The majority of cases of aplastic anemia remain idiopathic, although hematopoietic stem cell deficiency and impaired immune responses are hallmarks underlying the bone marrow failure in this condition. Mesenchymal stem/stromal cells constitute an essential component of the bone marrow hematopoietic microenvironment because of their immunomodulatory properties and their ability to support hematopoiesis, and they have been involved in the pathogenesis of several hematologic malignancies. We investigated whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the pathogenesis of aplastic anemia. We found that mesenchymal stem cell cultures can be established from the bone marrow of aplastic anemia patients and display the same phenotype and differentiation potential as their counterparts from normal bone marrow. Mesenchymal stem cells from aplastic anemia patients support the in vitro homeostasis and the in vivo repopulating function of CD34+ cells, and maintain their immunosuppressive and anti-inflammatory properties. These data demonstrate that bone marrow mesenchymal stem cells from patients with aplastic anemia do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease.

Immunoblastic lymphoma and associated non-lymphoid malignancies following two cases of Waldenström's macroglobulinemia. A review of the literature.

To the editor: Waldenstroms macroglobulinemia (WM) is a disease that usually appears in men over 50 years and is characterized by a clonal proliferation of B lymphocytes that infiltrate the bone marrow and other lymphoid organs with a capacity to synthesize and secrete elevated amounts of monoclonal immunoglobulin-M (IgM) (1). Its incidence has been estimated to be only 6% of all B-cell lymphoproliferative disorders, implying a global incidence of 2 to 5 new cases per million persons per yr. The clinical evolution of WM is variable but is usually chronic and progressive, the patients dying of infection, organ failure derived from infiltration, or from unrelated processes (2). However, as occurs in chronic lymphocyte leukemia, which may evolve to a Richter’s syndrome, patients with WM may undergo transformation to immunoblastic lymphoma (IL) (1, 2, 3). Owing to the low incidence of WM and the low frequency of this evolution (less than 10% of WM cases) (2, 3,4), the clinico-biological characteristics, the incidence and the pathogenesis of this transformation have not been well-documented. We report 2 patients with a WM who developed IL:

Allogeneic peripheral stem cell transplantation in a case of hereditary sideroblastic anaemia

We report on a case of pyridoxine refractory hereditary sideroblastic anaemia (HSA) in a 19‐year‐old man who underwent peripheral blood stem cell transplantation (PBSCT) from his HLA‐identical brother. By using short tandem repeat polymorphism, 100% donor cells were observed in peripheral blood on day +21; bone marrow showed mixed chimaerism from day +21 to day +221, when 100% cells of donor origin were observed. The patient developed extensive chronic graft‐versus‐host disease with favourable response to treatment. When the haemoglobin range was normal, a programme of phlebotomies reduced serum ferritin levels. Three years after transplantation, the patient has an ECOG rating of 0, with completely normal haemoglobin values (15u2003g/dl). To our knowledge, this is the first PBSCT reported in a case of hereditary sideroblastic anaemia.

Alternating mini-BEAM/ESHAP as salvage therapy for refractory non-Hodgkin's lymphomas.

Abstractu2002Mini-BEAM and ESHAP are two non-cross-resistant salvage regimens that have been used separately in patients with lymphoma. The aim of the present study was to investigate the efficacy of the combination of these two regimens, administered in alternating cycles, as salvage therapy for refractory non-Hodgkins lymphoma (NHL) patients. A total of 28 patients were included in the study: 14 patients were primary refractory, seven were partial responders, and seven were in relapse. The alternating cycles of mini-BEAM and ESHAP were given until there was maximum response or progression. The overall response rate to mini-BEAM/ESHAP was 39%; 25% of patients achieved a complete response and 14% a partial response. Nevertheless, it should be noted that none of the primary refractory patients responded to this protocol. Nine of the 11 patients who responded to mini-BEAM/ESHAP were consolidated with autologous transplantation using BEAM as a conditioning regimen. The survival at 3 years in this group of 11 patients who responded to the salvage regimen is 64%, with a disease-free survival of 67% at 2 years. No major toxic effects were observed with mini-BEAM/ESHAP. Myelosuppression was the most frequent complication, especially with the mini-BEAM cycles. Other toxicities were infrequent and no treatment-related deaths were observed. These results suggest that alternating mini-BEAM/ESHAP chemotherapy is a safe regimen that is effective in partial responders or relapsing patients with NHL who have sensitive disease, but not in primary refractory patients. Moreover, although this therapy has a potential advantage, combining as it does two non-cross-resistant regimens, it does not seem superior to ESHAP alone.

Response to erythropoietic stimulating agents in patients with chronic myelomonocytic leukemia

The efficacy of erythropoietic‐stimulating agents (ESA) in chronic myelomonocytic leukemia (CMML) is unknown. Our objective was to analyze erythroid response (ER) and overall survival (OS) in a series of 94 patients with CMML treated with ESA.

Blood Kininogen in Renal Hypertensive Rats

Summary In renal hypertensive rats whose hypertension was induced by a figure-in-eight ligature of one kidney and the removal of the contralateral one, a significant increase in blood kininogen was found (P < 0.001). Kininogen determination was carried out using trypsin as kininogenase, and the kinins formed were tested by using two bioassays: isolated rat uterus and cat jejunum. Kininogen average values in 15 hypertensive rats were equivalent to 7.75 ± 6.2 μg Br/ml when using the uterus, and 4.1 ± 1.5 with the cat jejunum bioassay. In a control group of 14 rats, both biological tests gave the average values of 2.15 ± 64 and 1.4 ± 33 μg Br/ml, respectively. In the hypertensive rats, a significant increase in uremia was also observed. Results indicate that the renal impairment produced by the kidney ligature alters the kallikrein substrate in the blood and lend support to the theory that renal kallikrein might be involved in some systemic regulation.