bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction and Prevention of Transplant Related Mortality from Pulmonary Causes Following Total Body Irradiation and Allogeneic Stem Cell Transplantation.
Authors: Savani Bipin , Montero Aldemar , Gochiuo Bernadette , Nlonda Nene , Childs Richard , Solomon Scott , Barrett John 
Published: October 2019

Abstract
Between 7/1997 and 8/2004, 146 consecutive patients with hematological malignancies received a T cell depleted peripheral blood stem cell transplant (PBSCT) from an HLA identical sibling using three successive conditioning regimens: (A): 13.6Gy total body irradiation (TBI) + cyclophosphamide 120mg/kg (Cy) (n=85) , (B) 12.0Gy TBI with lung shielding to 9.0 Gy + Cy + fludarabine 125mg/m2 (Flu) , n= 35, (C) 12.0Gy TBI with lung shielding to 6.0 Gy + Cy + Flu, n= 26. Ninety-four (65.4%) had standard risk disease (transplant in first complete remission of acute leukemia, CML in chronic phase, and MDS-RA); the remainder had more advanced disease or unfavorable diagnoses. Actuarial transplant related mortality (TRM) was 16.4 ± 3%, at a median time of 103 days (range 23–238). Of the 21 transplant related deaths 14 (67%) were from pulmonary causes (6, idiopathic interstitial pneumonia (IP), 4 acute respiratory distress syndrome (ARDS), and pneumonia from CMV (2), RSV (1) and bacterial origin (1). Median time to death from IP and ARDS was 71 and 66 days post-transplant respectively. Kaplan-Meier analysis was used to study factors affecting pulmonary TRM. Pre-transplant characteristics predictive for pulmonary-related TRM are shown in the table. Patients with high risk disease and CML patients who had received busulfan for more than one month were at significantly greater risk of developing both pulmonary TRM and IP. Patients who smoked were significantly more at risk to develop ARDS and fatal pulmonary infection. Pre-transplant pulmonary function tests were highly predictive for pulmonary TRM. Diffusion capacity of the lung for carbon monoxide (DLCO), vital capacity and FEV-1 were highly correlated, but the most predictive parameter was DLCO: Of 48 patients with <85% normal vs. 98 with >85% of normal diffusion capacity, 6 vs 0 had IP, p<0.001, 4 vs 0 had ARDS, p=0.01 and 11 vs 3 had pulmonary TRM, p=0.0003. The death from all pulmonary causes was highest in protocol A (no lung shielding) and significantly less in conditioning regimens B+C (lung shielding) (12/85 vs 2/61 deaths, p = 0.05). These results indicate that after TBI and PBSCT, pulmonary causes contribute significantly to TRM, but can be predicted by patient characteristics and pulmonary function tests and may be reduced by lung shielding.
Clonal Gammopathies, Immune Cytopenias and Autoimmune Thyroid Dysfunction Following Alemtuzumab Containing Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Akhtari Mojtaba , Raj Kavita , Ingram Wendy , Milojkovic Dragana , El-Hemaidi Ihab , Devereux Stephen , Pagliuca Antonio , Ho Aloysius , Mufti Ghulam 
Published: October 2019

Abstract
Reduced-intensity or “nonmyeloablative” conditioning (RIC) regimens, which include Alemtuzumab, results in stable donor hematopoietic and lymphoid engraftment with minimal graft versus host disease. At our institution 182 patients with myeloid and lymphoid malignancies have undergone RIC transplantation between March 1998 and March 2004. In order to ascertain whether the inclusion of Alemtuzumab affects post transplant immune reconstitution, we have assessed the incidence of clonal gammopathies and organ specific autoantibodies in all patients in whom information was available. We used 44 patients who had conventional nommyeloablative HSCT as our control group. In the RIC HSCT group 40(22%) developed clonal gammopathies. The median age at RIC HSCT was 55 years (range 24–66); the underlying dignosis was MDS(n=15), AML(n=15), NHL(n=8) and CML(n=2). A gammopathy was detected at a median of 19 weeks post RIC HSCT (range 8–44). Bone marrow aspiration and biopsy did not show increased numbers of plasma cells. Chimerism studies (unfractionated bone marrow and CD3+, CD15+, CD19+ and CD56+ peripheral blood fractions) showed that 18(45%) were fully donor, 18(45%) had mixed chimerism and it was not available for 4(10 %). By contrast clonal gammopathies were detected in only 4 of 44 patients who had conventional nonmyeloablative conditioning. There was a significant difference between two groups (P=0.05). 9 of 182 (5%) patients (AML=6, MDS=1, MCL=1) developed immune cytopenias at a median of 149 days(range 24–238 days). Those comprised of ITP(n=4), AIHA(n=3), Evans’ syndrome(n=2), red cell and megakaryocytic aplasia(n=1). Chimerism studies (unfractionated bone marrow and CD3+, CD15+, CD19+ and CD56+ peripheral blood fractions) showed that 6(66%) patients were fully donor, 1(11%) was mixed chimeric and for 2(23%) patients chimerism studies were not available. One patient did not need any treatment; one patient with AIHA had a complete response to prednisolone. 2 patients (1 ITP and 1 Evans’ syndrome) responded to IVIG. The five non-responders to IVIG (2 AIHA, 2 ITP, and 1 red cell aplasia and megakaryocytic aplasia) resonded to treatment with Rituximab 375mg/m2 weekly for 4 weeks with a maximal response at a mean of 30 days from commencing the treatment. 3 of 182(1.6%) patients developed autoimmune thyroid dysfunction. All patients had normal thyroid function tests and no antibodies to thyrotropin receptor before RIC HSCT. None of the patients, who had clonal gammopathy, immune cytopenia and autoimmune thyroid dysfunction, developed PTLD. We hypothesize that the RIC regimens incorporating monoclonal antibody Alemtuzumab causes clonal gammopathies, immune cytopenias and autoimmune thyroid dysfunction due to dysregulated B cell proliferation secondary to prolonged T cell recovery time.
Effect of Wine Phenolics and Their Analogs on Suppression of Tissue Factor Induction in Mononuclear Cells.
Authors: Kaur Gurjeet , Pendurthi Usha 
Published: October 2019

Abstract
Several epidemiologic studies suggest that moderate consumption of alcohol, particularly red wine, lowers mortality rates from coronary heart diseases. Aberrant expression of tissue factor (TF), a cellular receptor of coagulation factor VIIa, is thought to contribute to the pathogenesis of coronary heart diseases (CHD) and acute coronary events associated with atherosclerosis. Therefore we hypothesized earlier that consumption of red wine provides protection against CHD by suppressing the aberrant expression of TF in vascular cells, and showed two red wine phenolics, resveratrol and quercetin, suppressed TF induction in endothelial cells and mononuclear cells. However these studies revealed that relatively high concentrations of these compounds (10 to 100 μM), which were unlikely to be achieved in vivo after moderate consumption of red wine, were needed to suppress TF induction. The present study was undertaken to investigate whether other red wine phenolics potentiate the inhibitory effects of resveratrol or quercetin and evaluate the effect of various resveratrol analogs, which were shown to be 10 to 1000 times more effective than resveratrol in modulating other cellular effects, on TF induction in mononuclear cells. Mononuclear cells isolated from healthy human blood donors were treated with various wine phenolics alone or in a combination for 1 h and the cells were stimulated with LPS (10 ng/ml for 6 h) to induce TF expression. TF activity in cell lysates was measured as its ability to support factor VIIa catalyzed activation of factor X. Studies of treating mononuclear cells with varying concentrations of resveratrol and quercetin alone or in a combination revealed that their inhibitory effects were additive and not synergistic. Treatment of cells with a cocktail of red wine phenolics (in concentrations that present in red wine) completely suppressed LPS-induced TF activity. Exclusion resveratrol, epicatechin, catechin or rutin from the cocktail did not diminish the inhibitory effect. In contrast, exclusion of quercetin from the cocktail fully attenuated the inhibitory effect of the cocktail. Further experiments showed that quercetin (55 μM) alone fully suppressed TF induction. Among various resveratrol analogs tested, the cis-form methylated derivative of resveratrol (3,5,4′-trimethoxystilbene, TMS) was 10-times more effective than resveratrol in inhibiting TF induction. A 2 μM of TMS inhibited the induction of TF by more than 75%. None of the wine phenolics or resveratrol analogs had a significant effect on the cell viability. Overall these data suggest that quercetin is the principal inhibitor of TF induction among red wine phenolics and no synergism exists among various wine phenolics in inhibiting TF induction. Comparison of our data on the effect of resveratrol analogs on TF induction with previously published studies on other cellular functions suggests that resveratrol analogs exhibit varying potencies in modulating different cellular activities.
ATP-Induced Modulation of Norepinephrine Exocytosis in Human and Porcine Heart: Role of E-NTPDase1/CD39.
Authors: Machida Takuji , Heerdt Paul M. , Reid Alicia C. , Schaefer Ulrich , Silver Randi B. , Broekman Marinus Johan , Marcus Aaron J. , Levi Roberto 
Published: October 2019

Abstract
ATP co-released with norepinephrine (NE) from cardiac sympathetic nerve terminals increases NE exocytosis via a positive feedback mechanism. Since excessive NE release is an established cause of dysfunction in ischemic heart disease, we studied the role of endogenous and exogenous nucleotidases as part of the development of a novel therapeutic approach to myocardial ischemia and its consequences. Using sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes), we previously established that activation of ATP-gated ionotropic presynaptic P2X purinoceptors (P2XR) promotes exocytosis of NE. This effect was increased by inhibition of the endogenous ecto-nucleotidase (E-NTPDase1/CD39) and decreased by solCD39, a recombinant form of human E-NTPDasel/CD39. Furthermore, depolarization of synaptosomes with K+ also evoked NE exocytosis. This was potentiated by inhibition of E-NTPDase1 with ARL67156 (a selective E-NTPDase inhibitor), and attenuated by addition of solCD39. These findings indicated that ATP released by depolarization of sympathetic terminals enhances NE exocytosis, and that E-NTPDase1 plays an important modulatory role in adrenergic neurotransmission in the heart. In the present study, we investigated the role of E-NTPDasel in exocytosis of NE and ATP in porcine as well as human heart. Cardiac E-NTPDase1 is selectively localized in human and porcine cardiac neurons, and depolarization of cardiac tissue elicits an ω-conotoxin-inhibitable release of both NE and ATP. Inhibition of E-NTPDase1 with ARL67156 markedly potentiated release of ATP, demonstrating that E-NTPDase1 is a major control system for ATP availability at sympathetic nerve endings. Importantly, when ATP exocytosis was increased via inhibition of E-NTPDase1, NE exocytosis increased in parallel. Moreover, when ATP release was reduced by administration of solCD39, NE exocytosis was markedly diminished. Thus, ATP regulates NE exocytosis by activating presynaptic P2XR. This concept is further validated by our finding that the strong correlation between ATP and NE release was abolished by the P2XR antagonist PPADS. We conclude that released ATP governs NE exocytosis by activating presynaptic P2XR and that this is controlled by E-NTPDase1/CD39. Clinically, excessive NE release is a major cause of arrhythmic and coronary vascular dysfunction during myocardial ischemia. By curtailing NE release, solCD39 may offer a novel therapeutic approach to ischemic complications in the myocardium in addition to its role as an anti-thrombotic agent.
A Pilot Study Comparing Megestrol Acetate Concentrated Suspension (MA-CS) to Megestrol Acetate Oral Suspension (MA-OS) on Weight Gain and Body Composition in Patients with HIV-Associated Unintended Weight Loss (UWL).
Authors: Cilla Donald D. , Gutierrez Jodi L. , Femia Robert A. , Kramer Lynn D. , Wanke Christine 
Published: October 2019

Abstract
BACKGROUND: MA-CS is a new NanoCrystal® technology formulation of megestrol acetate that is bioavailable in the fasted state, which may provide benefit in the treatment of UWL in HIV patients.
METHODS: 63 patients with HIV-associated UWL (weight loss to 90% of the lower limit of ideal body weight) were recruited from South Africa, India and the US and then randomized to receive MA-CS (575 mg/5 mL) or MA-OS (800 mg/20 mL) once-daily for 12 weeks in a randomized, open-labeled, multi-center, pilot proof-of-principle study (sample size determined empirically). Patients had weight, body composition (bioimpedance analysis - BIA), and anthropometric measurements obtained at baseline and weekly thereafter, except BIA which was measured at 6 and 12 weeks. Weight changes were compared using the Wilcoxon Rank Sum test.
RESULTS: The demographics were comparable between the two groups. The mean weight change from baseline to Week 12 for MA-CS was 5.4 kg (55.6 kg to 61 kg, 10% of baseline body weight). The mean weight change from baseline to Week 12 for MA-OS was 3.5 kg (54.4 kg to 57.9 kg, 6% of baseline body weight). Differences from baseline, in the mean changes in weight, were observed as early as Day 3 (p=0.024) for MA-CS, however no increase was noted until the second week for MA-OS. Similar between group differences were noted consistently at the weekly assessment intervals until week 12 (p= 0.024). Of these weight changes, lean body mass accounted for ~40% of the increase in both treatment groups (MA-CS was ~5% greater than MA-OS). Of the anthropometric measures, the mean triceps skin fold increased by ~36% at Week 12, relative to baseline, in both MA-CS and MA-OS treatment groups. Other anthropometric changes were all smaller (less than 7%) and comparable between treatments. The types and incidence rates of adverse events were similar between MA-CS and MA-OS.
CONCLUSIONS: Both products were successful at increasing body weight. There was a greater and more rapid mean change from baseline in the weight gain for MA-CS than MA-OS. The observed weight changes reflected increases in both lean body mass and body fat. MA-CS had a greater change in lean body mass. This trial supports the principle that improved bioavailability of megestrol acetate in the fasted state with MA-CS may be associated with faster time to onset of changes in body weight.
Molecular Karyotyping by High Resolution Arrray CGH Uncovers New Deleted and Amplified Genomic Regions That Contain Genes of Biological Interest in Multiple Myeloma Cells.
Authors: Largo Cristina , Alvarez Sara , Blesa David , Prosper Felipe , Calasanz M. Jose , Cigudosa Juan 
Published: October 2019

Abstract
Multiple Myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. After defining the IGH-translocations present in a panel of MM cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes significantly differentially expressed among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Besides translocations, gene copy number changes are also frequent in MM but far less characterized than in other neoplasias. We conducted array Comparative Genomic Hybridization (arrayCGH) with the same cDNA platform that was used for the expression analysis with the double purpose of characterizing the amplified genome regions and identifying the amplified and overexpressed (A/O) genes within these regions. We focused in five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines where we found 60 A/O genes. Among them, twenty-five (42%) were only overexpressed when amplified, and six, CHI3L1, ELMO1, BNIP3L, PLAG1, LOC157567, and VPS28, showed a significant association between overexpression and gain/amplification.
In a second step, we are conducting a high resolution analysis of copy number changes in flow sorted CD138 myeloma cells from patients with normal karyotype, as stated by conventional cytogenetics. We are using the Human Genome CGH Microarray 44A platform from Agilent Technologies (Palo Alto, CA), which contains 44.000 60-mer oligonucleotides covering the human genome with an average resolution of 40 Kb. As expected, this genomic approach, performed on selected cells, allowed the identification of a high number of deletions and gains. We have found small regions (below 500 Kb of size) that were rearranged as follows:
Copy number changes on selected CD138+ MM cells Chromosome Rearrangement Some genes of biological interest loss 1p12-p21.3 STXBP3, SORT1, HRMT1L6, PSMAS loss 6q24.1–q24.2 STXBP5, IL20RA, MYB loss 11q14.1–q22.3 MMP1, 3, 7, 8, 10, 12, 13, 20, BIRC2 & 3 loss 14q12–q21.3 FOXA, FBXO33, SNX6 loss 16p12.1 TP53TG3, ZNF267, CREBPB gain 1q21 CKS1B, AIM2, SELL, CHI3L1 gain 8q24.12–q24.23 C-MYC, PTK2
Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis: A Report of the European Blood and Marrow Transplantation Group (EBMT).
Authors: Saccardi Riccardo , Mancardi Gianluigi , Tyndall Alan 
Published: October 2019

Abstract
Haematopoietic Stem Cells Transplantation (HSCT) has been successfully used in the last decade for the treatment of severe Autoimmune Diseases (ADs), including Multiple Sclerosis (MS). A retrospective analysis of 183 Multiple Sclerosis patients recorded in the database of the EBMT is reported. The patients received an autologous HSCT in the period 1995–2004. The disability at the time of HSCT was severe, with a median EDSS of 6.5 (range 3.5–9). Cumulative survival is 86% at 9 years with median follow-up time of 3.5 years. Overall Transplant-Related Mortality (TRM) is 5.3%; no toxic deaths were reported in the 62 patients transplanted after the year 2000. Conditioning regimens including Busulphan were statistically associated to TRM, both in uni- and in multivariate analysis. No toxic deaths were reported among the 53 patients treated with the BEAM/ATG regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Sixty-three percent of the 145 patients evaluable for the neurological outcome showed a sustained improvement or stabilization of their disability. A trend of a better clinical outcome in patients transplanted within 5 years of diagnosis was shown. HSCT was shown as an effective procedure to stop disease progression in patients affected by severe, progressive MS; safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.
SCIO-469, a Potent and Selective Inhibitor of the p38a MAPK, Inhibits TNFa-Induced Adhesion of Multiple Myeloma Cells to Bone Marrow Stromal Cells Via Downregulation of Chemokines CXCL10/IP-10 and CCL8.
Authors: Nguyen Aaron N. , Young Gilbert O’ , Quon Diana , Damm Debby , Kapoun Ann M. , Higgins Linda S. , Navas Tony A. 
Published: October 2019

Abstract
Multiple myeloma (MM) is a plasma cell cancer characterized by the accumulation and clonal expansion of malignant cells in the bone marrow (BM). Recent findings indicate that adhesion of MM cells to BM stromal cells (BMSCs) protects MM cells from drug-induced apoptosis and leads to upregulation of interleukin-6 (IL-6), a cytokine that promotes MM cell growth and survival. However, the molecular mechanism that determines the adhesion of MM cells to BMSCs is relatively unclear. Here we show that SCIO-469, a potent and selective inhibitor of the p38a mitogen-activated protein kinase (MAPK), prevents TNFa-induced adhesion of MM cells to BMSCs. Interestingly, TNFa-induced expression of ICAM-1 and VCAM-1, molecules that have been reported to mediate cell-cell adhesion, is not affected by SCIO-469 treatment. In an effort to identify additional factors that may play a role in the adhesion of MM cells to BMSCs, we performed a DNA microarray experiment on BMSCs. Of the BMSC genes that were strongly upregulated by TNFa exposure and reversed by SCIO-469 treatment, a set of chemokines was most prominent. To determine whether these chemokines are important for MM adhesion to BMSCs, various chemokines (CCL2, CCL7, CCL8, CXCL1, CXCL3, CXCL6, CXCL10/IP-10, and CXCL11) were added together with SCIO-469 in the adhesion assays. We found that reintroduction of the chemokines CXCL10 and CCL8 reversed the inhibition of adhesion by SCIO-469. These results suggest that SCIO-469 inhibits TNFa-induced adhesion of MM cells to BMSCs by downregulating the chemokines CXCL10 and CCL8. Intriguingly, these two chemokines were also recently demonstrated to be involved in leukocyte adhesion to endothelial cells. Thus, chemokines, especially CXCL10 and CCL8, appear to have a general function of localizing blood cells to various sites within the body. Together, our findings demonstrate another potential therapeutic role for SCIO-469 in MM in addition to its role of inhibiting the production of growth factors such as IL-6 and VEGF in the MM bone marrow microenvironment.
XBP-1 a Selective and Specific Target for Immunotherapy in Myeloma.
Authors: Bae Jooeun , Carrasco Ruben , Sukhdeo Kumar , Tassone Pierfrancesco , Neri Paola , Yu-Tzu Tai , Li Xianfeng , Coffey Rory , Prabhala Rao , Anderson Kenneth , Munshi Nikhil 
Published: October 2019

Abstract
X-box binding protein 1 (XBP-1) is a transcription factor is essential for the differentiation of plasma cells and the unfolded protein response. XBP-1 is significantly up-regulated in myeloma cells compared to both normal plasma cells and B-cells. Selective and specific requirement of XBP-1 for differentiation of B cells to plasma cells and its further up-regulation in multiple myeloma (MM) cells makes it a promising target for immunotherapy directed at MM. We have evaluated XBP-1 as a target antigen to develop MM-specific immunotherapy. In order to generate XBP-1 antigen-specific cytotoxic T lymphocytes (CTLs), we have identified HLA-A2-specific peptides derived from non-spliced (short form) and spliced (long form) XBP-1 proteins. We have further modified the peptide by altering one amino acid, which is critical for HLA-A2 affinity, to obtain epitope, which has higher stability to HLA-A2 clefts. The modified XBP-1 peptides were able to evoke higher levels of IFN-g release compared to native peptides and were able to induce CTLs highly specific to MM, demonstrated by Calcein-released cytotoxicity assay. Cytotoxic activity of these XBP1 peptide-specific-CTLs against U266, a HLA-A2+/XBP-1+ MM cell line was 60% and 79% by CTLs stimulated by non-spliced peptide and 69% and 88% by CTLs stimulated by spliced peptide at Effector:Target ratios of 20:1 and 60:1, respectively. The CTLs did not lyse HLA-A2− or XBP-1− cells. These results were further confirmed by the novel CD107 cytotoxicity assay, which detects MM-specific cytolytic CD8+ T cells by flow-cytometric analyses. The CTLs generated with XBP-1 peptide displayed distinct phenotypes, showing high CD69+CD45RO+ cell population (62% in non-spliced peptide-CTLs, 67% in spliced peptide-CTLs, 4% in unstimulated control-CTLs) and CD45RA+CCR7+ cell population (1% in non-spliced peptide-CTLs, 1% in spliced peptide-CTLs, 24% in unstimulated control-CTLs). In conclusion, we report the identification of highly immunogenic heteroclitic XBP-1 epitopes that have ability to generate MM-specific CTLs. Confirmation of in vivo activity of these CTLs in SCID mouse model is currently underway prior to its evaluation in clinical studies.