bluuebunny/crossref_metadata_2025_split huggingface dataset:
Left Ventricular Function Declines with Increasing Myocardial Ferritin Iron in Thalassemia Major.
Authors: Sheth Sujit , Tang Haiying , Jensen Jens H. , Altmann Karen , Prakash Ashwin , Printz Beth F. , Brown Anthony L. , Hordof Allan J. , Tosti Christina L. , Azabagic Andjela , Swaminathan Srirama , Brown Truman R. , Olivieri Nancy F. , Brittenham Gary M. 
Published: April 2020

Abstract
Using a new magnetic resonance method that separately estimates the two principal forms of storage iron, ferritin and hemosiderin, in the heart, we examined the relationship between myocardial storage iron fractions and left ventricular function in thalassemia major. In patients with iron overload, the amount of iron in functional and transport pools changes only slightly. Virtually all of the excess is sequestered in storage forms of iron, as ferritin, a diffuse, soluble fraction, and as hemosiderin, an aggregate, insoluble fraction. The two storage forms of iron strongly affect signal intensity in both T2 and T2* weighted images but influence MRI signal decay through different means because of their differences in solubility and in intracellular distribution (Magn Reson Med2002; 47:1131–8). Separate estimates of the iron concentrations of the two forms of storage iron may be obtained by measuring two distinct relaxation parameters, the “ferritin iron index” (“reduced” transverse relaxation rate) RR2, and the “hemosiderin iron index”, A. We studied 14 patients with thalassemia major, all being treated with subcutaneous deferoxamine. Study participants were examined with a Philips 1.5 T Intera scanner using three Carr-Purcell-Meiboom-Gill (CPMG)-like multi-echo spin echo sequences with varied inter-echo times, using electrocardiographic triggering and respiratory navigator gating to estimate RR2 and A. The left ventricular shortening fraction was measured using standard echocardiographic methods. The Figure shows the relationship (R=0.91, p&lt;0.0001) between the ferritin index, RR2, and the left ventricular shortening fraction.
Figure Figure
Overall, variation in the ferritin index explained more than 80% of the variation in ventricular function. For comparison, variation in the hemosiderin index, A, accounted for only about 33% of the variation in shortening fraction. Using an empirical calibration to estimate iron concentrations, variation in total (ferritin + hemosiderin) iron accounted for only about 40% of the variation in ventricular function. In patients with thalassemia major, the concentration of ferritin iron may provide a better indicator of the magnitude of the toxic iron pool than the total storage iron concentration. Magnetic resonance determinations of the partition of storage iron between ferritin and hemosiderin may be clinically valuable in evaluating tissue iron toxicity in patients with transfusional iron overload.
Vibrio parahaemolyticus Flagellin Stimulates the Maturation of Human Monocyte-Derived Dendritic Cells and Elicits Th1-Type Immune Response.
Authors: Kang Hyun-Kyu , Park Myong-Suk , Lee Shee-Eun , Rhee Joon-Haeng , Park Jung-Sun , Nguyen Thanh-Nhan , Zhu Xiao-Wei , Cho Duck , Nam Jong-Hee , Kim Young-Jin , Kim Hyeoung Joon , Lee Je-Jung 
Published: April 2020

Abstract
Flagellin, the principal component of bacterial flagella, interacts with Toll-like receptor (TLR5) and induces the generation of a pro-inflammation response and activation of host dendritic cells (DCs) in vivo. In this study, we investigated the role of Vibrio parahaemolyticus (V. parahaemolyticus)-derived flagellin as a DC maturation-inducing molecule. V. parahemolyticus-derived flagellin (100–1,000 ng/ml) induced the maturation of human monocyte-derived dendritic cells in a concentration-dependent manner with maximal effect at 500 ng/ml of flagellin as determined by increased levels of surface markers, namely, CD1a, CD80, CD86, CD83, and HLA-DR, a response which could be compared with the phenotypic change in immature DCs (iDCs) treated with lipopolysaccharide (LPS) or cytokine cocktails (CC) with TNF-α, IL-1β, IL-6, and PGE2. Moreover, V. parahaemolyticus-derived flagellin also reduced phagocytic activity, and increased IL-12 production in a polymyxin B-insensitive manner and DC-mediated T cell proliferation, which is comparable with that of LPS- or CC-treated iDCs at several responder to stimulator ratios, suggesting the functional maturation of DCs by V. parahaemolyticus-derived flagellin. Maturation of DCs by V. parahaemolyticus-derived flagellin also elicited a significant increase in specific cytotoxic activity against target cells at several effector to target cells ratios as determined by 51Cr-release assay, and induced Th1-type immune response, such as increase in INF-γ producing cells, determined by ELISPOT assay and analysis of intracellular cytokine staining assay. Taken together, this study demonstrates the role of V. parahaemolyticus-derived flagellin in the functional maturation of DCs, and suggests that V. parahaemolyticus-derived flagellin as a useful molecule for the development of a DC-based immunotherapy against tumors.
In Vivo Tracking of Macrophage Activated Killer Cells to Sites of Metastatic Ovarian Carcinoma.
Authors: Ritchie David S. , Mileshkin Linda , Wall Dominic M. , Bartholyens Jacques , Thompson Mick , Hicks Rod , Prince Miles 
Published: April 2020

Abstract
Radio-labelling of blood cells is an established technique for evaluating in vivo migration to sites of pathology such as infection and haemorrhage. We describe the use of two methods of cell labelling for tracking the destination of autologous-derived macrophage activated killer (MAK) cells linked to the bi-specific anti-her2neu antibody MDX-H210 delivered either by intravenous (iv) or intraperitoneal (ip) injection in ten patients with peritoneal relapse of epithelial ovarian carcinoma. Our results demonstrate the feasibility of generating high numbers and purity of GMP quality MAK cells, which can be efficiently radiolabeled. MAK cell administration produced minimal infusional toxicity and demonstrated a reproducible pattern of in vivo distribution to the lungs, liver and spleen in addition to active in vivo tracking to sites of known tumor following either iv (8 of 16 infusions) or ip (4 of 6 infusions) using either 18F-FDG or 111In-labelled cells. The addition of MDX-H210 monoclonal antibody did not alter the distribution of cells to tumor sites, but did alter the in vivo distribution of cells administered by iv injection. This study demonstrates that cellular cancer immunotherapies may be successfully delivered to sites of active tumor and allows selection of those patients who may benefit from these approaches.
Effect of Enzyme Replacement Therapy on Bone Mineral Density in Type 1 Gaucher Disease.
Authors: Wenstrup Richard , Kacena Katherine , Kaplan Paige , Pastores Gregory , Prakash-Cheng Ainu , Zimran Ari , Hangartner Thomas 
Published: April 2020

Abstract
Objective: To determine the effect of enzyme replacement therapy (ERT; Cerezyme®, imiglucerase for injection) on bone mineral density (BMD) in patients with type 1 Gaucher disease (GD).
Methods: The GD population included all adults (males 18–70y, females 18–50y) with type 1 GD enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom serial spine BMD measurements were submitted. BMD data with up to 12 years of follow-up were analyzed for 111 patients not on ERT, 218 patients on ERT only and 34 patients on ERT plus bisphosphonates. BMD was measured by dual energy X-ray absorptiometry (DXA) Z-scores (age and sex-adjusted) in the lumbar spine of each patient. All measurements were compared to a reference population (Hologic reference standard).
Results: DXA Z-scores for GD patients not on ERT were significantly lower than the reference population and remained approximately one standard deviation below the reference population over time (y intercept = −1.01, p&lt;0.001; slope= +0.012, p=0.63). The DXA Z-scores for GD patients receiving ERT-only were also significantly lower than the reference population at baseline, but improved significantly over time, and the model suggests that on average patients do achieve the same values as the reference population after approximately 12 years of ERT (y-intercept = −1.21, p&lt;0.001; slope= +0.092, p&lt;0.001). The DXA Z-scores for GD patients receiving ERT plus bisphosphonates had an even more rapid increase, on average approaching the reference population after approximately 6 years of treatment (y-intercept = −1.23, p&lt;0.001; slope = +0.202, p=.0003).
Discussion and Conclusion: Osteopenia and osteoporosis are common manifestations of type 1 GD. ERT with Cerezyme® significantly improves BMD in patients with GD. Response to treatment with ERT for BMD may be slower than other aspects of GD. On average, GD patients achieve age- and sex-adjusted normal BMD after approximately 12 years of ERT. The addition of bisphosphonates to ERT may produce an additive effect, with patients achieving a normal BMD more rapidly. A normal (age- and sex-adjusted) BMD should be a therapeutic goal for patients with type 1 GD.
Prognostic Factors for Neutropenic Patients Admitted to Intensive Care.
Authors: Silva Madalena , Checa Luisa , Costa Fatima , Moreno Rui , Silva Eduardo G. , Sousa Aida B. 
Published: April 2020

Abstract
The admission of neutropenic patients (pts) to intensive care units (ICU) is controversial, especially when mechanical ventilation is required. Knowledge of the relative prognostic impact of factors related to the underlying disease and to the severity of acute organ failures might help avoiding futile admissions. We retrospectively assessed predictors of 30-day mortality in neutropenic (&lt;1000/ul) pts referred from a single Hematology unit to the 2 ICUs of the institution over a 10-year period. Of 66 consecutive pts, median age 48 (15–73), 82% had acute leukemia (AL) and 21% were in complete remission (CR). On ICU admission 62% of the pts had a neutrophil count ≤500/ul; microbiologically documented infection was found in 42%. The main reason for ICU referral was severe sepsis or septic shock in 62% of the cases and respiratory failure in 38%. Seventy per cent of the pts were already on vasopressor agents. At ICU entry the median Simplified Acute Physiology Score (SAPS) II was 63 and 26% of pts had ≥ 2 acute organ system failures (OSF). Coma was present in 23%. Mechanical ventilation was eventually needed in 89% and dialysis in 9% of the pts. Mortality at 30 days was 73%. By univariate logistic regression analysis mortality was not significantly related to age, to status of underlying disease (CR vs no CR/not yet known) to duration of neutropenia nor to depth of neutropenia at entry (≤ 500 vs &gt;500/ul). Pts who died were more likely to have non-M3 AL subtype vs M3 (p=0.037), to have ≥ 2 acute OSF vs &lt; 2 (p=0.012) and a higher SAPS II score (p&lt; 0.001). In multivariate analysis only the latter 2 variables remained significant. In conclusion, our data show that 27% of neutropenic pts admitted to ICUs are alive at 30 days; that selection for admission should not be based on the characteristics of the underlying malignancy; and that the 30-day mortality is highly predictable by initial acute illness severity scores.
Autoimmunity Caused by Cell Type-Specific Deficiency in Apoptosis.
Authors: Chen Min , Wang Yui-Hsi , Wang Yihong , Sandoval Hector , Liu Yong-Jun , Wang Jin 
Published: April 2020

Abstract
Apoptosis in the immune system is essential for maintaining self-tolerance. Defective apoptosis causes systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone does not induce significant autoimmune responses, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. To study whether apoptosis in dendritic cells (DCs) regulates self-tolerance, we generated transgenic mice expressing a potent caspase inhibitor from baculovirus, p35, in dendritic cells (DC-p35). DC-p35 transgenic mice displayed defective apoptosis in DCs, leading to DC accumulation, chronic lymphocyte activation and systemic autoimmune manifestations resembling the phenotypes in Fas-deficient lpr mice. Our results suggest that apoptosis in DCs is critical for limiting lymphocyte activation and preventing autoimmunity.
Quantification of CD52 Antigen Expression by Normal and Leukemic Lymphoid Cells: Indications for Anti-CD52 Antibody Therapy?.
Authors: Guarini Anna , De Propris Maria Stefania , Intoppa Stefania , Milani Maria Laura , Lisci Alessandro , Martinelli Marilisa , Vitale Antonella , Mauro Francesca Romana , Foà Robert 
Published: April 2020

Abstract
CD52 is a glycosyl-phosphatidylinositol-anchored protein expressed on the surface of lymphoid cells. Polyclonal and monoclonal anti-CD52 antibodies have been utilized to purge T-lymphocyte populations from the peripheral blood and bone marrow in allogeneic transplantation procedures to prevent graft-versus-host disease. Nowadays, the anti-CD52 monoclonal antibody represents an established tool for the treatment of acute and chronic lymphoproliferative disorders. In this study, we have quantified the levels of expression of the CD52 antigen on the surface of normal B- and T-cell populations, as well as on different acute and chronic leukemic cells of B- and T-cell origin. The quantification of the CD52 antigen was performed by flow cytometry utilizing the QuantiBRITE system and the QuantiCALC software (all instruments, reagents and software came from Becton Dickinson, Immunocytometry System, San Jose, CA). The leukemic cell populations analyzed were obtained from primary B-cell chronic lymphocytic leukemia (CLL) and B- and T-lineage acute lymphoid leukemia (ALL) patients. All analyses were conducted on freshly drawn samples from untreated patients.
In a population of 20 normal adult donors, the CD20+ and CD19+ peripheral B lymphocytes showed 9,581 (median value, range 6,234 – 26,078) and 9,495 (7,259 – 26,196) molecules/cell of the CD52 antigen, respectively. T-cell populations had significantly (p = 0.0001) lower levels of expression of the CD52 antigen: 5,803 molecules/cell on CD3+/CD7+ cells (range 2,917 – 11,056 ). Interestingly, the CD4+ population expressed a significantly higher (p&lt;0.0001) number of CD52 molecules/cell than CD8+ lymphocytes (7,531 median value, range 4,340–12,092 vs 3,178, 2,204–7,591). In 98 CLL samples, the CD19+ leukemic cells showed a median number of CD52 molecules comparable to normal values: 10,205 (range 3,154–36,801). On the contrary, in ALL samples the levels of expression of the CD52 antigen by the leukemic cells was significantly (p = 0.01) lower: in the 8 T-ALL cases analyzed the median value was 1,939 molecules/cell (range 1,110–34,509) and in the 27 B-lineage ALL 1,678 molecules/cell (range 164–7,319). These data can explain the efficacy of the anti-CD52 antibody in the treatment of CLL patients and underline that a close monitoring of the CD4+ population should be performed, particularly in patients who have also received fludarabine. In ALL patients, the clinical results obtained following the administration of the anti-CD52 antibody need to be correlated with the levels of expression of the CD52 antigen on the leukemic cells.
Evidence That Functional Neural Tissue-Committed Stem Cells (NTCSC) Reside in the Human Bone Marrow and Are Mobilized into Peripheral Blood in a Patients after Stroke.
Authors: Kucia Magda , Paczkowska Edyta , Majka Marcin , Machalinski Bogdan , Ratajczak Mariusz Z. 
Published: April 2020

Abstract
The concept that bone marrow (BM)-derived cells participate in neural regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. We recently reported that murine BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSC), including neural TCSC (Leukemia2004:18;29–40). Here we show that these cells could be isolated from murine BM as a population of Sca-1+lin− CD45− cells that not only express neural lineage markers (β-III-tubulin, Nestin, NeuN and GFAP), but more importantly form neurospheres in vitro and cells from these neurospheres after replating into secondary cultures differentiate into neuronal (β-III tubulin+, nestin+) and macroglia (O4+, MBP+, GFAP+) lineages. Our data demonstrate that neural TCSC i) are very rare (0.01% of BMMNC) (ii) present in BM harvested from young (1–2 month) while being barely detectable in older (1-year) mice; iii) are mobilized from BM into peripheral blood (PB) during pharmacological mobilization and iv) are chemoattracted for potential brain regeneration in an SDF-1-CXCR4, dependent manner. In humans the corresponding population of cells is present among CXCR4+CD34+AC133+CD45− BMMNC. Our studies performed on 14 patients with stroke (age 48–75 years) demonstrated in the peripheral blood an increase in the number of CXCR4+CD34+AC133+ cells expressing neural TCSC. The maximal elevation of these cells was observed 24–72 hours after stroke and remained elevated up to one week. The degree of mobilization correlated with younger age, smaller size of the stroke, was best in the patients suffering from a less extensive stroke and worse in patients with dyslipidemias. Thus, we conclude that bone marrow is a potential source of CD45- neural TCSC for brain repair and since purified CD45+ HSC neither express neuronal markers nor differentiate in vitro into neurospheres, we provide for the first time evidence that neural TCSC residing in bone marrow but not trans-dedifferentiated HSC account for neural differentiation of BM-derived cells. Furthermore, our observation that the number of BM-derived neural TCSC decreases with age provides a novel insight into aging and may explain why the brain regeneration process becomes less effective in older individuals. These observations provide rationale for further studies aimed at optimizing therapeutic brain regeneration by BM-derived neural TCSC.
CD4+CD28+ T Lymphoctye Subsets Decreased in Healthy Donors after G-CSF Mobilization.
Authors: Weng Jianyu , Du Xin , Zhang Jianjun , Wu Suijin , Lu Zesheng , Zhou Maohua , Lin Wei , Huang Zilun 
Published: April 2020

Abstract
Objective Allogeneic transplantation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) -mobilized peripheral blood stem cells (PBSCs) is now being increasingly performed, but safety considerations for hematologically normal PBSC donors have not been fully addressed. The effection of G-CSF on donors’ lymphocytes have not been defined clearly. Our study was to detect and analyze the phenotypical and functional properties of lymphocytes from allo-PBSC donors treated with recombinant human G-CSF by flow cytometry. Methods Thirty-four HLA-identical sibling donors (13male, 21female; median age, 35 years) were treated by subcutaneous injection with rhG-CSF at a dose of 5 μg/kg twice daily for 4–6 consecutive days to mobilize HSCs to the peripheral blood. Leukapheresis was performed using a continuous flow blood cell separator (COBE Spectra, Lakewood, CO) on 1 to 2 consecutive days beginning on day 4 of rhG-CSF administration. Donor blood samples, which were obtained before the first administration of G-CSF (pre-G), on day 4 of G-CSF administration (post-G), and one week after the last rhG-CSF were analyzed by 3-color flow cytometry. Monoclonal antibodies included: CD3, CD4, CD8, CD20, CD16, CD56, CD25, CD69, CD45RA, CD45RO, CD28, CD95. Results Absolute counts of lymphocytes, B cells, T cells, CD4+ and CD8+cells post-G were significantly elevated two more times than pre-G (P&lt;0.05), but these changes recovered when the last G-CSF administrated one week later. The percentage of CD3+, CD4+, CD8+ and the ratio of CD4 and CD8 T cells had no significantly difference between pre-G and post-G. The percentage of CD4+CD25+, CD4+CD45RO+ and CD4+CD28+ T cells were significantly decreased post-G (45.26±9.68% to 37.34±11.12%; 65.53±13.74% to 52.32±13.47%; 94.75±4.02% to 91.74±8.72%, P=0.00329, 0.0003 and 0.0947, respectively). We found that CD4+CD28+ T cells(91.77 ± 6.15, P=0.00218) were still lower than pre-G when stopped administrate G-CSF one week later, while others changes have recovered to the Pre-G level. Conclusion: The study shows that CD4+CD28+ T lymphoctye subsets were still lower than pre-G, although most of other change recover one week later after mobilization
Analysis of PRAME Protein Expression in Normal Lymphoid Tissues and during B Ontogenesis.
Authors: de Figueiredo-Pontes Lorena L. , do Nascimento Fabio M. , de Abreu e Lima Rodrigo S. , Proto-Siqueira Rodrigo , Garcia Aglair B. , Matos Daniel M. , Gout Ivan T. , Filonenko Valery V. , Zago Marco A. , Falcao Roberto P. , Rego Eduardo M. 
Published: April 2020

Abstract
PRAME (Preferentially Expressed Antigen in Melanoma) gene was originally isolated in melanoma. A significant increase in the number of PRAME transcripts has been demonstrated in hematologic malignancies such as acute myeloid and lymphoid leukemias, multiple myeloma and chronic lymphoproliferative diseases. Furthermore, our group generated an anti-PRAME monoclonal antibody (MoAb) and by quantitative flow cytometry has demonstrated that PRAME protein was aberrantly expressed in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma. However, the expression of this antigen in normal lymphoid tissues and during B cells ontogeneis has not been characterized. To address this question, PRAME protein expression was studied by flow cytometry in peripheral blood (PB, n=15) and bone marrow (BM, n=6) from healthy donors, lymphonodes (n=4) and spleen (n=4) from patients submitted to lymphonode excision or splenectomy for non malignant diseases. First, we determined in which hematopoietic lineage PRAME was expressed by concomitantly staining PB, BM, lymphonode and spleen mononuclear cells (MCs) with anti-PRAME and a panel of MoAbs specific to B(CD19)/ T(CD3)/ NK(CD16/56), monocytic(CD14) and granulocytic(CD33) markers. PRAME was detected exclusively in CD19+ cells. The median percenatge of PRAME positive cells was 5,31% (2,55–12,34%), 13,01% (8,47–38,15%), 12,79% (3,15–23,06%) and 17,5% (12,67–27,43%) in PB, BM, lymphonode and spleen MCs, respectively. Amongst CD19+ cells, we have observed that PRAME was expressed by 42,39% (16,16–75,72%), 16% (13–69,5%), 15,16% (5,49–41,20%) and 48,82%(12,67–58,89%) in PB, BM, lymphonode and spleen, respectively. To establish in which stage of B ontogenesis PRAME was expressed on, cell suspensions stained with anti-CD19 were submitted to positive magnetic separation and labeled with anti-PRAME, CD5, CD27, CD38, CD34, CD10 and IgD MoAbs. PRAME+/CD19+ cells were CD5−, CD27+, CD38+, CD34−, CD10− and IgD+, thus suggesting that PRAME is expressed by the memory B cell compartment of the normal lymphoid tissues. This study defines PRAME as a B cell antigen that may accompany the neoplastic clone proliferation of mature B cell neoplasms. Although PRAME is mainly an embryonic antigen, expressed by carcinomas of immature phenotype, it is expressed by mature B cells in normal and pathological lymphoid tissues. Our findings suggest that maturational events occurring at the germinal center of lymphoid follicles affects PRAME expression.